Real World Oncology Rounds: Current Concepts and Recent Advances in Oncology | May 2021 (Webinar Video Proceedings)
Real World Oncology Rounds: Current Concepts and Recent Advances in Oncology | May 2021
Proceedings from a daylong symposium hosted in partnership with Medical Oncology Association of Southern California, featuring key clinical presentations and papers in acute myeloid leukemia and myelodysplastic syndromes, breast cancer, chronic lymphocytic leukemia and lymphomas, gastrointestinal cancers, genitourinary cancers, lung cancer and multiple myeloma. Featuring perspectives from Drs Kenneth C Anderson, Joaquim Bellmunt, D Ross Camidge, Harry Paul Erba, Rami Komrokji, Benjamin Levy, Wells A Messersmith, Craig Moskowitz, Ruth O’Regan, Eileen M O’Reilly, Sumanta Kumar Pal, Noopur Raje, Jeff Sharman and Tiffany A Traina moderated by Dr Neil Love.
Introduction DR LOVE: I’m Neil Love from Research To Practice, and welcome to Real World Oncology Rounds as today for the 10th year in a row we worked with the Medical Oncology Association of Southern California, where we’ve been traveling for the last 10 years, but today we work with them virtually. We’re so happy to be back together. We miss the old Fairmont Hotel and the big tree outside, but hopefully we’ll accomplish what we have done before. Today, we’re going to be focused on key papers and data sets and presentations, along with a whole bunch of cases. Here’s where we’re heading today. This is the first of 7 consecutive webinars I’ve worked with the general medical oncologists from MOASC as well as some of other places around the country to prepare about 50 cases that we’re going to show to you today. We’re starting out here today talking about breast cancer with Dr Ruth O’Regan from the University of Rochester and Dr Tiffany Traina from Memorial Sloan Kettering Cancer Center. Here are the oncologists that will be presenting cases today; there are quite a few of them. And here’s where we’re heading for our Breast Cancer program. We’ll start out talking about ER-positive disease, see a couple of cases there, then HER2-positive disease and finally triple-negative breast cancer. And of course, we’re going to reflect a little bit on what we think is going to be presented at ASCO. So, to do that, first, before we even get started with the cases, I have to talk about what may be the most important thing in breast cancer, which is that these data from the OlympiA trial looking at adjuvant olaparib either after adjuvant or neoadjuvant chemotherapy in patients with BRCA germline mutations and high-risk HER2-negative disease. We already know from the press release that “it’s a positive trial.” So I’m just going to start out with a little bit of a provocative question before we jump into our cases. So audience, here’s the question for you, you can just click on the answer that reflects how you’d be thinking about this. So, let’s say that the OlympiA trial shows something very similar that was seen a couple of years ago and continues to be seen in ovarian cancer — patients who get generally some type of surgery, debulking surgery, adjuvant chemotherapy, followed by olaparib or not. Again, SOLO-1 was BRCA-positive. We also saw the PRIMA trial, similar things. They saw a hazard rate of .33. We have no idea what we’re going to see with the OlympiA trial but there was no survival data. People jumped all over that and that’s now routinely being used, certainly in BRCA patients. I want to know from you, audience, assuming that the trial shows a similar result, which, of course we don’t know, with breast cancer, who do you think you’re going to be testing with localized disease? Do you think you’ll be testing all patients? Just those with HER2-negative disease, which were in the trial, higher risk patients, or you’re not going to be testing anybody? So, it looks like there’s a real spectrum of answers but Ruth, half of the audience says if they see that they’re going to test everybody. So, of course, we’re just speculating. Who knows what the hazard rate or what you’re going to see. But if we see what we saw in ovary, big disease-free survival advantage, Ruth, that now goes out to 5 years, what do you think you’re going to do in your own practice, Ruth? DR O'REGAN: Would probably test most patients. I think the big question is with patients with HER2-positive disease, I’m not quite sure what we do with that information. But I think we’ve really expanded the number of patients we test anyway, and I think this data will just meet it. So I think certainly all patients with HER2-negative disease and the HER2-positive, I probably would use the guidelines that we’ve used previously. But I think this is going to be a rapid expansion of testing if this trial is positive, as we hope it will be. DR LOVE: So, Tiffany, another issue of course, is going to be the issue of tolerability. What I am curious about, Tiffany, is if we do end up using olaparib in the adjuvant setting, how do you think that’s going to play in terms of tolerability? These patients may be getting adjuvant chemo. They may be getting adjuvant hormonal therapy. Reflecting back on what you’ve seen with PARP inhibitors in metastatic setting, Tiffany, how do you think this is going to go in the adjuvant setting, GI issues, cytopenias, etc? DR TRAINA: I think it’s a great question because whenever we’re thinking about intervening, it’s really a risk-benefit balance. And so we know from the metastatic data that actually health related quality of life endpoints were better with the PARP inhibitors as compared to treatment of physician’s choice chemotherapy. I think that the adverse events seen with PARP inhibitors are manageable, but duration of adjuvant therapy is for quite some time. And so, I think we need to be aware of what adverse events are, but given what benefits may be, we make that judgement shared with our patients. DR LOVE: And Ruth, there’s so many situations in oncology right now as typical with adjuvant trials where you see a disease-free survival benefit in the early analysis, but you don’t see survival. The issue comes up maybe they’ll do just as well waiting and treating with metastatic disease. Lat year we saw the spectacular results of adjuvant osimertinib in lung cancer, EGFR mutated, a hazard rate of .2. People jumped all over that. Any thoughts about how you weigh this issue when you’re in that intermediate stage, Ruth, where you see disease-free survival benefit, but you don’t yet know about survival? DR O'REGAN: So, I think it really depends, I think as Tiffany was saying, on what you think the patient’s risk of recurrence is, for example. If the risk of recurrence seems high, I think just looking at disease-free survival and using a drug based on that certainly would be acceptable. But obviously, the gold standard is to wait and see what overall survival looks like. So I think it’s really a patient-by-patient discussion when we just have these early data. DR LOVE: So it’s interesting, Tiffany, you have the perspective of the general medical oncologist. They’ve already have seen this ovarian data; they’re using adjuvant PARP — I would call it adjuvant in the ovarian setting. We see this really very profound effect in terms of recurrence that seems to stay all the way out to 5 years. But the other issue that’s out there is the possibility of MDS. In this particular trial, it seems pretty low. There are some trials in advanced disease where it looks like a little more. It looks like, in general, it’s about double. I don’t know if we’ll see that with breast cancer. Any thoughts about how that’s going to play out, Tiffany, particularly in a lower risk patient? DR TRAINA: I think we do need to recall that the patients that were eligible for OlympiA were higher-risk patients with germline BRCA mutations. So, as Ruth alluded to, it’s this risk-benefit balance. This study is focusing on patients who have high risk of recurrence and obviously, we’ll need longer follow-up. But I think that we are aware the adverse events are related to these drugs from our experience in the metastatic setting where there, we’ve seen consistently, hazard ratios of about .5. which is really encouraging. So, I think we need to remember that ovary cancer and breast cancer are not exactly the same. And so, I don’t know if ovary is our benchmark for a successful drug in the adjuvant setting for breast cancer. DR LOVE: Very good point. We make these analogies all the time because people think about it, but it is great to keep that in mind. ER-Positive, HER2-Negative Breast Cancer DR LOVE: Now it’s time to make rounds, what we call Real World Rounds. These are real patients. These docs typically, I sit down with them. We’re presenting cases all day long — they’re presenting CLL cases, myeloma, bladder cancer — a really amazing challenge to be a general medical oncologist. But speaking of challenges in terms of early adjuvant data, we’re going to get into that right away here with a patient of Dr Andy Stebel, a 58-year-old woman who actually was diagnosed back in 2009. She ended up putting her, even though she was postmenopausal, she ended up putting her on adjuvant tamoxifen, which she’s on for 9 years. She had a lot of osteoporosis. She was concerned about using an AI. She stops it after 9 years; 8 months later she has progressive disease and pretty significant metastatic disease. Here’s Dr Stebel. DR STEBEL: So my question is, had this woman presented today with a Stage IIIa tumor with 6 positive nodes, how would she be treated adjuvantly? Would there be a consideration of using a CKD inhibitor for her and adjuvant therapy? Also, I’m curious to see if anyone would use Oncotype DX®, based on the RxPONDER data, to see where her treatment should be had she presented today? I’m also curious in my choice of treating her for her metastatic disease after she recurred on the tamoxifen, if there would have been a different choice of first-line treatment for her using a different CDK or a different hormonal partner? DR LOVE: So, yeah, I should point out that last point that she, as I mentioned, was on adjuvant tamoxifen, and when she recurred, she actually used abema plus fulvestrant. The patient had a great response in metastatic disease, but she’s putting it out there, was that the best decision? Well, let’s go through the 3 points that she has questions about with this case. First, we can start out actually with a question for the audience related to Dr Stebel’s case. So, imagine you have a premenopausal woman, she’s got a 2.1 cm tumor, ER/PR-positive, HER2-negative, 2 positive sentinel nodes. So the question is would you order a genomic assay on this patient? And if so, which one? So, Tiffany, I’ll come back to you and ask you how you would answer this question nowadays. Of course, we’re going to talk about the RxPONDER data that was presented in San Antonio, but right now, Tiffany, how do you approach the issue of genomic assays in patients with node-positive disease, particularly 1 to 3 nodes?DR TRAINA: So reminding everyone, from the RxPONDER study that was limited to patients with 1 to 3 positive nodes. And what Dr Kalinsky presented showed that for women who were premenopausal, there did appear to be an advantage to the addition of chemotherapy with endocrine therapy. And so, in our practice, we’ve actually elected to not send a genomic assay for a premenopausal woman with 1 to 3 positive nodes. I think this remains a research question because there has been hypotheses that perhaps the chemotherapy benefit is coming from the impact on ovarian suppression. And so, I think it’s an area for research, to look at perhaps premenopausal women with 1 to 3 positive nodes and designing a study that would randomize chemotherapy/endocrine therapy to optimal endocrine therapy, Because I think this is now an area we could refine ever better who actually needs chemotherapy. For now, I think premenopausal women are benefiting. DR LOVE: Well, suppose you have the patient, you send the assay and she has recurrent score that’s low, 10. Tiffany? DR TRAINA: So those patients were not robustly represented in our RxPONDER. I actually just had this conversation this week when a similar situation came up. So, although RxPONDER was a large study, if you look at the proportion of patients that would meet those criteria, it’s a very small number to try to exclude a potential benefit from chemo. DR LOVE: So, maybe that will influence how people respond to this question, but anyhow, here it is, and Ruth, I’ll ask you to comment on it afterwards. And now we get into also the issue, not only of Oncotype and chemo, but also hormones and abemaciclib, of course. So, audience, I want to know what kind of adjuvant strategy would you have with the same kind of case, 2 positive nodes, ER/PR-positive, but the recurrent score is 10. So would you give this patient chemotherapy? It’s a premenopausal patient. What kind of hormonal therapy would you use? And of course, the question of the day is in a patient with 2 positive nodes, and now Andy’s case had 6 positive nodes, we’ll ask you about that, too, but let’s say 2, would you use abema? And we’ll see what the audience has to say about that. Let’s see here. It looks actually like relatively few people here are saying they’d use abema, maybe 10% of the audience. So, Ruth, right now, how are you thinking through the issue of adjuvant abemaciclib? In Andy’s case is 6 case positive nodes. This case here we said is 2 positive nodes. Is this something you’re presenting to your patients? DR O'REGAN: I mean I’m talking to patients about it if they’ve got higher-stage cancers, so 4 or more positive lymph nodes. I probably wouldn’t recommend abemaciclib to this patient. I think the chemotherapy is the standard of care, although I might consider ovarian suppression as an alternative if she really didn’t want to get chemo. I think if you look at the monarchE study, there was some very interesting data looking a Ki67, showing that patients who had this type of actual stage cancer, who had high Ki67s appeared to get quite significant benefit from the introduction of abemaciclib, or the addition of abemaciclib. So, based on the fact that this patient has a low recurrence score, that would kind of drive me away from actually giving her abemaciclib in this case, although I will say, as opposed to Tiffany, we don’t know the right answer at this timepoint with these low recurrence scores. So, overall, I would offer her chemo, based on the fact that she is premenopausal, but I would consider ovarian suppression, either after the chemotherapy or instead of chemotherapy in a patient like this. DR LOVE: That’s really interesting that you would consider the recurrence score in terms of choosing endocrine therapy. Tiffany, what’s your approach nowadays in terms of do you bring up abemaciclib? I mean when I think about low recurrence score patients, I think about people who have more sort of endocrine sensitive. I don’t know what that means in terms of abema. But for practical purposes, right now, who are you discussing abema with, if anybody, Tiffany? DR TRAINA: I think as Ruth said, the monarchE study really was enriched again for higher-risk patients and multiple positive nodes, high-risk biology. So, in the absence of an indication, acceptance into guidelines, recognizing the tolerability of abemaciclib is challenging. We had many discontinuations on the study, high diarrhea concerns. So I think here I’m reserving it for the highest-risk patients, and really would like to see longer follow-up in the context of the PALLAS data, really which was not in support of adjuvant CDK4/6 inhibitors. DR LOVE: And I’ll mention as usual, we’re really focused on discussions here today. We’re really looking forward to getting some feedback from the audience. But also, the slides, which we hope you’ll take a look at and download — we’re not going to go through all of those. We know a lot of people end up listening to this or driving in their cars, once we post it, or in the gym. So, we’re going to focus more on kind of discussion, so to speak. Well, let’s go to another case. This is Dr Maen Hussein who has a 60-year-old lady with metastatic disease who goes through fulvestrant/anastrozole, interestingly, in 2015. Palbo/letrozole, and then alpelisib/fulvestrant. Here’s Dr Husain with his questions about this case. DR HUSSEIN: I checked for PIC3CA at that time, and it was positive, so I switched her to alpelisib with fulvestrant and she had response for almost like 6 months. Unfortunately, the pleural effusion came back, and she became more short of breath and tumor marker also rose. She didn’t have any other sites of disease at that time, so I switched her to capecitabine. Actually, now she has good quality of life. No recurrent pleural effusions and stable disease basically. DR LOVE: How did she do on the alpelisib? DR HUSSEIN: Actually, she was one of the few that tolerated it very well. I really have a hard time with alpelisib in patients tolerating it. But this patient did well. I was wondering what is the experience that they have with this medication? What kind of tricks you’ve used to manage the side effects? DR LOVE: So this lady just cruised right through alpelisib? No problem? DR HUSSEIN: No problems really. I mean she really did very well. DR LOVE: So I want to reflect back a little bit about the integration of hormonal therapy into metastatic disease, Tiffany. And maybe before we even get into what you would do after CDK inhibitors, I’m curious about the initial use of CDKs. Your choice of CDK and its partner. In the case we just heard from Dr Stebel, she previously had adjuvant tamoxifen and she elected to leap over AIs and go to fulvestrant and abema. How do you decide in various clinical situations, Tiffany, which CDK do you use and which endocrine therapy in first-line metastatic disease? DR TRAINA: I think we’re fortunate that we have a lot of options in this setting. So in terms of choice of CDK4/6 inhibitor, often I’m using palbociclib. Abemaciclib is very reasonable. There’s data for ribociclib. All of these sort of independently appear to have comparable hazard ratios in the first-line setting. I think that in the choice of endocrine therapy for the first-line setting, many times we’re doing next-gen sequencing to explore if a tumor has derived an ESR1 mutation, which might help select for fulvestrant and a SERD, as opposed to the aromatase inhibitor in the first-line setting. But I tend to use the partner of AI and CDK4/6 inhibitor to start and then have my option of fulvestrant in the second-line setting with or without the PI3 kinase inhibitor, depending on their genomics. DR LOVE: So, which CDK in general? Do you generally use one, or do you adapt it to the patient’s situation, Tiffany? DR TRAINA: Very much towards the patients’ situation, given underlying sensitivities, if you will. Abemaciclib has a bit more in the way of GI toxicity, yet maybe a little bit easier on the cytopenia and neutropenia. Palbociclib, a bit more in the neutropenia realm. So patient preferences help in that regard too. DR LOVE: So, right, Nicole in the chat room has an interesting question. As you heard, this patient went from alpelisib/fulvestrant to capecitabine. Nicole wants to know what about everolimus/exemestane? Do you ever go with third-line therapy in metastatic disease? And also, another question is that Bonnie brings up is, you mentioned ESR1 mutations, Tiffany mentioned that, does that preclude AIs completely or do you come back to them? So those 2 questions, third-line endocrine therapy, Ruth, as well as how does the ESR1 affect your choice? DR O'REGAN: So, for third-line treatment, I certainly would consider using everolimus, depending — this lady may have needed some chemotherapy at that timepoint, but I think — it’s funny, the amount of patients that you see in this scenario that have never been given everolimus and I think it’s a good option because you can give with exemestane, you can give it with tamoxifen. There’s lots of hormone options. I was just going to add to Tiffany’s, the first-line question because I think it’s very hard to get — not using fulvestrant makes sense because it’s been hard to get alpelisib with anything but fulvestrant. So, that’s why I tend to use a non-steroidal aromatase inhibitor as well. With the ESR1 mutations, they are acquired. And the data suggests that they’re associated with resistance to endocrine therapy, aromatase inhibitors. I don’t think that these tumors suddenly become more sensitive — or regain sensitivity to aromatase inhibitors. But I will say that I think it may be more of a pan endocrine therapy issue because if you recall at San Antonio, I think it was not last year but the year before, there were some liquid biopsy work basically showing that in fact patients with ESR1 mutations detected on the liquid biopsied actually do very poorly with fulvestrant as well. So, some of the newer SERDS may not be. But I think the idea that fulvestrant works well in these ESR1 mutations is a little bit unclear. But I think once you have them, they persist. I’m not aware that they can kind of go away or whatever. DR LOVE: So, Tiffany, you mentioned NGS and in a second, I want to ask you about where things are with anti-androgens, an area that you’ve taken a leadership role in terms of breast cancer. But first, let’s talk a little bit about alpelisib. And the question you hear from a lot of oncologists is tolerability, hyperglycemia, other issues. Can you talk a little bit about your own personal experience with the drug, Tiffany? What you see in terms of tolerability? And how you attempt to ameliorate it? DR TRAINA: Happy to. I think the 2 side effects that I see most commonly are hyperglycemia to some degree, and rash. So, rash, knowing that’s common, we can prophylax for that with antihistamine. The hyperglycemia is something that really takes awareness, so counseling from the beginning on diet, checking your hemoglobin AIC, and intervening early as necessary with metformin to really manage the glucose. Ruth, I’d be curious if you have any other experience with it? DR LOVE: Ruth, go ahead. DR O'REGAN: I was going to say, yeah, I think it’s a tough drug for sure. And I think the other thing Tiffany said, the hyperglycemia is certainly a challenge and I think watching their labs. Obviously, the data with the antihistamines, the rash, does look reasonably that they do help. But, yeah, I think overall it is a tough drug to give, I think a lot tougher than everolimus actually. DR LOVE: So, here’s what you’re referring to, the data from the BYLieve trial, looking at the impact of prophylactic antihistamines. It seems like —- there’s so many drugs today we’re going to be talking about, just kind of flashing on selinexor, where initially, when it comes into practice there are big challenges. And then as we sort of get our feet on the ground more, we learn how to use better, particularly, I think, a lot of the oral drugs. So, one final question before we go back to HER2-positive disease, Tiffany, update on anti-androgens and targeting the androgen receptor in breast cancer. DR TRAINA: This is some work I know Ruth has been quite interested in as well, and we actually are about to launch a randomized study finally, looking at the anti-androgen enzalutamide, versus enzalutamide with a glucocorticoid receptor antagonist, versus chemotherapy. Because I think there’s really encouraging work here in this space, but we ultimately have needed this randomized trial to better understand the biology and predictive biomarkers. So, that should be coming soon to a location near you. DR LOVE: Now, this is for people who are androgen receptor-positive? And what fraction are? DR TRAINA: Yes. Androgen receptor-positive, triple-negative, based on the assay with IHC, roughly about 50%, setting a benchmark of staining of 10% or greater. HER2-Positive Breast Cancer DR LOVE: Let’s move on to our second segment here. We’re going to talk about HER2-positive disease. We have another case from Dr Stebel to start out with. She asked a very provocative question. So, this is a young patient, 35-year-old, ER — actually sort of borderline, but thought to be positive, HER2-positive disease. She presents with a 3 cm lesion, clear axilla, and she’s given neoadjuvant TCHP. She has a path CR. So, Dr Stebel, in her very kind of open, creative way, brings up the issue of does everybody need neoadjuvant therapy? Did this patient really need neoadjuvant? And does she really need to give both trastuzumab and pertuzumab in the adjuvant setting? Here’s Dr Stebel. DR STEBEL: Do we need to give all of these women, particularly those who have a negative axilla, neoadjuvant therapy? What I’m seeing now out in the community, is everybody’s getting neoadjuvant chemotherapy. I’m just wondering, this woman did have a small breast size so I could understand trying to shrink it down. With her complete pathologic response, did she need to continue the HP for the rest of the year? When does one really consider extended adjuvant therapy with neratinib? I’m very curious to see where people are using neratinib. DR LOVE: So, Tiffany, breast cancer has really taken the lead in the concept of de-escalation of therapy. Now we have T-DM1 and trastuzumab/pertuzumab as options in the adjuvant setting. And yet, as Dr Stebel notes, seems like everybody, at least over 2 cm, is getting neoadjuvant therapy, particularly with TCHP. Any thoughts about whether or not we should de-escalate the use of neoadjuvant therapy, Tiffany? Of course, the thing that we have in our back pocket nowadays is, of course, the KATHERINE trial. Any thoughts? DR TRAINA: Exactly. So, I think that we have the data form the APT study of paclitaxel and trastuzumab for a year. And that study allowed for patients with tumors up to 3 cm with negative nodes. That being said, when we have the data from KATHERINE showing that you could enrich for who will benefit from adjuvant T-DM1 in those that fail path CR, having that sort of in vivo feedback is really helpful when you see that you could impact survival by using neoadjuvant therapy. So, as we’ve put this all into context, our practice is still for patients who have tumors 2 cm or greater, or node-positive disease, we still favor a neoadjuvant approach knowing that we have that option for adjuvant T-DM1 for those who failed to achieve a path CR. DR LOVE: So I just want to flip back to a question I see in the chat room, I want to just clarify something I think really important, Ruth. And we were talking about the use of genomic assays, specifically Oncotype in patients with premenopausal, node positive as having some issues. What about postmenopausal patients, Ruth, in terms of people who are node positive. Are you doing assays, genomic assays? Which one? And how many nodes? DR O'REGAN: Well, I think for N1 disease, I certainly would consider sending the 21-gene recurrence score based on the data from RxPONDER. I mean you could look at this way that there was really no benefit from chemotherapy, so you may not actually get that much information from it. But, again, there may be patients with scores over 25 where you would certainly want to give them chemotherapy. So I do send it in that group of patients. But we know that the majority of time we will need chemotherapy. I think also the 70-gene score, you can certainly send that as well. I just tend to prefer the 21-gene recurrence score just because I think it really is able to tell you how much benefit the patients going to get form chemotherapy. DR LOVE: So another issue, before we jump into metastatic HER2-positive disease, Tiffany, that Andy Stebel brought up is neratinib. And of course, things have changed so dramatically since the ExteNET study looking at post-adjuvant therapy with neratinib. Nowadays, Tiffany, in what situations, if any, are you thinking about neratinib? Do you consider it in a patient who neoadjuvant therapy? What about the adjuvant situation? What about how ER affects your use of it, Tiffany? DR TRAINA: Such a great question. I mean the science is moving so quickly that some of these older trials didn’t have the similar populations that we do today. So, ExteNET did not include patients with prior exposure to pertuzumab; certainly didn’t include patients that would have had prior exposure to T-DM1 in the adjuvant setting. Where the benefit was seen in neratinib, if we remember from ExteNET, was in patients with hormone receptor-positive/HER2-positive tumors. So, for my highest-risk patients, those who failed path CR after neoadjuvant anthracycline/taxane/trastuzumab/pertuzumab who may have gone onto T-DM1 and completed out their 14 cycles and had, say, node-positive disease, hormone receptor-positive disease, I will have a discussion with them about neratinib. Remember diarrhea is an issue. This is a long, extended adjuvant course. But I feel that — I do have that discussion with my patients. DR LOVE: So, speaking about how things change, we’re going to talk a little bit about HER2-positive disease. And I think almost the last live meeting we did was at San Antonio a year and a half ago, and at that point I think that was the big San Antonio meeting were tucatinib and HER2CLIMB and the T-DXd came out and everybody’s trying to figure out what to do with that. And now it’s a year a half later, and people still have a lot of questions. We actually have a case from Dr Del Rosario, a 53-year-old woman, ER-negative/HER2-positive. Actually inflammatory breast cancer, with liver and bone mets, who gets both initial therapy with paclitaxel/trastuzumab/pertuzumab and then T-DM1. Now on T-DM1. And his question which is maybe the question of the day in HER2-positive metastatic disease, is what’s next? Here’s Dr Del Rosario. DR Del ROSARIO: This was a 53-year-old female with a left-sided ER/PR negative HER2 positive Stage IV disease, Grade 3 inflammatory breast cancer, and her metastases were into bone and the liver. She received multiple lines of treatment starting with weekly paclitaxel, trastuzumab, and pertuzumab. And then unfortunately, she progressed and was placed on T-DM1. My question for the panel is for third line treatment, what is the expert panel’s preferred sequencing of treatments? When would we consider tucatinib and trastuzumab as a line of treatment with capecitabine? DR LOVE: So, Ruth, maybe you can talk a little bit about how you’re thinking through third-line therapy? We know when we ask people, well, let’s just ask the audience, actually. Audience, I’m curious how you might deal with this situation, 65-year-old woman, ER-negative/HER2-positive, this is basically this case, except we’re saying the patient has brain mets. So, the question is, what’s next? Are you going to go with T-DXd? Are you going with the HER2CLIMB regimen, tucatinib and trastuzumab/cape? Neratinib/capecitabine? We saw some data before all the new stuff came out. So, Ruth, curious how you think third-line therapy? It looks like the audience here is almost completely in favor of the HER2CLIMB regimen, I’m sure because of the brain mets. So how do you think through third-line therapy with and without CNS mets, Ruth? DR O'REGAN: I mean if they have CNS mets, I certainly would use tucatinib. And I think a lot of us are actually using it even second line in that scenario because the data was really quite compelling for the brain met groups in the HER2CLIMB study. The other question was, if they don’t have brain mets — again, we can talk about whether we should start screening patients or not, I don’t typically do that — I do think the data with the trastuzumab deruxtecan is very striking as well. So, I might pick that instead of tucatinib in a patient who doesn’t have brain mets. But I think the good thing here is that we’ve got so many great options for these patients. But I think the thing that really kind of needs us to make the decision is the presence of brain mets. I think that’s what most of us do. DR LOVE: So, Tiffany, I’m curious. Here’s the New England Journal paper on the HER2CLIMB study. Had these really spectacular results. Hard to indirectly compare to what you see with T-DXd. We saw subsequent papers specifically looking at CNS activity. But also the question of just how much antitumor effect, and we’ll get to T-DXd in a second, trying to compare indirectly. Can you talk a little bit about your experience with both of these regimens in terms of tolerability, Tiffany, and how you decided which one comes first? Also, if you want to use the HER2CLIMB regimen what do you do if the patient’s already had capecitabine or had capecitabine recently? DR TRAINA: I think million-dollar questions right there. So, in terms of tolerability, the tucatinib regimen, together with capecitabine, really has adverse events largely driven by capecitabine. So we’re seeing GI tox and hand-foot syndrome. It is a pill burden to be aware of. But we balance that by the fact that the HER2CLIMB study is a randomized Phase III trial with an overall survival advantage for the entire population. So I think that is really compelling, sort of gold standard data to support its use. And as Ruth said, actually the FDA label is second line or later. Trastuzumab deruxtecan has one of the most amazing waterfall plots I think I have ever seen with pretty much every patient deriving some benefit from that drug. And the patients in that study, although it was a single-arm trial, had a median of, I think, 6 prior lines of therapy. So, the concern around trastuzumab deruxtecan is the very rare but significant risk of ILD, interstitial lung disease, that was associated with some fatalities on study. And so, that is the tension that I have as I’m trying to make choices. And this is something, knowing that we can sequence these drugs right now, I certainly would reach for tucatinib in my patients with brain mets. In the absence of brain mets, really look at what the most vulnerable adverse events are, and what my patient has experienced to date, in helping to choose which agent comes next. DR LOVE: I should mention too, we’re really getting some great questions in the chat room, a lot about Oncotype in node positive, all the things we’ve been talking about. So I’m curious about your perspective on these 2 options, Ruth. Also, a question we commonly get from oncologists for all these cancers where T-DXd is considered, what do you do to try to screen for ILD? So you look harder at your staging and CAT scans? I’ve heard people talk about using DLCO. Ruth, any thoughts about your experience with these 2 options? DR O'REGAN: I mean I thankfully, haven’t seen a case yet, but I don’t think there is much support in doing just pulmonary function tests to follow patients. But I do think that making sure you scrutinize the staging scans obviously makes perfect sense because that’s what we used to see a lot with everolimus as well, right, asymptomatic patients that had changes on their restaging scans. So I think that makes sense. But thankfully, I haven’t seen it yet. DR LOVE: And of course, Tiffany, we have this fascinating thought about the possibly of a bystander effect in HER2-low disease. Any thoughts about where that’s heading, Tiffany? And do you see that in the future of breast cancer management? DR TRAINA: Certainly, as we think about options for triple-negative breast cancer where you could have somebody with ER/PR-low — or ER/PR-negative and HER2-low disease potentially deriving benefit from trastuzumab deruxtecan, I think this is the point of a randomized trial actually, in looking at T-DXd in HER2-low disease. Very encouraging. Triple-Negative Breast Cancer DR LOVE: So we’re going to move on now. We’re getting some questions. We may come back a little bit to these questions about HER2 metastatic disease. But lets’ talk about triple-negative breast cancer. We’re going to see some interesting data, hopefully at ASCO that might be relevant to this. So actually, before we get into the cases we have prepared, we had one that flew into the chat room, just going to read it. I hardly even looked at it, but Tiffany, you can take a shot at this one. 41-year-old woman, Grade 3, T3/N0/M0 triple-negative breast cancer. Tiffany, you’re in the elevator and they turn to you and you’re going down, and they say, okay, I’ve got this patient here. So, path CR with weekly Taxol/carbo x 12, followed by dose-dense AC. Status-post mastectomy ALND and radiation therapy. So, the question is would you, in a patient who has a path CR, consider adjuvant capecitabine? What about patients with path CRs? Are we going to do a KATHERINE kind of strategy there also? DR TRAINA: So we have the data from CREATE-X from several years back now, showing the benefit to capecitabine in those patients who failed to achieve a pathologic complete response. And there have been a lot of studies over the years looking at incorporating capecitabine into chemotherapy regimens in the adjuvant setting without selection, and there really has been mixed data there. And so, it is not a standard of care with the data I have today to tack on capecitabine after someone has achieved a pathologic complete response. I think we will want to keep an eye out for, as you heard already, the OlympiA data. We want to know for sure, is this woman a germline BRCA1 or 2 carrier because that may be actionable. And as you know, the KEYNOTE data that we just saw had a press release showing an event-free survival benefit, I think there might be other tools in the toolbox to reach for based on particular biomarkers. So we have to stay tuned. DR LOVE: That’s really a great thought though about the OlympiA strategy. Because you want to do something. So I’m curious, Ruth, I mean what would you say the chance of relapse is in this patient who had pretty significant disease but still had a path CR? And also, of course, there’s already questions, as you were mentioning about IO in the neoadjuvant setting. But somebody else wants to know about the carbo in the neoadjuvant setting. So, Ruth, any thoughts about that? DR O'REGAN: Well, I think the first thing I want to say is because she had a path CR, her risk of recurrence is going to be lower. It’s going to be less than 10%. So I would agree with Tiffany about not giving the capecitabine. But I think the data with the PARP inhibitor would be interesting. As far as the immune therapy, obviously, there’s an ongoing study looking at pembro versus placebo in these patients. So, we will get some data in that front as well. I mean I think we have to keep in mind as well, obviously there are toxicities with these agents, so I think that’s very important to take into account as well. As far as adding in carboplatin, I think the data obviously shows that you can increase the pathologic complete response rate. But I certainly do use it in patients with large triple-negative breast cancers or those — and I know there’s really no data to support doing this, but patients who maybe don’t respond as well to the upfront AC, is adding in carboplatin at that timepoint. And then the question is then should you add in pembrolizumab as well? I think these are all options and we’ll get more data. DR LOVE: So, Bonnie in the chat room says, vis-a-vis OlympiA, suppose the patient had somatic BRCA. I won’t even bring that up yet. Let’s see the data. But you know that discussion’s coming up fast. Actually, I think that the SOLO-1 trial allowed somatic BRCA in there, but I don’t think OlympiA did. So that’s going to be quite debatable. And you’re shaking your head no, so you agree. So, anyhow, let’s go back to cases. We have another one from Dr Del Rosario, a 68-year-old woman. Of course, the question of the day, the question over the last year, the question that’s going to get even more intense recently because of the press release everybody is, I think, aware, but we’re going to talk about. This is a patient with a large triple-negative breast cancer. Here’s Dr Del Rosario. DR Del ROSARIO: She’s a 68-year-old female with localized left triple negative breast cancer, and they wanted to refer her to us for neoadjuvant chemotherapy prior to BCT (breast conservative therapy), is immunotherapy a valid option? And if so, which immunotherapy agents can we use and would a PD-L1 status be needed? The tumor size was quite large, 4 or 5 cm, and she has palpable nodes. For a patient that received neoadjuvant chemotherapy, and at the time of surgery had residual disease, what options do we have then? Would we consider immunotherapy or possibly capecitabine? DR LOVE: So, of course, Tiffany, this is the press release that came out from the KEYNOTE 522 study that everybody’s had their eyes on ever since we started to see this. And it looks like the trend towards event-free survival has now turned into an actually primary finding here. Interested in what your thoughts are, Tiffany. Also, another thing that was interesting about this case that he sort of alluded to is the fact that the patient wanted breast conserving surgery. So maybe even increase in response rate for a patient like that might be enough. I don’t know if you could even access pembro in the neoadjuvant setting easily, Tiffany, but where are you know and where do you think you’re going to be when we see these data? DR TRAINA: We’ve had multiple studies, from ISPY to IMpassion031, now with KEYNOTE, to show that adding a checkpoint inhibitor to neoadjuvant chemotherapy improved pathologic complete response rates. But we did hear from the FDA not too long ago that that did not appear to be sufficient to lead to an indication based on the balance of risk and benefit and toxicity in the adjuvant setting. So this press release of now having event-free survival data I think may really change how we’re going to practice medicine for our patients with tumors larger than 2 cm, node-positive triple-negative breast cancer. Remember, also, the chemotherapy backbone here in KEYNOTE was both anthracycline, taxane and carboplatin. So, this may actually change, not only our use of checkpoint inhibitor, but also potentially our use of platinum in the neoadjuvant setting. I think at this point I would still hold on and see what those event-free survival data look like and also get an update on what the toxicity is. Remember, the checkpoint inhibitor here was used not only in the neoadjuvant setting but continued on for a full year. And so, we’ll really have to see what the whole package looks like to make those decisions. DR LOVE: So, any thoughts, Ruth? And also the question of post-neoadjuvant, sort of the KATHERINE model with the residual disease, IOs there? And straight adjuvant situation, where do we stand right now on data? And any thoughts about maybe how these neoadjuvant data would affect that? DR O'REGAN: Well, I think the bottom line is we don’t know. I mean as I mentioned earlier, obviously we have this ongoing trial looking at pembro versus placebo or versus no treatment in this setting. So, I think for now, the data that we have really would support capecitabine and somebody with residual disease but enrolling them on one of these studies. We are going to hear out of ASCO the results of the ECOG study that compared platinum versus capecitabine in patients with residual triple-negative breast cancer. And the word is, is that’s a negative trial. But of course, it was initially designed just to look at platinum versus no treatment and then it got changed. So, alternate trial design kind of meant that it didn’t really answer, I think, the question it was designed to kind of put to rest. I think most of us do tend to use a neoadjuvant approach in these patients. But I think typically the patients that we treat adjuvantly have smaller cancers, so we try to get away with less chemotherapy in that scenario and there’s just no data right now to add immunotherapy in a patient like that. DR LOVE: So, Tiffany, I guess at ASCO we’re also going to see some data from durvalumab, an IO we talk a lot about. there’s a paper there looking at the use of durvalumab in triple-negative breast cancer, the neoadjuvant setting, in addition to chemo. So we’ll see where that heads. Before we get to this case though, Tiffany, just kind of curious about the platinum. We’ll see what the OlympiA trial says about PARP, but what about your BRCA patients, Tiffany, in terms of the use of platinum neoadjuvantly or adjuvantly? Does that make you lean more towards platinum there? DR TRAINA: So, ironically, it does not make me lean towards platinum, certainly not in the adjuvant setting. And in the subset analyses of GeparSixto in the neoadjuvant setting, those patients who carry the germline BRCA mutation did not have incremental advantage to adding the platinum. And it may just be that these patients are so highly chemo sensitive that you don’t need that additional platinum. This may all become a moot point once we see OlympiA, to be honest. DR TRAINA: There was a question around whether we need PD-L1 testing in the neoadjuvant setting. And I should call out that all of these studies in TNBC have shown that PD-L1 status was not a predictor of benefit actually. So early-stage disease is different than metastatic with regard to checkpoint inhibitor. DR LOVE: Hmm, that’s really interesting. All right, let’s talk about metastatic disease. And Dr Del Rosario has a 70-year-old woman who actually just got started on sacituzumab, or as Joyce O’Shaughnessy calls it, saci, one of my favorite nicknames. Anyhow, here’s Dr Del Rosario with his questions about this case. DR Del ROSARIO: This is a 70-year-old female with initially a localized right triple negative breast cancer. She is status postmastectomy and received adjuvant paclitaxel. Unfortunately, she progressed with a right malignant pleural effusion and is now status post multiple lines of chemotherapy. She also has a pleural catheter in place due to recurrent malignant pleural effusion. Her PD-L1 has been negative, and she is started on sacituzumab govitecan. So, for a patient with triple negative metastatic breast cancer that has recurred multiple times and is placed on sacituzumab govitecan, what adverse events should we monitor? In particular, diarrhea. And would we even consider UGT1A1*28 allele prior to starting sacituzumab govitecan? And in regard to the neutropenia, would we start GCSF on the get-go? DR LOVE: Maybe you can share your experiences with this agent that you’ve had in breast cancer patients and some of the questions, including an interesting question about the UGT1A1*28 allele, Ruth? DR O'REGAN: So definitely a very interesting drug. I think overall, the main toxicities are, as Dr Del Rosario mentioned, neutropenia, I think fatigue, GI issues like diarrhea. You see hair loss. The question about the allele was because there was some initial data suggesting that patients who have that allele actually have more toxicity, but it’s not standard practice to check that in a patient starting sacituzumab at this timepoint. I think, like what we do in most scenarios in the metastatic setting, we typically just monitor blood counts initially. I wouldn’t proactively give growth factors, but I think, obviously some patients may need it depending on how much neutropenia they get. The rate of febrile neutropenia on the ASCENT study was relatively low, but obviously, if somebody has a febrile neutropenic episode, we would definitely think about growth factors in subsequent cycles. So there are the main, I think, toxicities associated with this agent. DR LOVE: So, Tiffany, here’s the big New England Journal paper on saci. Anything you want to say about, kind of exactly was it just another antibody drug conjugate? Anything specifically about it you want to comment on? And also, what they saw in terms of the findings? DR TRAINA: So, I mean I think one thing is interesting in that the target, Trop-2, is just highly expressed in epithelial cells and in triple-negative breast cancer as well as in hormone receptor-positive breast cancer. So you do not need to be screening for a biomarker for benefit here because it is so highly expressed. And I think that the results were really quite profound from ASCENT, the randomized Phase III study, showing not only a significant improvement in progression-free survival, but really overall survival as well. And quite sobering to see how poorly the control arm did. I think this is a call for really need for improved therapies overall and antibody drug conjugates are a step in that right direction. DR LOVE: So, just kind of curious, Ruth, what you see on the horizon in triple-negative breast cancer? What you see on the horizon in general in breast cancer in terms of new agents and strategies that we’re going to be seeing over the next couple of years, Ruth? DR O'REGAN: Well, I think we still struggle with triple-negative breast cancer. I think, as Tiffany alluded to, some of them are very sensitive to chemotherapy, but many are not. I think the subtyping that we’ve had available for a few years I think hopefully can guide us. I’m still like Tiffany, very interested in the androgen receptor targeting in triple-negative breast cancer because I think they’re quite different. But I think a lot of what we’re going to see is going to come from next-generation sequencing and learning more about these cancers and what’s the best way to target them therapeutically. If you look at the HER2 setting, there’s been so many drugs that have been approved in the last year or so, it’s just so exciting as there’s just so many agents coming out. I think the other place that we really need to focus as well, those luminal-B endocrine-resistant cancers because I do think they’re a huge issue. And overall, I think we all agree that, despite the results of monarchE, the adjuvant CDK inhibitors isn’t really a homerun at this timepoint and further follow-up with those trials is going to be very important. So, I think that’s a space where both in the metastatic and early-stage setting, we definitely need new agents to learn more about those cancers. DR LOVE: So, Tiffany, we’ve talked about IOs, specifically in triple-negative breast cancer. Of course, the first-line setting for PD-L1-positive patients, that’s becoming standard with chemotherapy. But Nicole in the chat room is relating a case, and actually I remember she emailed me about this case because it was very disturbing to hear about, which is sort of the other side of the coin, so to speak, of neoadjuvant IO. So she wants to know would you limit IOs to people with node-positive disease? She’s also leery about continuing the IO afterwards in terms of tolerability. “She just got burned by putting an HR patient on pembro neoadjuvantly, although the patient had — with chemo. The patient had a path CR, but also had a hypophysitis, systemic sarcoidosis, major IO problems.” And I think IOs are so well tolerated by the majority of patients, but you still see Type I diabetes, hypophysitis, and of course worse, in terms of pulmonary and GI. Any thoughts about, just globally, looking at IOs in breast cancer in terms of tolerability issues that you see, Tiffany? The common ones? And any thoughts about this case here with the hypophysitis? DR TRAINA: Yes, and I’m so sorry to hear about this patient. And I think it is sobering. But the enthusiasm we have for benefit but being very cautious in recognizing particularly moving these drugs up into the early-stage setting, that you could commit a woman to lifelong and significant impact. So, this is not trivial by any means and quite powerful when we start manipulating the immune system. So, I do think this is the exact example of what we are so cautious about and, therefore, really looking at these agents in those patients at highest risk of recurrence so you can justify that risk-benefit balance. DR LOVE: So, Ruth, Daniel in the chat room wants to know which PD-L1 assay do you use for metastatic triple-negative breast cancer? So, he says he sent the 22C3 and it was 0. Should he send the “atezo” assay? DR O'REGAN: I mean that’s typically what I do send with different data/assay, I think pretty much, if one’s negative, it’s not like the other one’s going to be positive, as far as I know. But there may be some cases where there is and there probably isn’t any harm in sending it. DR LOVE: So, Tiffany, any other thoughts again — I asked Ruth — in terms of new research initiatives. You talked about your really exciting initiative focusing on anti-androgens. Any new, other novel strategies that we ought to be looking for in the next couple of years? DR TRAINA: I mean as we think about triple-negative breast cancer, I think not only looking at the luminal subtype and AR, as well as doublets in that setting, we’re really going to be describing triple-negative breast cancer by what its molecular driver is. And so, we should, hopefully, be seeing data around AKT inhibitors. We had some disappointing data with 1 agent, ipatasertib, but capivasertib, those trials are still ongoing. So that could account for a particular targetable pathway. We’re looking at other immunotherapy options, aside from checkpoint inhibitors, as strategies as well. There are trials looking at antagonists to the Notch inhibitor signaling or the Notch signaling pathway as well in triple-negative breast cancer. And so, I really think that, hopefully, next-generation sequencing helps guide us in what the drivers are of a particular triple-negative breast cancer. And then also having hopefully, markers to know who will benefit from immunotherapy. DR LOVE: Just kind of curious, Tiffany, do you send MSI on your patients with breast cancer? Have you seen MSI-positive — MSI-high breast cancer? DR TRAINA: Yes. So this often in our next-generation sequencing panels, as well as tumor mutation. And I will remind folks that a high tumor mutational burden of greater than 10 is actually an indication for single agent pembrolizumab patients with breast cancer who have hormone receptor-positive disease. So, be sure to be looking out for that TMB on your next-generation sequencing reports. Introduction DR LOVE: Right now we’re shifting into the management of multiple myeloma, again we’re going to make rounds. We have some more cases. We’re presenting about 50 cases here today, so we’re making rounds. We have the pleasure of working with Dr Ken Anderson from Dana-Farber, and Dr Noopur Raje from Mass General Hospital and Harvard Medical School. And just to remind everyone, we have a whole bunch of general medical oncologists, mostly from the Medical Oncology Association of Southern California where we typically go every year for the last 10 years, but today we’re doing it virtually. So we’re going to start out talking about newly diagnosed disease. And then we’ll talk about relapsed disease. Just before we get started, just maybe go back to the faculty, and start with you Noopur, and I’m must kind of curious, what ae some of the most common questions you get from general medical oncologists nowadays about myeloma? DR RAJE: I think because we made so many different advances, Neil, there’s a lot of debate on what should be used in the treatment and it’s right from the upfront setting — should we use 2 drugs, 3 drugs, or now 4 drugs, which I’m sure we’re going to be talking about today. And in the relapse setting, when is it the right time to refer patients for clinical trials? When do you do immune-mediated strategies such as bispecific T-cell engagers, CAR T cells? And it’s an exciting area to be in right now because there’s so much, and that creates a lot of debate and sometimes questions from the community. DR LOVE: So, yes, Ken, usually we bring up myeloma and people sort of throw up their hands and go, there’s so many things I don’t know what to do, whether it’s upfront or in the relapse setting. Just kind of curious, we have a lot of people new to oncology, fellows, etc, who tune into our program. Maybe you could provide a little perspective about myeloma today compared to 10 or 15 years ago in terms of what the options are and how patients do? DR ANDERSON: It’s been remarkable, Neil, in terms of the progress. You are right, I’m old enough to have seen this progress occur and participate in it, along with many patients over the years. We first had high-dose therapy and transplant come into our treatment paradigm in the ‘70s and ‘80s, first with bone marrow, then with peripheral blood stem cells in the ‘90s. And then from the late ‘90s to the present time, we’ve had the IMiDs and the proteasome inhibitors, monoclonal antibodies and now, as Noopur was saying, we have different kinds of targeted therapies, whether it be nuclear transport inhibitors or excitingly, in my view perhaps most excitingly, the immune therapies such as CAR T cells and bispecific T-cell engagers. So, as a result of all of this progress, the paradigm has completely changed and fortunately, which is why this course is so important, we have these new medicines, we really need to learn how, as caregivers together, to makes sure the patient gets the best benefit. As a consequence, myeloma is a chronic illness nowadays in many patients. DR LOVE: Yeah, I was curious, Noopur, when you meet with, let’s say a standard risk patient, a younger patient, what do you discuss with them in terms of what to think about for the future, in terms of usual prognosis? DR RAJE: So, looking at a standard risk patient, today we have lots of different options, Neil, and that really makes such a big different for our patients. And I think one has to think about trying to get from that chronicity, which Ken was talking about, to can we cure some. And I do think with all of the different options we have today, we are able to cure or will be able to cure a significant subset. And in my mind, it’s the standard risk patient that we’re going to be able to actually have long-term disease control on. So, this is the patient population that I do talk to about combination treatment approaches, and really, I think all patients should get the best possible treatment upfront. And as of right now, at least in my mind, it would be a 4-drug regimen, which is under investigation as we speak. Newly Diagnosed Multiple Myeloma DR LOVE: So let’s get into some real cases and explore these paradigms. And I’m curious when you mentioned the word “cure” that’s an interesting thought. We’ll get into that in a second. We’re going to start out with a patient — a couple of cases of upfront therapy, but before we do that, let’s just see where the audience stands. Audience, in general, if you had a patient who’s eligible for transplant, but they’re high risk, they have del 17p, what kind of strategy are you going to be thinking about in a patient like this? And of course, we saw data last year at the ASCO meeting on the ENDURANCE study in standard risk — we’ll talk about that in a second. But interestingly, Ken, looking at the audience, first of all, almost everybody is saying daratumumab, it’s either RVd or KRd, and it’s almost split 50/50 between those 2. I should say a third, a third, a third. Some people say RVd alone. How do you think through del 17p upfront? Again, putting reimbursement issues aside, Ken? DR ANDERSON: I think, Neil, that’s again reflecting the big change in paradigm. And as Noopur just mentioned, there is the possibility to cure some patients. On the other extreme, the 17p deletion high-risk patients still require more advanced treatment. So in this young, eligible for transplant patient, I do think RVd/daratumumab or KRd/daratumumab would be useful. The RVd/daratumumab is shown in the GRIFFIN trial which I think we’ll probably talk about later, to achieve more deep responses, more MRD-negative responses that are durable than RVd. The KRd paradigm has been popularized by Francesca Gay in Europe and honestly, the one-time where we consider carfilzomib to be utilized upfront — I guess we’d use it if somebody has neuropathy — but otherwise, we do think about it, Neil, upfront because in patients who have high-risk disease, we really need to get the deepest response as quickly as we can. So, RVd/daratumumab is not unreasonable. KRd/daratumumab would be what I would choose. There is a recent JAMA Oncology review where daratumumab is put into the upfront treatment of myeloma, transplant or non-transplant candidates, and it does benefit even high-risk disease. So clearly daratumumab upfront and this is one setting where perhaps carfilzomib would come upfront as well. DR LOVE: So carfilzomib definitely a consideration, although I don’t know. When we asked our investigators, they bring that up more commonly when we present a higher risk case. So let’s get into some real cases here. This is Dr Gigi Chen who has a 65-year-old man with IgG kappa myeloma. You can see the numbers on this patient, 90% involvement in the bone marrow. You can see the cytogenetics there. Here’s Dr Chen’s questions. DR CHEN: What would be the best induction treatment for him, RVd versus KRd? Or what about an induction treatment that has dara as part of the induction as well? He’s had a very good response to the VRd and is being prepped for autologous stem cell transplant. So, another question would be that I have seen a number of patients coming back from academic institutions after autologous stem cell transplant, that they go on the consolidation treatment after the stem cell transplant. So my question is kind of the role for the consolidation? How long they should be on the consolidation before maintenance? And also another question is the role of MRD monitoring in the setting of the multiple myeloma, whether before transplant, after transplant, and how do we monitor the MRD? And also, whether to switch treatment based on MRD? DR LOVE: So a lot of nitty-gritty questions of practice here, Noopur. What about MRD outside a trial setting in myeloma, particularly in this situation of a patient who’s going for transplant? Does it affect your use of or choice of maintenance? And what about consolidation? DR RAJE: So, I think that these are all really important questions, Neil, and the role of MRD is becoming increasingly important. It allows us to understand the depth of response in patients. And from a prognostic standpoint, it is really quite important. As far as using it as a tool to change treatment, I’m going to say we’re not quite just there as yet. I think looking at MRD and more the kinetics of MRD and making sure that they remain MRD-negative is critical. Will I change treatment based on MRD changing? We just don’t have the data to speak to that. There are ongoing studies as we speak and therefore, I think we need to wait on some of those. I think the future, specifically in the high-risk patient population, and I don’t believe this patient necessarily had high-risk genetics, maintaining MRD-negativity, and sticking with trying to maintain MRD-negativity is going to be really quite important. In the standard risk patient, we should wait on some of the data which we are trying to generate, with respect to tailoring treatment to MRD. DR LOVE: So, Ken, of course the questions been out there for a long time, kind of the context seems to change over the years is, is transplant still an important option? Is it standard of care in a patient who potentially is eligible? And also, who’s eligible? So to get into that, I want you to check out this next case from Dr Jeremy Lorber, a 78-year-old woman, a history of well-controlled mycosis fungoides, who presents — and you can see how she presented with lambda light chain myeloma. I found the therapeutic approach to this 78-year-old woman quite interesting. Here’s Dr Lorber. DR LORBER: What is the role for quadruplet regimen, like the one she was started on, versus a triplet therapy? DR LOVE: So what’s her current situation? DR LORBER: She had a very good partial response and was evaluated for autologous stem cell transplant, underwent the stem cell transplant, did well, and now is on maintenance therapy. DR LOVE: Hmm. 78 years old, huh? DR LORBER: She was 78 but both myself and the transplant team were shocked when they look at her age and then look at her. She appears at least 10 to 20 years younger than 78. DR LOVE: Any other questions that you’d like to hear myeloma people discuss? DR LORBER: there a role for quadruplet therapy in a patient who is not eligible for autologous stem cell transplant? And for patients receiving triplet therapy, when or is there a role for DRd versus VRd regimen? With the impending approval of CAR T agents and other novel agents in myeloma, is the role of autologous stem cell transplant going to shrink or be maintained given that there are so many lines ahead of a patient even if they don’t undergo a transplant? DR LOVE: So, Ken, it’s always tough to find a transplant trial that has contemporary therapy because contemporary therapy keeps changing so fast. But first of all, just curious — they say age is just a number, Ken, but I’m just kind of curios what the oldest patient you’ve sent for a transplant? This woman was 78. DR ANDERSON: I think this is on the old side. We usually call it, Neil, physiologic age 70, so perhaps this person — this woman does qualify — but adequate liver, heart, lung and kidney function so the transplant can be done safely. But I think in someone who’s usually — the cutoff is really around age 70. In some of the big, randomized trials, Neil, it’s actually 65 years of age or younger. Maybe I can take on some of the questions real quickly here. I think that the quadruplet regimen, there is a role for quadruplet regimen even in the transplant-ineligible patient. Remember, that daratumumab was actually upfront approved for treatment in non-transplant eligible patients based on a trial we don’t use very often, but melphalan, prednisone/bortezomib and daratumumab. We don’t do that here. But there are trials here, for example, of RVd-lite, a regimen that has attenuated doses of RVd that Noopur and her colleagues pioneered, together with daratumumab. So that would be a quadruplet regimen. We already mentioned that the MAYA trial, the daratumumab/len/dex trial with daratumumab upfront, those are very effective regimens with long progression-free survival. So, it’s perhaps a little unusual that she got a stem cell transplant. In terms of her maintenance, real quickly, which was asked also, lenalidomide is a standard of care for maintenance in myeloma. In the standard risk patients, Sagar Lonial has reported with his colleagues that you get RVd, a transplant, and lenalidomide maintenance and your overall survival is well over 10 years and still going strong. My point that might be of use here is the gain of 1q does confer a high risk, and this kind of a patient, we might think about incorporating a proteasome inhibitor, either bortezomib or ixazomib into the regimen because that is found to be effective, risk-adapted maintenance, as the Emory group has reported, really makes a difference, and can overcome the early relapses that are the hallmark of high-risk myeloma. And I’m sure we’ll talk about this more, Neil, what is the role of transplant nowadays in general? We have the RVd with an early versus late transplant, the DFCI/IFM trial that started in 2009. We still don’t know the answer to the question of whether the transplant adds value, and the reason we don’t is now 12 years later, there can’t be differences that are significant between either efficacy or side effects because if there were, the study would have been unblinded. So, I think we don’t know the answer of transplant. And nowadays, RVd with daratumumab is being tested with or without transplant, which will make the transplant, perhaps, value even less. Having said that, I do think that we are soon to see some of these new strategies like CAR T cells, which are so exciting in very advanced disease move more early in the disease course management. And so, for example, Neil, the day is not too far away where patients will get induction and then where transplant is now done currently, I do think you’ll see trials of CAR T cells right at that point. DR LOVE: So, Noopur, it’s so difficult for docs out there to try read between the lines. Ken, some of the things he just quoted makes you really question whether it’s necessary to do transplant. I’m curious what your thoughts — yet, when you ask investigators most people I think, at least asking them, consider it standard of care. Any thoughts about this? And also, whether MRD ties into the question of transplant? I know there are not that many patients that become MRD-negative from induction therapy, but if you had somebody like that, do you feel better about holding off on transplant? DR RAJE: So, again, transplant is still considered the standard of care. And honestly, that’s based on close to a 9- to 10-month progression-free survival benefit, Neil. We’ve been using transplant now for the last 50, 60 years, and to date have never been able to show that patients actually live longer because of survival — because of a transplant. And therefore, I think the study which Ken alluded to, the IFM/DFCI study is a really important study, and that’s going to tell us where the transplant upfront, or even delayed, is something we should be doing. Should we be using MRD as a tool to figure this out? Well, there is data from the DFCI/IFM trial, and it didn’t matter how you got to the MRD-negative disease state. So if you go there by just the triplet, your progression-free survival was very similar to whether you go there with a transplant or not. So MRD will, in fact, be a tool going forward in helping us figure out how to intensify treatment. I don’t think we can base our treatment algorithm just as yet on the MRD testing, because remember, the MRD testing was done at close to a year and the transplant decision is more around 4 or say 5 months or so. So, future studies will help us out with MRD. And I do think transplant is going to be a moving target, specifically with some of the immune strategies which we’re already using in the upfront setting as we speak. DR LOVE: So, Ken, a couple of questions in the chat room about maintenance. Amy has a patient who’s intolerant of lenalidomide, presumably standard risk. What do you do in that situation, Ken? And you mentioned proteasome inhibitors in high-risk situations, I’m curious a little more about your experience with ixazomib. Of course, we’re trying to keep people out of the hospital even more than ever, even now, because of COVID. So what do you do with len intolerance? And any reflections on the use of maintenance with ixazomib? DR ANDERSON: So, these are wonderful questions. Lenalidomide maintenance, Neil, is commonly given at 10 mg orally daily for 21 out of 28 days continuously. And I can share that we do have some side effects with diarrhea primarily, and some low counts. But most of the time it’s well tolerated. I still have the very first patient, Neil, ever put on lenalidomide 20 years later. DR LOVE: Wow. DR ANDERSON: And many people out 5, 10, 15 years. So, I do think it can be well tolerated. I think the first issue is, in terms of what intolerance really means here, but we can reduce the doses. Remember, lenalidomide is a biologic, so at these low doses, it stimulates the patient’s immune system, their own God-given NK cells, NKT cells and T-cells to mediate anti-myeloma responses. Noopur and I showed that 20 years ago. But in any event, if you can use the lower doses, that would be the first — most desirable. If you can’t, then we’d try to substitute, and I think ixazomib would be a reasonable 1 tablet a week, 3 weeks out of 4, alternative. In the high-risk patients, Neil, we do try to use, as I mentioned, lenalidomide and a proteasome inhibitor, just because the Emory group and others have shown that a proteasome inhibitor can, at least in some of the patients, overcome the hallmark early relapses in the high-risk patients. I want to mention one other quick thing about what COVID, if I could for a second. COVID did affect every aspect of each our lives, including our patients and everything that we do. Treatment-wise, we did switch over sometimes, Neil, to oral therapies to try to minimize clinic visits and COVID exposure. So that’s true. I think what I would like to share that we, together with the International Myeloma Society, looked at all of the world’s data with COVID-19 infection in patients with myeloma or plasma cell dyscrasias, and the main factor that came out in terms of doing poorly with a COVID-19 infection was having myeloma that wasn’t controlled. So the punchline — and there’s a Blood paper editorial — but the punchline here is don’t compromise myeloma care because of COVID. That’s the worst thing we can possibly do. DR LOVE: So, okay, you brought up COVID because you know what I’m going to ask next, and I’ll turn to you, Noopur. First of all, what do we know about the response to the vaccine? Do you ever test for antibodies? What kind of antibodies do you test for? We heard about spike antibodies. Do you ever hold any forms of therapy? How about the vaccine. And of course, Noopur, you’ve had some personal experience with COVID, I’m sure you’re even more interested. DR RAJE: Yes, this is a really important question for patients, which comes along every time. So I do think we’re recommending vaccine for everybody, and it doesn’t matter which vaccine you have access to, but all patients should be vaccinated. We are looking at immune responses to the vaccine. So we have an ongoing study at MGH and Dana-Farber, where we’ve actually included 100 patients, Neil, with plasma cell disorders. This is myeloma and Waldenström’s, and we’re looking immune responses. We’re looking at both B-cells as well as T-cell immune responses. The B-cell responses are mostly to what you just alluded to, to the spike antibody. And the T-cell responses are more sort of research and we’re trying to figure out what the level of response here is. What we’re seeing already is that the response rates are very variable. And I do think the most important thing, and Ken has alluded to this already, is myeloma in remission with a good intact immune system, results in a good immune response. We already know with drugs like the immunomodulatory drugs, so patients who are on drugs like pomalidomide and lenalidomide, the chances of them mounting an immune response tend to be higher. About some of the other drugs, I don’t think we have enough data to speak to that. And as of right now, at least we are not telling people to hold drug just because of the vaccination. The one thing we do tell patients not to do is while getting the vaccine if they can hold off in getting IVIG. If they are getting it constantly, that’s something that we would recommend so that it doesn’t mask the effect of the vaccine itself. DR LOVE: So, still getting a lot of questions about maintenance after transplant, following patients. So, Charles wants to know about following people after transplant who are non-secretory, Ken. We were doing our Oncology Nursing Society series and one of the nurses there was saying that people give up on lenalidomide too early. They see some rash and they don’t aggressively dose reduce. So, any thoughts about following people with non-secretory disease? Also, questions about tandem transplant, Ken. DR ANDERSON: So, following patients with a non-secretory disease is still very difficult. Often times we will, as in the past, we will try to look at bone marrows perhaps annually. But PET-CT scanning might also be useful here, Neil, because it’s very sensitive, not specific, but sensitive and can pick up early signs of disease. But I do think the bone marrow is still the major way that we try to follow the non-secretory disease. It reminds me, or it gives me a chance though, to say that we have new, more sensitive methods, Neil, for monitoring myeloma such as mass spec, and mass spec is going to be able to detect monoclonal proteins at a level of sensitivity that we just can’t do right now. So, I think in the very near future, we’re going to have an opportunity to do better in terms of monitoring the non-secretory folks. I would mention one quick thing then about MRD and then tandem. When you’re following patients along, as Noopur said, we can measure MRD and so doing a marrow and looking with multicolor flow or sequencing, even in non-secretory patients, which is why I was thinking about this, can be very helpful. We can detect 1 in 100,000 or 1 in a million myeloma and normal cells. So it makes it a little bit easier, even in a non-secretory setting to find such a benefit. In terms of double transplant, there is the STAMINA trial in the United States which had patients who got RVd and a transplant or RVd consolidation and a transplant, or 2 transplants followed by maintenance. And there was a trend towards a benefit for 2 transplants, potentially in the high risk. There’s also the European Myeloma Network trial that shows a benefit, if you will, restricted to the high-risk patients. I would say though, we rarely do double transplants nowadays, Neil. We have, as we’ve already said here, the incorporation of carfilzomib and daratumumab upfront, which do work in the high-risk setting. And we have so many other drugs now, all of which have bene FDA-approved in high-risk patients that I think the double transplant paradigm is really not used very often I want to take a minute here just to say we’ve recently published with Dr Munshi and his team, what happens when you get high dose melphalan. We all know for years that there’s a risk of secondary cancer. But the number of mutations in patients after having received high dose melphalan is markedly increased compared to those who just got RVd in our DFCI/IFM trial. So that it’s not surprising therefore, that the incidence of secondary malignancies is higher. So, one transplant I think still can be said to be a standard of care, but I don’t think 2 transplants is used very much longer. DR LOVE: One other issue that came up in the chat room, Noopur, about subQ versus IV dara. The person in the chat room wants to know do you use subQ when you do induction therapy? What’s your approach right now in terms of subQ dara, Noopur? DR RAJE: We’ve transitioned everybody to subQ. This COLUMBA study is a really important study, and it’s really very convenient giving it subcutaneously. We’re doing it in combination. We’re doing it in the upfront setting with other drug partners as well. The important thing to remember with the subcutaneous version of daratumumab, Neil, is that it is way better tolerated. The infusion reactions that you typically see with the IV version are a lot more mutated, and with the first dose of the subcutaneous we do watch our patients about 5 to 6 hours in the infusion room. But in general, patients tolerate it quite well. When we first started using subcutaneous, my concern was if you have a very small person, are you going to be able to give enough of the dose, because it’s about 15 cc’s that we’re injecting into the subcutaneous tissue. But I think having the hyaluronidase has made such a big difference, and I see very petite young women also tolerating the subcutaneous version quite well. So, again, I think the standard of care with CD38 monoclonal antibodies should be the subcutaneous version. Relapsed Multiple Myeloma DR LOVE: So we’re going to back and talk about some cases, makes some rounds. We’re going to start out with a patient of Dr Justin Favaro, but before we do that, just a quick question to the audience. I want to know, there are a lot of options available to patients who progress on proteasome inhibitors, IMiDs and anti-CD38, often daratumumab. I’m just kind of curious, in general, what are you thinking about next? What’s your usual go-to regimen when you kind of get beyond those initial 3 options? And it looks like it’s kind of split between 2 anti-BCMA strategies, belantamab and actual CAR T, although I’m not sure you can get it. Another issue that relates I think to this next case is, if you have a patient who has t(11;14), do you utilize venetoclax? And if so, in what line of therapy? I’d be curious to hear what the faculty think about that. I see second line, at least that’s what the audience is saying. Well, we’ll get to that in a second. This patient actually got venetoclax. The patient had t(11;14) but something — another aspect of this case was very, very interesting, sort of life in the general medical oncology world. Here’s what happened. Here’s Dr Favaro. DR FAVARO: Last year while on daratumumab, doing well with his myeloma, he developed abdominal pain that turned into a bowel obstruction. And we took him to emergently to the hospital. He had a right hemicolectomy. At the time of surgery they saw peritoneal studding. I actually stopped his myeloma treatment and put him on pembrolizumab for 1 treatment. But then I stopped it because his monoclonal labs were going up and started treating him again for multiple myeloma. I put him on venetoclax for 3 months. He progressed on it. Would it have been better to combine venetoclax with another agent, such as bortezomib or lenalidomide? Would we have seen a better response rate than just venetoclax alone in 11;14 translocation patients? He progressed on selinexor. And so the question for the panel is when secondary malignancies come up in the setting of multiple myeloma, what do you do? Is it better to treat surgically the secondary malignancy and then go back to treat the myeloma? I think the other interesting question would be whether or not somebody in their 80s, somebody with slightly poor performance status, would they be a candidate for CAR T therapy? And if they’re not a candidate, are there any other anti-BCMA antibodies that they may be a candidate for? DR LOVE: So, Ken, such an interesting situation here because the solid tumor that this patient got actually is very interesting, MSI-high metastatic colon cancer, not curable but highly treatable with IOs, pembrolizumab in particular, which is what he started the patient on when he was diagnosed. And yet the myeloma started to get worse. I’ve heard cases of people get 1 dose of an IO for MSI-high and do well. They have to stop for toxicity. But trying to balance that out. I don’t know if you’ve encountered situations like that in the past. Any thoughts about how to deal with a case like this that Dr Favaro has? And also, how you approach the use of venetoclax. The audience says maybe second line. DR ANDERSON: This case, Neil, really highlights the importance of what you’re doing. These are real world cases. And I very much sympathize with Justin’s patient. I think in this person, I think it’s probably not related, but I do think it just reminds me to say that there is an incidence in myeloma of 10% of patients with myeloma have a second cancer, so it’s not that unusual. And the IMiDs can increase the risk of secondary cancers. Having said that, I think it’s likely that these two are not related events. I do like this strategy of the surgical attempt to see what he’s dealing with and using pembrolizumab. I think from our discussion so far, and going forward, we can treat myeloma effectively. So we really need to deal with colon cancer as much as we can as we would otherwise. I think in this person, just looking at and listening to the story, RVd initially, and what could be utilized now, I like the 11;14 translocation venetoclax, but probably wouldn’t use it second. There are many other FDA-approved regimens, pomalidomide containing, daratumumab/pomalidomide with isatuximab. Carfilzomib/pomalidomide/dex would be active. So there are other regimens. So I probably wouldn’t be using venetoclax second. However, I think it was a wonderful idea to use venetoclax. As everybody knows, it’s approved in leukemia and lymphoma, and in myeloma, 40% response rate as a single agent in the 11;14 translocation. And when it’s combined with a proteasome inhibitor, which is what you were asking, response rates go up as high as 80% to 90%. But it’s in the group that have 11;14 translocation or, otherwise, have an increased BCL2 gene and protein expression that venetoclax really confers value, especially when you add a proteasome inhibitor. The other quick thing I’ll mention with venetoclax, in other settings, 800 mg of venetoclax a day is given. That’s too high in multiple myeloma. We will start low and escalate up and we might proceed to 400 mg daily, but we rarely go higher, Neil, than that dose. DR LOVE: So, Noopur, I feel like venetoclax ought to be in the drinking order, with CLL, really revolutionized CLL management. We have a session on AML, in older patients, venetoclax/HMA, revolutionized the patients. These people were sent for palliative care, now they’re going into remission. Of course, the issues, particularly with CLL, also is the issue of tumor lysis syndrome. Do you see that in myeloma? Do you do any kind of pre-emptive amelioration of that? And how are you using it? Are you using it by itself? In combination? What line therapy, Noopur? DR RAJE: So again, I think having venetoclax as an option for our patients, specifically those with 11;14 translocation, is fantastic. We typically do not see the tumor lysis. We do see blood counts going down. So I do remember Justin having mentioned combining it with an IMiD. I’d be a little bit careful about combining it with an immunomodulatory drug because you’re going to find more myelosuppression there. But we start low. We build up. And typically, our patients are on 400 or 600 mg of venetoclax. And I like combining it with bortezomib because of the data from the BELLINI trial, which has really shown an 80% response rate in this 11;14 or BCL2-high expressing multiple myeloma. Over time, though, I think it is really important to remember that you can dial down the dose of venetoclax. I have a patient, Neil, who’s on venetoclax now. We stopped the bortezomib, largely because of thrombocytopenia, and then I’ve continued. And she’s currently, for the last year or so, she’s been on venetoclax for 2.5 years, but last year she’s only 100 mg of venetoclax and that’s holding her disease quite well. So a really useful treatment, but dose adjusting is really, really important. And our hope is that it will get FDA approved, at least in the 11;14 translocated patients. DR LOVE: So, the chat room has really become a real great part of this meeting here today. Draupadi says that there’s no venetoclax in his drinking water because there are too many cytopenias, which you just addressed. I’m curious if you could comment in a second, Ken, about the issue of cytopenias and dose reduction. But Charles has a really interesting case in the chat room: t(11;14) at initial diagnosis that goes away after initial treatment. Can’t find any more t(11;14). Do you still use venetoclax or no? DR ANDERSON: That’s a super question, Neil. I wish we knew the answer. I do think what it illustrates though is myeloma, even right from the outset, is very heterogeneous. We and others have shown 3 to 5 clones of myeloma initially, and clonal evolution occurs and underlies relapse of myeloma. So what I think this case is illustrating nicely is honestly, how effect venetoclax is; perhaps it was with a proteasome inhibitor, but you can deplete the abnormal clone, but unfortunately, those cells that are not sensitive then become predominant and underlie relapse of the disease. So I think in this patient, honestly, I would continue venetoclax. Larry Boise at Emory and people at our place, Tony Letai, and others, are studying. Even though the majority of the responses to venetoclax are in the 11;14 translocation/BCL2 overexpressing myeloma, it’s not totally restricted to that subset. So there may be other mechanisms that we don’t yet have defined whereby venetoclax can help in myeloma. DR LOVE: So, Noopur, I see another interesting question in the chat room from Ming. This reminds me of, is there a difference between pembrolizumab and durvalumab in lung cancer? I’ll explain in a second. But Ming wants to know what’s the difference between daratumumab and isatuximab? Because I’m going to say it’s the data. DR RAJE: So I think both of them are CD38 monoclonal antibodies, both are directed against the same protein. And if you look at the data also, both data looks quite similar. There’s a slight difference in the dosing schedule for isatuximab, for example, where we start out weekly and then go to every other week, and that’s something that is continued. With daratumumab, we start out with the weekly, go to every other week, and eventually go to monthly. The difference between dara and isa: again, daratumumab, we do have now the subcutaneous version, and isatuximab is working on getting a subcutaneous version to us. There is some data preclinically would suggest that isatuximab can in fact impact the enzymatic activity of CD38. Whether that pans out in the clinical setting is something to be — we need to look at that. We do know though, that if a patient has had 1 CD38 monoclonal antibody, you’re not going to be able to necessarily rescue with another CD38 monoclonal antibody right after. I think the key to remember here is at least give a 6-month window for that antigen expression to come up again before you use a similar CD38 directed strategy. Subtle differences between mere infusion-related reactions, but to be honest, I think we’re targeting the same antigen in this case. DR LOVE: The reason I was jokingly saying durva versus pembro is because there’s a trial in Stage III lung cancer that was positive for durva, wasn’t really positive for pembro. People are now using durva. So, kind of like people follow the data. I’m curious about your thoughts about isatuximab, Ken. In which situation, if any, are you using isatuximab, Ken? DR ANDERSON: So, isatuximab, we actually did study it preclinically also, Neil. And it does have some differences that Noopur has already mentioned. There’s a direct killing mechanism that isatuximab has that is not shared by daratumumab. And I mention quickly, on the other side we’ve also been very interested in reasons for resistance and one of them is downregulation of CD38 to either antibody. And we’ve shown that others have tried ATRA or HDAC inhibitors to upregulate CD38 and restore sensitivity. And we’ve recently shown that STAT activation downregulates CD38 and the only potentially clinical relevance there is that if you inhibit — so if you use ruxolitinib, for example, a JAK inhibitor, we’ve shown, at least in preclinical studies, you can restore CD38. The other quick thing I’ll tell you is we really desperately need some data, Neil, that tells us whether, in fact, if you start with daratumumab, as we’ve said here many times already, does isatuximab work or not in the daratumumab-refractory patient? That has not been really tested in many big clinical trials. I think one quick thing I’d like to mention, it’s very exciting, but carfilzomib or bortezomib or the proteasome inhibitors inhibit the proteasome and kill myeloma. What we and others have recently shown, is there are also immune agents — they kill the myeloma, and the dying myeloma cell triggers immunogenic cell death. This has been described in many solid tumors, but now in myeloma. So that you get an immune response that’s selective against the tumor from the dying tumor cells. The reason I mention it here, Neil, is if you were to kill the myeloma cell with carfilzomib and then you add daratumumab to that, you’ll have the independent activities of the CD38 antibody, daratumumab or isatuximab, but either of them causes a proliferation of T-cells. So the idea I’m mentioning here is kill with carfilzomib, induce an immune response called immunogenic cell death, and then amplify that response with a CD38 antibody. So, again, I think we would use the antibody on-label with pomalidomide/dex. That’s how it was approved, and more recently now with carfilzomib. It also, I think, is a reasonable alternative. We simply don’t know though how often, even in combinations, isatuximab will be active in daratumumab-refractory myeloma. DR LOVE: So, Ken, you’re one of the few people that I can understand the translational stuff when you explain it. It’s so interesting. I didn’t realize there was so much difference between these 2 anti-CD38 antibodies. It sounds very different than what I was talking about with these checkpoint inhibitors. But really interesting. Okay, let’s get back to the real world here with more cases. I have a 54-year-old patient, young, with myeloma who actually got CAR T after multiple earlier therapies, starting out with KRd. Thought to have high-risk disease. Interestingly, went on a trial where the patient got CAR T and it was followed by an allo. But in any event, here’s Dr Del Rosario’s questions, particularly about CAR T. DR Del ROSARIO: How do patients do on anti-BCMA CAR T therapy in relapsed multiple myeloma versus to patients who receive the CD19 CAR T therapy for patients with relapsed lymphoma? Is there any research for anti-BCMA CAR T therapy in relapsed multiple myeloma in terms of giving the CAR T therapy sooner in the disease versus later? DR LOVE: Any questions you have about other new agents in myeloma? DR Del ROSARIO: Any recommendations on sequencing these new therapies such as selinexor, melflufen, or belantamab? The use of selinexor, how tolerable is this for patients and what can we look out for? For a patient who received anti-BCMA CAR T therapy, would there be any indications for belantamab vedotin after progression on CAR T? In terms of belantamab vedotin in relapsed multiple myeloma, how do we manage the eye toxicities? DR LOVE: So, Noopur, do you feel like you’re on rounds and they’re firing questions at you? You can have 45 minutes to answer this question. Let’s start with CAR T. Why don’t we see a shoulder in CAR T, like we do with diffuse large B-cell that we’re going to talk about later with CAR T anti-CD19. What do you see with CAR T? And of course, now we have the approval. In what situations are you using it, or would you recommend using it? DR RAJE: So I think with CAR T cells, what we have shown is really high response rates and clearly the durability of response is not similar to lymphoma, which is what you’re alluding to. And that’s largely I do think defined by the biology of myeloma. We started out by talking about the continuous treatment paradigm for myeloma. That’s something we’ve done for the last now 15 or 20 years. And this is the first time where we’re using a 1 and done treatment strategy with nothing at the back end. The other really important thing to recognize and remember, Neil, is the fact that we’ve used CAR T cells right now in the very end stages of myeloma, wherein patients have had no other options of treatment, and yet what we are seeing in that patient population is MRD-negative disease and if a patient achieves stringent CR and the data which Nikhil has just published in The New England Journal of Medicine shows that the progression-free survival of patients achieving a stringent CR, the median PFS in these heavily pretreated patients is about 20 months. So agree, we need to do better, but as a first start here, we’ve shown proof of concept and we do need to start improving. As of right now, the CAR T cells are being used in patients who’ve had at least 3 prior lines of treatment. They should have had a proteasome inhibitor and immunomodulatory drug as well as CD38. And based on what we’ve been talking about today, that would be after your first or second relapse today, since we are combining all of these agents. So think about CAR T cells early. We’re already doing some of the trials which you were talking about, and this is bringing it up front, so we are replacing a stem cell transplant with CAR T cells. We’re focusing right now on the high-risk patient population, but the future would be to do it even for the standard-risk patient population. And the hope is that the earlier we do these CAR T cells, we’re going to start seeing a plateauing of the responses which we, to date, have not yet seen. DR LOVE: So, even the way things stand nowadays, Ken, one of the things about CAR T is that it’s a one-time treatment. And so, patients are then not treated after the CAR T. and even if they have only, let’s say a response a year or so, it’s still being off therapy, which for a lot of these patients is something they’ve never had. Any comments on that? And also the fact — it seems like there’s not as much cytokine release and neurotoxicity. Do you think that’s sort of tied into why it’s not as effective? DR ANDERSON: I think a couple of points. Very good question. I think that part of the reason — firstly, the responses are miraculous, the fact that you can get MRD-negative responses even in such advanced disease is really precedent-setting. There’s no other treatment that accomplishes this. As Noopur already said, I think as we move it earlier, Neil, that we will see more effectiveness when the tumor burden is lower and the therapeutic index is better, I think we will see much more in the way of durable responses. People are trying to select for memory T-cells in the CAR in order to prolong the responses. There are many strategies. But as you said, they are right now used as single agents. Already, as we’re talking here today, combination trials are ongoing as well with maintenance, with lenalidomide, or other agents are being utilized in combination as we do in myeloma otherwise. So I’ve used this analogy with patients, but we have a new CAR that’s approved and it’s a Model T Ford®. So the people who need to drive that car right now are those whose myeloma needs treatment, but we need to have clinical trials so we get a better CAR, Neil, that will be used earlier and more effectively, and I do believe it will be combination. I hope, since we can achieve MRD-negatively so frequently, even in advanced disease, we’ll get MRD-negativity at a higher frequency earlier. We may or may not use maintenance then. But my sincerest hope is that we will not need to use prolonged maintenance when we use the CAR T cells earlier. DR LOVE: So I love that analogy of the car. And Noopur, I guess I’m going to ask you about the upcoming Tesla, which, for example, teclistamab. So what about bispecifics? Where do you see that heading? Do you think it’s going to replace CAR T? DR RAJE: I don’t know if it will replace CAR T cells but having bispecific T-cell engagers is a huge edition to the myeloma treatment paradigm. And what it does here is you’re using an off-the-shelf approach, so there’s no reason to wait on the 3 to 4 weeks which it takes to actually generate a CAR T cell. And what we are using with the bispecific T-cell engager is the patients’ T-cells to create the antitumor activity. So a bispecific is essentially an antibody which targets the antigen of interest and also engages the T-cell, activates the T-cell, brings the T-cells. So essentially does exactly what a CAR T cell does, but it’s off-the-shelf. A couple of things that we’ve seen with all of the CAR T cell strategies so far is again very similar to the CAR T cell world is high response rates where we’re seeing MRD-negative disease. You do see similar toxicity as well, and that similar toxicity is you will still see the cytokine release syndrome, you’re still going to see some level of ICANs or neurotoxicity which is seen with cellular therapy as well. And the issue with bispecific T-cell engagers right now is we are early in development. We’re still with Phase I and Phase II trials as we speak. And we just have to wait on the durability of the responses. The downside here is we are giving these treatments in a weekly or every other week basis, and over the next year or two, we’re going to learn how to use them less frequently, how to manage their toxicities better. The future I think is probably going to be combining some of these strategies, Neil, whether you use CAR T cells first followed by a BiTE so that you do not need protracted maintenance to deepen that response and to improve the duration of response. So again, I think a very exciting area and a lot more to learn about in the next several years. DR LOVE: So, Ken, so many new options now out there and lots of questions about it. So getting a lot of questions about selinexor. Maybe you can talk a little bit about your vision of how it works and particularly the issue of tolerability and what we’ve learned over the last couple of years. I was making the point in the breast cancer program we did about alpelisib, how a lot of the new agents take a while to shake out until you figure out how to give them tolerably. Can you talk about selinexor, Ken? DR ANDERSON: I surely will. Many years ago, Neil, we did, among other groups, the preclinical work, and this selinexor is a nuclear transport inhibitor which is the only drug of its class for multiple myeloma. And it keeps, if you will, gene and gene products where we would like them. So, in your slide that you’re displaying, it keeps tumor suppressors where we want them to suppress, so p53 in this slide, to act as a tumor suppressor. So, it is nuclear transport inhibitor. There are many genes that are changed when it’s utilized. And as you mention, it has been approved in the penta-refractory myeloma and that means in patients who are myeloma refractory to 2 immunomodulatory drugs, 2 proteasome inhibitors and a CD38 monoclonal antibody, and in that context the prognosis is very poor, as has been shown in the MAMMOTH trial with Dr Shaji Kumar and his colleagues. In any event, the challenge here, it’s an oral agent and it has significant GI toxicity. In the original trial, the approval was based on response rate of about 23% and the durability, which was only 4 months or so. But as you’re displaying now here on these slides, the BOSTON trial was then done after it had already been approved, selinexor had already been approved, and selinexor was combined weekly with bortezomib subcutaneously, and now the tolerability was much improved. And as is shown on the BOSTON trial, so this was a trial in relapse myeloma, 1 to 3 prior therapies which compared selinexor and bortezomib with bortezomib and dexamethasone. And there was a significant difference in the progression-free survival. Having said that, I think it’s still a challenge to manage the GI toxicity, one needs to be very aggressive in terms of antiemetics in particular. Many patients lose their appetite and have weight loss. So I think to make your point, Neil, pretty much every drug we have had approved in myeloma we test it on a given dose and schedule. But it’s only really after its FDA-approved, when it gets out into the community that we really learn how to use it in terms of potentially attenuating the dose or schedule so that we can optimize the therapeutic index. DR LOVE: So I can see we won’t get through our list of all the things we want to cover. But I did want to bring up the issue of melflufen, Noopur, another recently approved agent and people are asking about it. For practical purposes, can you talk a little bit about what it is? It’s very interesting in terms of its targeted effect. How you’re using it now? And where you see it going in the future? DR RAJE: So, again, melflufen, this is something they’re quite familiar with. It is an alkylating agent. It has the melphalan as the active agent. But the nice thing about this is it targets in amino peptidase. And by doing so, it’s able to rapidly release the alkylating component of melflufen directly into the tumor cell. And this has been really quite useful. Paul Richardson has led some of the trials here with melflufen with dexamethasone in really heavily pretreated patients. This was the HORIZON trial where the overall response rate was close to 30% with a median duration of about 5.5 months. Now, again, really quite important here was there was a significant number of people who had extramedullary disease and that goes to speak to its effect on the amino peptidases and allowing this drug to enter places where typically we’ve not seen a lot of efficacy. The other thing I will say about melflufen it’s given intravenously. It is given once every 3 weeks. So very convenient schedule and going forward I think this could be part of as a bridge to some of the other things that we’re trying to do, for example, CAR T cells where you can give a dose of melflufen, wait for the 3 or 4 weeks while the CARs are being generated, and then get those on board. So I do think this is going to be useful in that relapse/refractory space to try and get to a place where you’re going to use something more sustained. Introduction DR LOVE: We’re going to be talking about CLL and lymphoma management. We have a great faculty here today. This is our Real World Oncology Rounds we’re making with the Medical Oncology Association of Southern California. Here’s where we’ve been and where we’re heading for today. We’re going to be talking about CLL and lymphomas with Dr Craig Moskowitz from the University of Miami where we’re located in southern Florida, and Dr Jeff Sharman, at the other end of the country in Eugene, Oregon as part of the US Oncology network. So as we’ve been doing today and we’ll be doing all day, we’re basically making rounds with a bunch of general medical oncologists, mostly from the Southern California. We’ll be presenting a bunch of cases here today that we’re going to try to get through; we’re actually going to dive right into the cases and start out with the management of diffuse large B-cell. Diffuse Large B-Cell Lymphoma DR LOVE: And Dr Anthony Nguyen has a patient he would like to get some feedback on. Here’s the case. DR NGUYEN: He was treated with 6 cycles of R-EPOCH with intrathecal methotrexate. And he actually had complete response and was in remission for about 2 years. Then all of a sudden in about September of 2020, he came in with B symptoms, worsening lymphadenopathy, and the PET scan showed PET-avid activity involving the gastric wall. He underwent an EGD biopsy and that was positive. So I put him on R-GemOx and then when I repeated the scans on him, it showed a complete response. I offered him an autotransplant. And speaking to the transplant physician over at the other institution, she recommended instead of autotransplant, because of the condition regimen, she actually recommended CAR T cell therapy. So he’s kind of on the fence about whether he wants to do — whether it’s CAR T cell or whether it will be autotransplant. For the investigators, I was wondering what your thoughts were doing an autotransplant versus CAR T cell therapy? DR LOVE: Any other questions about this case? DR NGUYEN: I know that tafasitamab is indicated with lenalidomide for relapsed/refractory diffuse large B cell who aren’t eligible for autotransplant. So if this patient is deemed not to be eligible for autotransplant, and also not eligible for CAR T cell, or does not want CAR T cell, would tafasitamab be a therapy that you would consider, given that this patient has relapsed after R-EPOCH or even using it instead of the R-GemOx? DR LOVE: So, Craig, a 75-year-old man with recurrent diffuse large B-cell, double expressor mix and BCL2. Can you comment about how you think through relapsed diffuse large B-cell in the older and younger patient? DR MOSKOWITZ: Well, we can begin with this patient who had a 2-year disease-free survival interval and is older. My knee-jerk response is that these patients are not eligible for any cellular therapy, certainly not an autotransplant. And the question is what to do first? To use R-GemOx these days when tafa/len is available and loncastuximab is available now, probably doesn’t make much sense anymore. The results of R-GemOx are uniformly terrible. This patient got lucky, obviously, and had a complete response. So the question — there’s on 3 issues: to stop and do nothing, or to consider consolidation with CAR T cells. And obviously, the data out there in patients older than 70 with CAR T cells is less robust. I just treated a 78-year-old with mantle cell lymphoma who got CAR T cells and she did fine. If you had all the CAR T cells available to you, I think in this age group the JCAR is probably the safest, with the least likelihood of having neurotoxicity. So neurotoxicity in a 75-year-old is not fun. So I would try to certainly avoid Axi-cel if I could. In a younger patient, we just published in the JCO an algorithm that I wrote with one of the junior people, Alvaro Alencar, in the era of CAR T cells and autotransplant. That’s all based upon response to salvage chemotherapy. Doesn’t matter what salvage chemotherapy you want to give. But if the patient achieves a complete response to salvage chemotherapy, less than 70, they should get an autotransplant. You cure close to 50% of the patients in that setting. If the response is a PR or less, then we would recommend bridging therapy to CAR T cells in the younger patient population currently. That would be my take these days. DR LOVE: So, Craig, tafasitamab was mentioned. Can you talk a little bit about what it is? What your experience is with it? And when you use it and how? DR MOSKOWITZ: So I’ve given quite a bit of tafasitamab, and we have a few studies that we’re going to be doing with tafa, investigator-initiated studies. It’s a naked antibody to CD19. In itself, not unexpectedly, it has very little single agent activity. When combined with lenalidomide, surprisingly both the response rate and the complete response rate was rather surprising – a CR rate of 40% in patients with diffuse large B-cell lymphoma with anything in the so-called chronic or palliative setting, is something that should be paid attention to. It’s very important, however, though, with this program is that patients who achieved a CR, and many of the CRs have been prolonged, is continuous therapy. So, even though the median duration response to the CR patients is close to 3 years, all the patients are on treatment. I like the program. It is a little bit too much treatment, it’s weekly x 12, and then you spread out the treatment a little bit. The dose of lenalidomide commonly has to be reduced, especially in the older patient population. But this R-GemOx, this is definitely a much more active program than that particular salvage therapy platinum-based treatment. In my opinion, the only downside tafasitamab, is that it hits the same CD19 target. So if a patient gets tafasitamab and lenalidomide and has disease progression, you always have to make sure you repeat the biopsy and make sure there’s still CD19 expression, because if you want give CAR T cells, obviously the target has to be there. DR LOVE: So, Jeff, just kind of curious, I know you focus more on CLL, but I think you kind of see everything. This patient got CNS prophylaxis with intrathecal methotrexate. We saw some data at ASH that seemed like a question of whether or not CNS prophylaxis actually works. There’s been so much debate about this over the years. Any thoughts about that? DR SHARMAN: I think that this is one of these historical ping pong balls that’s gone back and forth and the perception for quite a while was that intrathecal methotrexate really covers the leptomeninges but doesn’t penetrate into the brain parenchyma. And many of the relapses are parenchymal relapses, and so a high dose systemic methotrexate would presumably cover the brain parenchyma as well. And I think that the data we saw at ASH sort of throws that again into just, I think, reasonable to question how effective these things are. The challenge with all these is that they’ve all been retrospective. It’s hard for me to envision when we’re going to see a huge amount of prospective data comparing the two. I think everybody’s got their preferences and biases. So it’s, I think, a field that lacks to some degree for the nature of the data that’s out there. DR MOSKOWITZ: So I haven’t given intrathecal methotrexate in like 5 to 7 years. I think there’s almost no role for that. I think that’s only treating the doctor. And as Jeff just said, in the era of rituximab, almost all the relapses are parenchymal. So, to do that is – first of all, it makes the treatment unbearable. I usually just give standard treatment and at the end I mop up with 2 doses of high dose methotrexate. And I think most colleagues these days are doing that. Whether or not that works is unclear. But clearly, just giving 6 doses of intrathecal methotrexate doesn’t do anything. DR LOVE: So, Craig, you made an interesting comment about the choice of CART, which, of course, we now have choices. And actually, there was a presentation by Dr Maloney at ASH trying to indirectly — we see this more and more in oncology, you don’t see a head-to-head trial so you try to indirectly compare all different kinds of techniques that can be used. But they attempted to compare the 3. And I’m just kind of curious what you think in general, what you think about that analysis? But also, what you think globally in terms of efficacy, tolerability? Also time for preparation to be available? DR MOSKOWITZ: So this is a tough analysis to do something like this. When I compare these 2, a lot of depends upon what your center does, for example. I think the beauty of Liso-cel is that it is fairly easy — most people can give it as an outpatient. And it’s very clear that Axi-cel cannot be given as an outpatient. And my take of this is, as these come more and more available and everybody’s learning curve becomes equivalent, it’ll be a lot easier to give an outpatient program and be admitted if there’s a problem than just admitting everybody right off the bat. So my personal bias is that in general, Axi-cel and Liso-cel are about equivalent, and Liso-cel is less toxic. DR LOVE: Interesting. Hodgkin Lymphoma DR LOVE: So let’s move on and talk about Hodgkin lymphoma. And Dr Nguyen has a 26-year-old patient with classical Hodgkin lymphoma. And Jeff, I’m going to ask you a second to respond to his questions about this case. Here’s Dr Nguyen. DR NGUYEN: This 26-year-old woman. She’s very healthy. She works as a medical assistant in our area. And we decided to go with BV, brentuximab vedotin, plus AVD. And we had chosen that because of the progression-free survival improvement. Plus, we wanted to avoid bleomycin and the complications of bleomycin for her in the future. And it turned out very well. She underwent 6 cycles of brentuximab vedotin plus AVD. And she actually entered a complete remission. And interesting, her pituitary mass turned out to be a prolactinoma. So my questions for the faculty here is would the faculty consider using BV plus AVD, or ABVD? One of my big considerations for using this, I know we don’t have a lot of data, but this patient, we couldn’t get fertility preservation in a timely manner, and she declined because of the burden of disease at this time. Is there any data or anything that you’ve seen of rates of infertility, comparing brentuximab vedotin versus the ABVD regimen? DR LOVE: Did she have any, like endocrine issues with the prolactinoma? DR NGUYEN: She actually had elevated prolactin levels and she was started on cabergoline. And interestingly she became pregnant on her cabergoline. So that was another interesting development. DR LOVE: What’s her current situation? DR NGUYEN: As far as I know her baby’s growing very healthy. So her pregnancy is moving along well. DR LOVE: So, Jeff, it seems like age-old question, but it’s really only been out there a few years, choice of first-line therapy of Hodgkin lymphoma? How does it vary based on risk status and particularly based on age? Any comments? And any comments about this case, Jeff? DR SHARMAN: Just a few things. I think some of the first part of that got cut out, but I was able to read it. So, for a younger individual, particularly younger women, just sort of as a paradigm, I certainly try to avoid radiation when we can, particularly to the mediastinum for concerns about secondary breast malignancies. And of course the younger you are, the greater that risk. That doesn’t necessarily seem like a huge point in this case because she really had disseminated disease. With the brentuximab-based regimen, there’s definitely more neutropenia than with the bleomycin. So, I think there’s a feeling that some of the efficacy in the clinical trial may have been tempered to some degree by the additional toxicity of the regimen. But in the original protocol they didn’t mandate growth factors. So, if I’m going to use a brentuximab-based regimen I always use it with growth factors. The magnitude of the PFS benefit tends to be concentrated in those patients who are higher risk. And so, I do use brentuximab in the higher-risk population and amongst those patients who are going to get 6 cycles, if they have an interim PET-negative scan and they’re on ABVD with the bleomycin, potentially dropping the bleomycin is another strategy to reduce that, depending upon access and insurance risk. With regard to fertility, fortunately ABVD is not the most difficult regimen with regard to fertility. BEACOPP, the German regimen, and particularly escalated BEACOPP, has very high rates of infertility, universal. ABVD, that number is well under 10% and probably closer to 5%. And I think we’ve just seen some data recently showing that brentuximab-based therapy doesn’t appear significantly different from a fertility perspective than bleomycin. It’s hard to compare these things in small numbers and so forth but doesn’t look like the brentuximab has much of a new or unexpected infertility signal. DR LOVE: So, Craig, I’m kind of curious about your take on this. Of course, I’ve been asking you about this ever since ECHELON-1 came out. These are some data, updated data presented at ASH looking at resolution of, or natural history in terms of peripheral neuropathy in these patients. And also, they had some data on pregnancies. Any comments about this case and this decision? DR MOSKOWITZ: So I think in general patients with Stage IV disease in 2021 should not get ABVD. There’s clear data that BV-AVD is superior for Stage IV disease. And I’ve been doing that for years now. Of course there were concerns about fertility when this started, but now the subset analysis from the ECHELON-1, and we have data, when I was at Sloan Kettering, when we gave quite a bit of BV-AVD in early-stage disease, that there was no impact on either hormone levels or fertility, or babies being born. So that shouldn’t impact your decision on whether or not to give BV-AVD or ABVD as far as initial treatment. The data, as it’s getting more mature, the results with brentuximab is about 7% or 8% better. I think in general, there are fascinating survival curves. The curves split at CR and that’s where there’s less relapses in patients that get BV-AVD. But as far as primary progression, meaning your disease growing on chemotherapy, there’s no difference between BV-AVD and ABVD. That’s where escalated BEACOPP folks champion their program that there’s less primary progressive Hodgkin lymphoma. But we in the United States are not in the escalated BEACOPP camp. Obviously, we’ve chosen in the national study to compare BV-AVD and nivolumab and AVD. So that’s really an important take-home message. I think you probably even have the curves, but the curves splay shockingly at the time of CR. They are parallel on treatment. So they’re really bad actors, those with terrible Hodgkin Lymphoma with active B symptoms and 5, 6, or 7 risk factors. There’s very little difference between BV-AVD and ABVD, as far as achieving a CR. Once you’re in a CR, it appears that the BV-AVD program is superior. DR LOVE: Interesting. So we’re going to move on and talk about CLL. We did so many webinars this past year in CLL and I swear not one of them was the same as the other. Once you start presenting cases, they’re all different. Chronic Lymphocytic Leukemia DR LOVE: We’ve got a couple of cases just to sort of get into the real-world aspect of management of CLL nowadays. Got even more complicated this past year with COVID. This is a 75-year-old man, a real saga here that you’re about to hear in just a minute from Dr Neil Morganstein. This patient was initially diagnosed in 2009, actually got FR at that point and was switched over to BR. And then ended up on ibrutinib when it first came out. And you’re going to hear what happened. Here’s Dr Morganstein. DR MORGANSTEIN: He got treated many years ago with ibrutinib — this is where you see this homerun, you think this is the greatest drug in the world. Lymphocyte count normalized, lymph nodes normalized. He was on it for a long time. He developed atrial fibrillation while on ibrutinib and we treated him through it in conjunction with the cardiologist. And then developed shingles. And this was crippling, okay. And I’d be interested to see of that’s a typical side effect seen with BTK inhibitors and what the appropriate prophylaxis would be. He started to rapidly progress with severe anemia. Never showed any evidence of transformation. He was hospitalized. His white count went up to 400,000. Critically ill, anemic to the point where it was getting difficult to transfuse him, started to develop cardiac and chest pain. Started on venetoclax and despite tumor lysis prophylaxis, including rasburicase, went into tumor lysis. Creatinine bumped. He was critically ill. Didn’t need dialysis, and we were able to get him through it. He did become profoundly neutropenic on the venetoclax. He dropped his ANC down to about 200. Dose reduced him to venetoclax of 200, and now he’s on a dose of 300 mg and actually doing quite well. He does have evidence of disease. So, he’s got a slight elevation in his lymphocyte count, but tolerating medication well, good quality of life, zero side effects. Where do we go next in an elderly person? DR LOVE: So, Jeff, so many questions there. Let’s start out with the early phase of this when the patient was on ibrutinib, before acalabrutinib was even around actually. And this scenario of a patient developing atrial fibrillation while on a BTK inhibitor, nowadays how do you approach that, Jeff? DR SHARMAN: Well, boy, we’ve got 2 press releases out with second generation BTK inhibitors, head-to-head, in CLL against ibrutinib. So, the acalabrutinib and the zanubrutinib have both issued press releases citing statistically significant different rates in acquisition of atrial fibrillation. On account of that, for the most part, when given freedom of choice, will frequently use acalabrutinib. Zanubrutinib, of course isn’t approved yet in CLL but getting that isn’t necessarily impossible. So, I do like the novel BTK inhibitors. It’s perfectly fine to treat somebody with atrial fibrillation and I think you’re going to just see that some patients aren’t tolerant of their atrial fibrillation and need to stop therapy either because it’s recurrent or they need cardioversion or they’re very symptomatic when they develop atrial fibrillation, or, as is the case in many patients, you can continue BTK and either give them rate control with anticoagulation as appropriate, typically avoiding warfarin and using the direct oral anticoagulants, which is what they had done in the studies. That at least addressed the first part of this case. But you’re right, there’s a lot of aspects here. DR LOVE: So, Craig, I guess we’re actually going to see, and Jeff mentioned the 2 press releases, here’s the first one from the ELEVATE-RR trial comparing directly in a Phase III trial acalabrutinib with ibrutinib. And the other press release Jeff was referring to with zanubrutinib, again no specific data here other than non-inferiority. But it says in the title superior ORR and reduced rates of atrial fibrillation or flutter head-to-head. Any thoughts where we’re going to be landing by the time we see these 2 data sets, Craig? DR MOSKOWITZ: Well, I agree with our colleague who presented the case. When ibrutinib came out it was a miracle. It was a miracle drug. And those of us who are little bit more mature, that have given ibrutinib now for a long time, have seen the side effects become more and more common. A good analogy is the cholesterol drugs quite frankly. They all seem to be about the same but as you make a new one, they tend to be equivalent with less side effects. And you tend to get the newer drug. I’m on a cholesterol lowering drug and I’m on a more modern one. And it’s probably similar with ibrutinib. It’s very clear that acalabrutinib and certainly zanubrutinib, is less toxic than ibrutinib. And quite frankly, the LOXO-305, which we’ve been studying, patients don’t even know they’re taking anything and there’s almost no side effects. So that’s another drug I guess that will be a third-generation drug. Jeff has more experience in CLL than me, but that drug — that’s a beautiful drug. Now my take is, if a patient’s on ibrutinib, they’ll continue ibrutinib. But if you need to start something new, it seems naïve, in the current state, to start ibrutinib when you have other drugs that available and are less toxic. DR LOVE: So, we’ll see how these new data look and then reevaluate. I want to go back to this case though, Jeff, in terms of when the patient ended up in the hospital, it sounds like really dire situation when he got started on venetoclax. Actually, had TLS in spite of their best attempts to prevent it. Very, very sick, as you heard. Any comments about that part of the case, Jeff? And in general, your experience using venetoclax, usually with obinutuzumab, particularly in these very sick patients? DR SHARMAN: This transition is really rich in this case and there’s a bunch of different ways you could talk about it. We’ve seen in the ECOG frontline study that for patients on frontline ibrutinib who stop ibrutinib for one reason or another, oftentimes they can get up to roughly 20 months of disease control even after discontinuation before they might need a new therapy. This is a relapse patient, so it’s not surprising that that’s going to be slower. The one thing I would typically do in this situation is I would — before starting acalabrutinib in a patient who’s relapsing after a BTK inhibitor, is I might check to see if they have a cysteine 41 serine or a PLC gamma mutation. Those would render acalabrutinib ineffective. And you could potentially know that in advance. And it sounds like this patient only got a short duration of benefit from acalabrutinib and I kind of suspect that there might have been an underlying mutation there. The other thing is it is very different to stop a BTK inhibitor in a CLL patient who’s in good disease control. It is much more challenging to stop a BTK inhibitor in a patient who’s already progressing. They have a higher burden of disease; it’s already moving. And I think that the BTK inhibitor plays a very suppressive role in somebody who’s progressing well on therapy. And when you stop the BTK inhibitor, you can really get this very explosive disease and you can almost get this critically ill phenotype that’s being described by Dr Morganstein, just from simply stopping the BTK inhibitor. Finally, the last piece I’ll try to make is if you know that venetoclax is your next line of therapy, I typically try to do that relatively early on so that you if you know a patient’s moving in that direction I try not to wait too, too long. Because you find yourselves in these situations where, with a white blood cell count of 400,000, there’s nothing you can do to stop that TLS freight train, I meant that’s coming at you based upon the patient’s presentation. So, when you see that patient failing BTK I would move early. And then the last part I would just comment on this is for patients who have transient or low-level lymphocytosis on venetoclax, I’d probably get a flow cytometry on that to see if it’s CLL. We shouldn’t be seeing circulating CLL for a patient on venetoclax. And if you are, that patient’s going to have a very short duration of benefit for venetoclax. So I’ll be thinking about what that next line of therapy is. And that’s going to enter you into what we call the double-refractory population, refractory to BTK, refractory to BCL2, where there’s a lot of development going on right now as Dr Moskowitz indicated with pirtobrutinib, CAR T, and to some degree the PI3 kinase inhibitors may have a role in that space, although their level of efficacy in that setting is unclear. DR LOVE: I wanted to ask you, Craig mentioned LOXO-305, as you mentioned now with the name pirtobrutinib. And Dr Morganstein was bringing up what’s next in his patient, if he needs something, which he probably will. Any thoughts about pirtobrutinib, Jeff, and where you see it heading? I mean are there first-line trials? DR SHARMAN: Pirtobrutinib is a fabulous drug. I agree with the characterization by Dr Moskowitz. We’re conducting a study currently amongst patients with prior BTK exposure, so you had to have had prior covalent inhibitor. And it’s going to be randomized to pirtobrutinib versus a PI3 kinase inhibitor. Pirtobrutinib is a fabulous drug and works well even once the covalent inhibitor stops working. So resistance to ibrutinib, acalabrutinib, zanubrutinib can occur through the acquisition of these mutations, pirtobrutinib still works. So you get the benefit of going after that target even after those other drugs have failed. So, pirtobrutinib is coming and thank goodness it’s going to be a great drug. DR LOVE: So, let’s hear another case. You can hear cases of CLL all day long and no two are ever the same. This is Dr Gigi Chen talking about a 66-year-old lady who got acalabrutinib, actually doing very well in remission, but an interesting tolerability or side effect that came up. DR LOVE: So how long has she been on the acalabrutinib now? DR CHEN: A couple months. It’s interesting. She’s overall tolerating very well. She does have tachycardia on the acalabrutinib, and I did send her to cardiology. Her echocardiogram was completely normal. She had Holter monitoring, which showed this episodic tachycardia. But she opted to continue with the treatment at this time. She does have a medical background, and she’s very much in tune in terms of how she feels. DR LOVE: No headache? DR CHEN: No headaches. We talked about multiple treatment options with her, ibrutinib, acalabrutinib, venetoclax. And I think at that time acalabrutinib was the newest approved medication, and the side effect profile looked good. Efficacy looked very good. The role of MRD is a question that we’re hearing more in the academic setting, but how do we apply that in the community setting? So, if this woman were to present today, a very healthy woman in her late 50s, presents with symptomatic CLL, IGVH mutated, would the best treatment option still be FCR? DR LOVE: So, Craig, I should have mentioned that she actually initially was treated with FCR in 2012 and then switched over to BR and didn’t relapse until 2020. So, first question is, is there any role still for FCR or chemoimmunotherapy, particularly the mutated patients? And the other question is have you seen sinus tachycardia with BTK inhibitors? DR MOSKOWITZ: So, Jeff might disagree with me, but I’m never giving fludarabine again. That ship has sailed a long time ago. I’ve taken care of a number of patients with lymphoma that have died from MDS/AML that got fludarabine-based treatment. So I’m not doing it anymore. So, the real question is in a favorable patient who needs to be treated, I don’t see any reason not to give a BTK inhibitor, so I would do that. As I stated before, I’m very comfortable with giving any of the BTK inhibitors. I would try to put the patient on a protocol especially if they’re untreated. Off of protocol, I’ve been starting patients with acalabrutinib over ibrutinib these days. I have not seen intermittent tachycardia with acalabrutinib. I have seen quite a bit of rash, which sometimes can be difficult. Obviously, the patients get headaches. And down here in South Florida, we just tell them to take a shot of Cuban coffee. But I have not seen intermittent tachycardia. I don’t know what my colleagues have seen. But I first would make sure it’s related to the drug quite frankly. DR LOVE: Well, she’s on therapy and doing well. Jeff, any thoughts about this case? And also, Craig’s disavow of ever using fludarabine again. How about you? DR SHARMAN: Patterns of care currently show that in the United States, chemoimmunotherapy in the frontline setting is down to about 10% to 15%. I think that’s probably still even a little bit high. When we have advisory boards discussing patterns of care and so forth, there’s some split amongst sort of key opinion leaders as to whether or not FCR has any role anymore. There are some people who will still give it for very young, very fit, molecularly favorable patients and those are you mutated with favorable FISH. And I go the extra mile in those patients and I’m going to look for TP53 mutations. Any of those being sort of disqualifying for chemoimmunotherapy. But, boy, if give FCR once a year that’s about it. For somebody who’s young, I think the fixed duration benefit of an obinutuzumab/venetoclax regimen is very appealing. A lot of times these folks don’t wish to be on therapy indefinitely. And I find that obinutuzumab/venetoclax is very well tolerated in the frontline setting. And we have 4-year follow-up data from the German study showing at 4 years you still have about 75% - 80% of patients who are progression-free. So, it’s a very effective regimen for 12 months of therapy. And that’s commonly use in a younger population for whom fixed duration therapy is often times very appealing. COVID notwithstanding, with COVID I have probably given more BTK inhibitor than obi/ven. There’s definitely plenty of emerging literature that shows vaccine response, post-CD20 antibody, is considerably diminished. And amongst my colleagues when we discuss cases of COVID breakthrough, there’s almost always a CD20 antibody in the picture. DR LOVE: Interesting. Suwanee in the chat room says when do you use venetoclax/obinutuzumab and when do you use a BTK? So that has been a question we’ve talked about a whole lot this last couple of years. I’m curious about your general approach, Craig. And the other question that Dr Chen brought up about MRD. In what situations, if any, do you change what you do, for example, at the end of the venetoclax/obinutuzumab? If they’re MRD-positive, would you consider continuing treatment? DR MOSKOWITZ: So I also give a lot of obinutuzumab/venetoclax. I have found it to be very easy to give, other than for cycle 1. So, I am a big fan of that. As far as assessing MRD at a year, it depends on how sophisticated you want to be. I would be comfortable stopping and have in patients who were MRD-negative. And those patients who are MRD-positive, I have a discussion with the patient. I think most people even so, want to stop treatment and take a break. But obviously, the treatment can be continued at various schedules if that what shows. But honestly, I have an open dialogue with the patient at that particular point. Because when you initiate that treatment, it’s the implication that it’s going only be a year and the patients are so excited that they’re going to stop that you tend to have to regroup at the 1-year point. DR LOVE: So, I’m curious. One final question back to you, Jeff, in terms of TLS prophylaxis. Again, in the era of COVID, still trying to keep people out of the hospital, out of the clinic, do you still follow the package insert approach? Do you ever try to accelerate that? And in terms of the approach to it, do you find that starting with obinutuzumab has a big impact on TLS risk, and, therefore, that ameliorates a lot of the problem? DR SHARMAN: So we’ve run a study asking exactly this question, what benefit do you get out of TLS prophylaxis with obinutuzumab? And it’s a pretty clear answer, you quickly eradicate the lymphocytosis and you don’t do a whole lot to the lymph nodes with 2 months of obinutuzumab. So, it depends on how somebody qualifies for their higher risk, because both lymphocytosis and lymph node size factor into that. But for a patient who’s predominantly leukemic or doesn’t have a whole lot of lymph nodes, giving that running of obinutuzumab makes pretty much everybody low risk if they start at less than 5-cm lymph nodes. I think the key thing here is that oncologists have to look at the scans themselves. Radiologists are trained to measure lymph nodes and they do so by measuring from one edge to the other edge. But you could have aggregate lymph nodes and matted adenopathy in the retroperitoneum where maybe the individual lymph nodes are only 3- to 4 cm, but in total it’s 12 to 14. And where I have seen people get into trouble is leaning too heavily on the radiologists who define what tumor lysis is and you just simply have to look at those images for yourself. Follicular Lymphoma DR LOVE: So we’re going to move on now and talk about management of FL and Dr Amanda Blackmon has a young patient, 50 years old, Stage III, Grade 1 to 2. FL. Interesting choice of initial therapy. Here’s Dr Blackmon. DR BLACKMON: This is a 50-year-old who presented to me initially with diffuse adenopathy. We didn’t treat him initially. We watched him. And then his fatigue got so bad that he actually quit his job and he wanted to be treated. So, we treated with R2 instead of R-chemotherapy. And I’ve had some mixed opinions on which one would be better in terms of treatment choice and just to discuss the RELEVANCE trial and which patient populations you would choose, one versus the other. DR LOVE: So, what’s his current situation? DR BLACKMON: He is in a CR and doing well after treatment and we’re now 2.5 years out. I would like to know the panel’s opinion on R2 versus R-chemotherapy. Does the extent of this patient’s disease have any influence on which regimen you would choose? DR LOVE: So, Craig, I was kind of surprised when the RELEVANCE trial came out. It kind of seemed like not a very enthusiastic response to using R2. Now it’s been a couple of years, how’s it shaking out in your practice, Craig, in terms of upfront management? Still sticking with BR or sometimes using R2? DR MOSKOWITZ: So, the RELEVANCE study was a protocol that was not written well. That’s probably the only way to describe it. It was an underpowered study to look at the superiority of R2 over BR. And it did not meet its endpoint because it was not superior. It is, however, fairly equivalent to BR, so you have to keep that in mind. So, of course, it didn’t really get approval in the first-line setting because it did not meet its appropriate endpoint. That doesn’t mean it’s not given. So that’s one point. The second point is always somebody with tremendous fatigue and diffuse adenopathy should get a PET scan and make sure there’s not a disparity in the SUVmax, in any of the lymph nodes, especially if SUVmax’s are in the 12 to 15 or 16 range — that has to be biopsied to make sure you don’t have de novo transformation. But making believe that everything is okay, I give BR, usually still, to patients with follicular lymphoma. I do it for one reason, I actually think it’s better tolerated than R2. It causes much less fatigue. It’s al to easier to give. There are no dose reductions. And then the question after that of maintenance is dependent upon the investigator and the patient of whether or not you want to do that or not. Obviously, if you’re thinking of doing that, the marrow has to be negative and the PET scan has to be negative. I continue to give BR as opposed to R2, but I do commonly give R2 in first relapse off of a clinical trial. If that helps answer your question. DR LOVE: Yes. So let’s hear another case of FL also from Dr Blackmon. This young woman, 37 years old, starts out in 2013, gets R-CHOP, then BR. Then R2. Copanlisib. And now on tazemetostat. So, I’m going to be curious to see what Jeff has to say about this new agent. Here’s Dr Blackmon. DR BLACKMON: She is a 37-year-old that was diagnosed in 2013. She initially got R-CHOP. Then she relapsed and she was started on BR with response for 6 months. She relapsed again. She was started on R2. She progressed after 6 months on R2. She received copanlisib. She did have a response for 1 year. She has now relapsed again, and this past month was recently started on tazemetostat. She’s EZH2 negative by peripheral blood. Some of my questions are should we be testing EZH2 before starting this treatment? Or given the fact that it has activity in wild-type patients, would you test it at all? Can you test on peripheral blood or do you need to rebiopsy this patient? And then given her young age, should we be considering a CAR T or a BiTE treatment? And then the role for transplantation, either an auto or an allogeneic transplant? DR LOVE: So, Craig, a lot of questions there. First, can you talk a little bit about what tazemetostat is? And maybe a little bit about how you utilize it in your practice? And also, her question about how you factor in EZH2 levels? DR MOSKOWITZ: So, I’ll answer the second question first. In a patient who’s heavily pretreated like this, they should have NGS sequencing. And I would only give an EZH2 inhibitor if there’s a mutation. I hope that answers your question. I do not give this drug in patients with lymphoma, outside of a mutation. And I don’t specifically test for this mutation. I will already have had the results because I would have sequenced the patient earlier. In a 37-year-old who’s had 5 treatments for follicular lymphoma, this patient is going to die from follicular lymphoma unless, in theory, they get some type of consolidation, typically my knee-jerk response would have been that she would have already had an allogeneic stem cell transplant. However, in the era of CAR T cells, and as you know the Axi-cel equivalent study in follicular lymphoma was approved. I would be okay with a person who has a short remission duration, like this patient had, and as you know patients with an initial remission duration of less than 2 or 2.5 years, they’re going to have problems with follicular lymphoma. I would be okay giving this patient CAR T cells as sort of like a third treatment with such short remission duration as opposed to giving additional chemotherapy and bridging that to an allogenic transplant because I don’t really know if they’ll be a long-term, disease-free interval with CAR T cells. And I do know that the technology in allotransplantation is ever improving, and if I can wait, I’d rather wait. So, this particular case in a 37-year-old, everybody who’s listening knows this is going to be a problem and they’re going to need something a little bit more significant that’s curative. To continue giving them chronic treatment when we know it’s going to be an issue, I would really just rather get it over with and give them some type of treatment with curative intent. DR LOVE: So, Jeff, any thoughts about some of these issues? Also, your experience with tazemetostat? And sort of flipping into the other end, when you see a more typical patient in their 70s or 80s, how you think through patients with multiple relapses, Jeff? DR SHARMAN: So I very much highlight the point made by Craig, that after this patient got BR and had 6-month relapse, that’s where the search for a permanent solution has to really kick into high gear, because nothing is going to work for long for this patient. And to me, something like tazemetostat or copanlisib is really only, in a young patient like this, serving as a bridge to something definitive because both allo and CAR T do take some amount of time. I do want to highlight I think maybe underserved in this entire discussion is the emerging role of the bispecifics. These are very, very effective medications. And I think that their availability, meaning you don’t have to prepare them the same way you’d have to prepare a CAR T is very exciting. And I think that is also something that could serve as a bridge for this patient. So, probably before I put this patient on tazemetostat, I would be contacting colleagues at centers that have those sorts of antibodies. Tazemetostat is well tolerated. I don’t think it has a whole lot of side effects. Patients generally do well on them. In the community setting, sometimes it’s harder to get access to testing, but that would be from a tumor sample, not so much from peripheral blood. And I have been using it in the unmutated population, sort of with the expectation that its lower response rates, but the duration of control is similar. But that’s primarily in settings where it’s a very palliative approach. And I think in follicular lymphoma we’re lucky that we have so many new options that are looking very effective. And I think before I get to tazemetostat, I would be trying to get that patient to either a bispecific or a CAR T study. Mantle Cell Lymphoma DR LOVE: So let’s talk a little bit about mantle cell and we have a case in a second, I want to run by you. But first, audience, just kind of curious, if you’ve got an older patient — we’re saying 78 years old — who gets upfront treatment with BR and gets R-maintenance for 2 years and then 3 years later with mantle cell, relapses. In general, what are you going to be thinking next? It looks like we’ve got acalabrutinib and zanubrutinib about equal, and some R2, but mainly the biggest two answers that are about the same in the audience, Craig, is acala and zanubrutinib. Can you talk a little bit about how you think about second-line therapy in mantle cell, Craig? DR MOSKOWITZ: So, first I would repeat the biopsy and make sure there’s not a p53 mutation. If there is, then there’s trouble coming. That’s number one. Number two, in someone who’s 78, I still think it’s a possibility that the patients can get CAR T cells. As I said before, I just treated a 78-year-old with CAR T cells, a little bit more heavily pretreated than this patient, and she’s in CR, but only at day 100. So, I always keep that in the back of my mind. Once again, in 2021, nobody would start with ibrutinib these days. Whatever you’re more comfortable with, either zanubrutinib or acalabrutinib is fine. I’ve given very little zanubrutinib. I’ve either given acalabrutinib or I’ve put patients on the LOXO study. So, my experience with zanu is not as extensive. I will say though, that we are opening up a study with tafa and zanubrutinib in first relapse mantle cell lymphoma in patients who are transplant-ineligible that will move to upfront. So, I do think it’s a great drug, zanubrutinib, but my personal experience with it is not high. So, I hope that answers. I would usually give acalabrutinib and then I would discuss the issue about CAR T cells with this patient. DR LOVE: So, let’s bring in a real case, again Dr Blackmon has a 50-year-old patient with blastoid mantle cell, who starts out with the Nordic regimen, goes for a transplant. R-maintenance. But then 15 months later relapses. Gets ibrutinib. Interestingly, the ibrutinib was stopped because of mucositis. I’ll be curious what Jeff has to say about that. Then went on a clinical trial, got CAR T. Progressed. And then got acalabrutinib. Here’s Dr Blackmon. DR BLACKMON: This is a 50-year-old male who had blastoid mantle cell lymphoma diagnosis. He received the Nordic regimen with a molecular CR. He had an autologous transplant with rituximab maintenance. He relapsed at 15 months post-transplant. He was treated with ibrutinib, developed severe mucositis, so this was stopped after 3 weeks. He received a CAR T with liso-cel on a clinical trial. He had a refractory 30-day PET with progression. Started on acalabrutinib and went into CR within 1 month. He’s now 5 months status post an allogeneic transplant. This is a case of acalabrutinib use in a patient intolerant to ibrutinib. The question here is should acalabrutinib maintenance be used in this patient? Are late responses being seen after CAR T therapy in mantle cell lymphoma? This patient went into a remission about 2 months after his CAR T and we’re attributing this to acalabrutinib, but he did receive the CAR T. DR LOVE: So, interesting question there. Jeff, I know you were involved in the development of BTK inhibitors. Do we know about mucositis with BTK inhibitors in ibrutinib? And any thoughts about this case in particular? DR SHARMAN: So, I really chuckled when I saw that looking through the slides last night. I presented a case of mucositis from ibrutinib on one of your prior programs. DR LOVE: Good memory, Neil. DR SHARMAN: I think I surprised you then, but the other panelists hadn’t heard of it either. Yeah, you can. It’s not common. You see it in, oh, I’m guessing it’s a 2% to 3%, but it you’ve seen aphthous stomatitis or you’re prone to canker sores. But I’ve had 2 patients where you simply could not give ibrutinib and then the alternative BTK inhibitor was considerably better tolerated. So, rare. I don’t know if it’s an EGFR phenomenon. There is some EGFR activity in ibrutinib, but it’s not a lot. What’s so fascinating about this and I sort of want to run this one past some of my colleagues in the CAR T space, so in CLL it looks to be the case that CAR T works better in the setting of BTK inhibitors, and it probably has to do with the way that the B-cells and the T-cells interact. And the B-cells themselves are fairly immunosuppressive, and when you reverse that immunosuppression, you enable those CAR T cells to work better. And that raises the question, getting a CR off of 1 month of a BTK inhibitor in mantle cell lymphoma, you don’t see that. So I have to think that this is a patient who did get some form of synergy with the CAR T. There’s a lot of effort to look at ways to salvage those CAR T patients who aren’t working, whether that’s giving them bispecifics or lenalidomide or PD-1. There’s a lot of different ways you could do that. And the BTK narrative is mostly built around ibrutinib in this situation, but we’ve wondered whether or not the other BTK inhibitors could work. And it appears that may have been the case in this particular patient. DR LOVE: So, Craig, we were talking about LOXO-305 or pirtobrutinib, and I’m curious about its efficacy in mantle cell. This is a waterfall plot, with mantle cell specifically. Craig, any experience with LOXO-305? And also, venetoclax in mantle cell, Craig. Where does that fit in in your menu or your sequence? DR MOSKOWITZ: I’ll start with the venetoclax. I have found venetoclax to have very fleeting responses. And even the patients in CR, the response duration is very brief. So, you must have a plan of attack if you’re starting venetoclax. There has to be something that’s coming quick. I used to give venetoclax as a bridge to an allogeneic stem cell transplant in patients with mantle cell lymphoma because you could get a robust, quick response, but you had to have your act together. LOXO-305, once again I’m going to state this again, I think will be the best of the BTK inhibitors that we have available, at least of the 4. I’m sure there are many more to come. Many of the patients on that waterfall plot may have had BTK inhibitors already. So, I think it’s a drug that in my personal experience is well tolerated. And I expect that it will be very easy to combine with other drugs. So, I expect it to get approved. And I also suspect that the IIT program that the company’s going to have is going to be very broad. DR LOVE: And actually, at the ASCO meeting there’s a paper here looking at venetoclax with R2, lenalidomide and rituximab. We’ll see where that ends up. Any thoughts Jeff, about CAR T in mantle cell? It seems like it’s quite effective. What do we know in terms of how it’s tolerated? Cytokine release? Neurotoxicity? And how do you sequence it, Jeff? DR SHARMAN: Well, I mean mantle cell is an incurable disease and it tends to be older folks who get it. And because of the age, there may be some difficulty with CAR T, but CAR T will have an important role in this disease. A lot of patients, they get their autotransplant upfront so you’re not looking at auto as salvage. Currently, it’s approved in the third line setting. And I think that involving your CAR T center early on enough that they know the patient before they get to that stage I think is useful. And I would like to believe that CAR T is going to become more broadly accessible. I think that’s one of the biggest challenges for CAR T right now is that it remains primarily the domain of large academic medical centers, which is appropriate in many ways, but it does make access quite a bit more challenging for many of the older individuals who may not be able to relocate for a month at a time. So, anyhow, how do you sequence it? It’s currently approved in third line clinical trials. It’s a potentially definitive solution, very high response rates that appear to be quite durable. DR LOVE: Craig, any final comments about mantle cell and strategies moving forward that you’re excited about in the disease? DR MOSKOWITZ: I think that, once again, the role of p53 mutation cannot be understated. There’s probably no role for an upfront transplant in patients with p53 mutated mantle cell lymphoma. So, when you’re doing the pathologic workup make sure that that’s done. If it is, then A) try to get the patients into remission and move towards a CAR T cell approach earlier if you can. The real issue with mantle cell lymphoma is do people need to be getting this aggressive chemotherapy upfront with all of the novel agents that are available. Many times now patients are getting ara-C and platinum-based upfront treatment and that may not be necessary when we have a rare disease that has like 10 drugs approved in it. And many of us are trying to come up with outpatient, more user-friendly programs to get the patients into remission and then making a decision tree that happens at the time of CR. I think that that’s the wave, almost certainly. And with these newer generation BTK inhibitors, with new generation anti-CD19 drugs, including tafa and loncast, I think you’re going to see a change in the management of mantle cell lymphoma. Introduction DR LOVE: Alright, let’s talk about GU cancers as part of our Real World Oncology Rounds here today with the MOASC group. We’re going to talk now about the management of GU cancers, what’s new? We have Dr Joaquim Bellmunt from Beth Israel Deaconess Medical Center and the Harvard Medical School, and we have Monty Pal from the City of Hope to talk about bladder cancer, prostate cancer and renal cell cancer. So much going on. And of course, we have a bunch of general medical oncologists presenting cases. We’re going to jump right in with prostate cancer. Prostate Cancer DR LOVE: I’ll begin with a patient of Dr Nguyen, an 86-year-old man who presented initially biochemical recurrence after local therapy and then was found to have metastatic disease. So the question of how do you manage hormone-sensitive metastatic disease in an 86-year-old man? Here’s Dr Nguyen. DR NGUYEN: He’s an 86-year-old gentleman with initially Gleason score of 3+3, T1N0M0 Stage II prostate cancer. And he was treated with proton therapy. And he had biochemical recurrence after 3 years. His PSA rose rapidly from 2.8 to 76 over 2 years. I did an MRI of his abdomen and pelvis and the pelvis showed inguinal lymphadenopathy, suspicious for metastatic disease. And he was started on q3month leuprolide injections with down trending PSA. And due to his older age, I didn’t add anything else onto his treatment. So, my question for the faculty is, given this gentleman, 86-year-old, very, very, ECOG of 0, I was wondering if the faculty, would you consider adding abiraterone, enzalutamide or apalutamide for this patient? Or would you wait until the patient progresses or if the PSA rises? In younger patients with lymph node involvement, would you consider using docetaxel upfront even though the patients do not have a high burden of disease? DR LOVE: So, Joaquim and Monty, welcome. Thanks for joining us today. And I want to start out with M0 situation because Dr Nguyen was telling me that the Rad Onc was following the patient, watching the PSA go up. By the time he got to Dr Nguyen, he had metastatic disease. So let’s just start out first talking about when to treat M0 disease, Monty. In the past, doubling time has been key. I think they missed the window here. This patient ended up having metastatic disease. Any comments though about you approach the initial use of ADT, Monty, in a patient who has M0 disease, assuming they’ve already had either radiation therapy primarily or after surgery. DR PAL: I think you’re absolutely right, Neil, in this scenario we probably could have jumped in a little sooner with ATD. Any time I see a doubling time of less than 10 months I’m really prone to suggest use of intermittent androgen deprivation therapy. Now with the approval of relugolix, we have an oral option that probably confers less in the way of cardiovascular risk. So, I think the risk-benefit ratio is really sort of tilting towards offering ADT earlier in patients like this. DR LOVE: So, Joaquim, I’m curious about your thoughts about when you pull the trigger? In the past, people thought these patients were getting overtreating. This is a situation maybe the patient might have benefitted from earlier therapy. How do you approach that? And also, what about the choice of ADT? As Monty mentioned, now we have an oral agent. How are you factoring that in? DR BELLMUNT: So, in the situation of rising PSA, post local therapy, what Monty has said, something that we need to take into consideration is the PSA doubling time. In this patient, if you see — in addition to the PSA doubling time and when his PSA starts rising up. So, as later the PSA starts rising up, and whenever longer is the PSA doubling time, then the likelihood of having still local disease or some area that you could treat with any local therapy is something to take under consideration. So, in this patient where Axumin scan could help, but as mentioned, this gentleman had a pretty short PSA doubling time. Usually we say that less than 10 months is a PSA doubling time that likely the patient might have widespread disease, not locally disease, but it’s something that at some point that if you see this situation, we need to question is there still any way to rescue this patient with any type of local therapy? If the patient even is having oligometastatic disease, could we use radiation therapy in these oligometastatic areas? And obviously, as mentioned, when the PSA doubling time is that short, that is when you might decide to start hormonal therapy. DR LOVE: So, Monty, getting back to the choice of ADT, any comments, not just in the M0 situation, but all through metastatic disease, when you think about an antagonist versus an agonist? And any thoughts about using an oral option as opposed to parenteral? DR PAL: When it comes to leuprolide versus the conventional oral therapy, I tend to sort of stay away from the traditional agents like bicalutamide. I think now with relugolix we have a very well-tolerated option, something that, as I noted before, confers less in the way of cardiovascular risk. To me, it’s a relatively straightforward option. If I have a patient who has metastatic disease, like this patient ultimately developed, then it’s a little bit more of a toss-up. There’s the constraint of starting on an oral therapy chronically, the patient has to remember to take dosing and remain compliant for the rest of their life. In that scenario, I might start with an injectable agent. But it’s a bit of a toss-up there. DR LOVE: So, Joaquim, what about the patient who has M0 disease, no evidence on even sophisticated scanning of metastasis but is progressing on ADT? We have several options available in terms of adding in endocrine agents. How do you think that through? DR BELLMUNT: So then we will be jumping on the M0 castration resistant, meaning it’s a patient that the PSA is rising despite castrate levels of testosterone. So, in that space, if we’re talking this patient is progressing is when we have now 3 agents approved, that is apalutamide, darolutamide and enzalutamide based on the SPARTAN, the ARAMIS, and the PROSPER trials, where these agents in this M0 CRPC, castration-resistant, because, also, we need to consider that these agents, apalutamide and enzalutamide, and also abiraterone, are approved in patients with M1 hormone sensitive. But we are talking now specifically in patients that the PSA is rising, there is no evidence of metastatic disease, using conventional radiological approaches — that is something that nowadays we might need to talk further — in this situation, M0 CRPC we have, as mentioned, based on these trials, that have shown a survival advantage, the SPARTAN, the ARAMIS and the PROSPER, apalutamide, darolutamide and enzalutamide, might play a role adding these agents. DR LOVE: So, Monty, how do you make the decision between these 3 agents? We hear some people believe that darolutamide is better tolerated, less CNS penetration. How do you make the choice between these agents, Monty? DR PAL: It’s a challenging choice. And as Joaquim had mentioned, I think this is a vanishing space. As our imaging starts to improve with PSMA PET and Axumin scans, as Joaquim had mentioned, I think we’re going to recognize that a lot of these patients that we’re calling M0 CRPC are actually M1 patients. Having said that, between those 3 agents, I probably have the best experience so far with apalutamide. You do have to be prepared to manage the rash that may be associated with the drug. I have found that it causes much less in the way of fatigue. I’ll also say, and I’m sure we’ll talk about this later, that I’ve been impressed by some of the data that’s associated with apalutamide as it pertains to quality of life for M1 CSPCs. So, with those parameters, I think apalutamide tends to be my go-to. DR LOVE: Interesting. I want to bring in the audience now and ask about this kind of situation that we’re talking about now, which is metastatic disease, but we’re going to say it’s an older patient, 80 years old, and the metastatic disease is 3 asymptomatic bone mets. This is a patient who is on ADT already, now develops metastatic disease. The question is what, if anything, you’re going to add to it? So, audience, just kind of curious how you would think this thing through? Would you use hormonal therapy in this patient in general? Would you use chemotherapy? Docetaxel? Would you just use ADT and wait and see how they respond to the ADT? Let’s see how the audience is voting on this thing. Actually, abiraterone looks like it has — abiraterone, apalutamide, enzalutamide kind of split pretty much between the 3 of them. So, Joaquim, how do you think through endocrine-sensitive disease, particularly in an older patient? Is it reasonable to just use ADT or do you think it general something should be added to it? DR BELLMUNT: So I think that that’s really an interesting question and I sometimes end up asking people, senior or people with huge experience, is maybe in these asymptomatic, low volume metastatic, hormone-sensitive, do we need to add one of these agents that are expensive, have potential toxicity? And the answer they say, well, now we have randomized trials that in that space of metastatic, hormone sensitive: abiraterone, based on the LATITUDE and STAMPEDE trial, apalutamide based on the TITAN trial, and then enzalutamide based on ENZAMET, those are agents that you might consider. And here is when you need to take under consideration the comorbidities of the patients. We know that abiraterone is the one that has been widely used, you need to add steroids here, and some patients are unable to receive steroids. Other patients have mental problems and then enzalutamide, in some patients, this might be an issue. So, the decision of the drug to use, it’s based on experience. We are much more used to using abiraterone in that space, but other drugs, as mentioned, apalutamide and enzalutamide, need to be considered. DR LOVE: So, Monty, what about the option of chemotherapy? Before COVID, a lot of people were talking that up. You kind of get it over with and I heard that people like that, although it is chemotherapy. Now we had COVID come along and initially, there was — I think a lot of people were pulling back from chemotherapy. Now I think maybe people are more comfortable. So today, Monty, what is a patient where you might use chemotherapy as part of the upfront treatment of endocrine-sensitive disease? Does age or disease volume matter? DR PAL: Certainly, they both play a role. I would argue that in a much younger patient and certainly in one with much more extensive disease, I would favor use of chemotherapy. In an older patient like this, I’ll have the conversation but inevitably, my experience really mirrors a lot of the data out there from real world studies that shows that utilization of chemotherapy in this space is exceptionally low; it’s a small percentage of patients that are actually getting chemo ultimately. And I think it boils down to the conversation of the patient — they’re not excited about the risk of infection, neuropathy, fatigue, etc, that comes with the chemo. So most are steering away from it by and large. DR LOVE: So, I want to move on and talk about another issue that’s come about in the last couple of years in terms of prostate cancer in the metastatic setting and of course this is an issue in a number of other situations the use of PARP inhibitors. PARP inhibitors are also now part of the management of metastatic prostate cancer, and Dr Helen Moon has a 65-year-old patient with a germline BRCA2 mutation. Here’s the case and here are her questions. DR MOON: There are 2 drugs that are FDA approved in this particular field. One is rucaparib with a very tight approval of just BRCA1 and 2. And the other is olaparib. And olaparib is a little bit fuzzier. I’ve kept my practice very tightly, with just the BRCA1 and 2s that are being offered that particular drug. So, I’m wondering if I’m thinking through the data correctly? Is it something that I’m denying patients with other mutations that opportunity? Because I certainly wouldn’t want to do that. DR LOVE: Any case that you’ve had that was maybe interesting either because of the response that the patient had or tolerability problems that the patient had on a PARP inhibitor? So this patient was in his 60s. He was placed on olaparib, and he did relatively well. We’ve had to take 1 dose hold because of white blood cell count, which in this case I was prepared for. But he’s just second line in that sense, and I think his marrow’s not that beat up, and he’s done well. He has disease in the bone. Bone mets in prostate cancer can be a headache, right, because sometimes you cannot tell if they’re coming and going. But his alkaline phosphatase was in the 400s, and now it’s normalized. There’s certainly no new spots, but the last bone scan I got 2 months ago shows sclerotic lesions more or less in the same area. One may have healed up. But to me he has had an objective response with a PSA drop of more than 50%, normalization of alkaline phosphatase, even though the imaging is always kind of iffy on these people. DR LOVE: Monty, any comments about what kind of genomic alterations you see in prostate cancer? It was kind of surprising how many patients have BRCA, particularly BRCA2, with metastatic disease. And also, somatic mutations. And maybe a little bit about your experience with PARP inhibitors in prostate cancer, Monty. DR PAL: Absolutely, and I think this really lends itself to the fact that we’ve got to start thinking about genomic profiling earlier in this population. It’s really not a last-ditch effort anymore. Now earlier on the lineage of treatments we can start thinking about treating BRCA1 and BRCA2 and possibly some other alterations. I think Helen’s absolutely right, the approval for rucaparib is pretty tight and probably appropriately so. It’s really confined to BRCA 1 and BRCA2 alterations. It’s an even tighter approval because it’s supposed to be used post-chem. In contrast, olaparib had a broader approval. It’s also approved across wider span of alterations. I think, beyond BRCA1 and 2, it’s a little bit questionable how your ATMs, how our PALB2s, how some of these other DNA damage repair alterations are going to respond to olaparib. Do I think it’s worth a shot? Possibly in the context of non-BRCA1 and BRCA2. But I try to use other active agents first, potentially. DR LOVE: So, Joaquim of course here’s some of the data that we’re talking about, first with olaparib. And pretty impressive hazard rate here of .34 in terms of disease progression. We’ve also seen survival data that looks favorable. Monty was mentioning rucaparib, which also seems to show very good benefit. Before we get into that, just curious in what situations you use a PARP inhibitor? Which one do you use, Joaquim? In what line of therapy do you think about it? DR BELLMUNT: So usually I use olaparib in the setting that the trial was done, and these were patients that did have receive 1 of these new anti-androgens, that could be abiraterone or enzalutamide. And then at the time of progression — and the trial was done this way, so randomizing these patients with DDR genomic alterations to receive olaparib, or the alternative anti-androgen that didn’t receive in, let’s say this first line of anti-androgen therapy — they received enzalutamide — they were allowed to receive abiraterone. And this is the way that this trial was conducted showing these benefits, the PROFOUND trial is the one you mentioned, with this magnitude on the PFS and also an overall survival benefit. I am familiar with olaparib. I have not been using rucaparib based on the TRITAN trial. And as mentioned, it seems that the approval was wider for olaparib, despite the benefit was mainly, as Monty mentioned, the benefit was seen mainly in patients with BRCA2, followed the BRCA1. And then ATM is there but it’s uncertain that ATM mutations might predict benefit. For rucaparib, the TRITAN trial, the indication is only restricted to patients with BRCA1 and BRCA2. DR LOVE: So, Monty, any comments on tolerability of PARP inhibitors in men with prostate cancer? In the other diseases we hear about GI problems. And we also hear about cytopenias. I think about men with a lot of bone disease with prostate cancer. What’s your practical experience using PARP inhibitors in terms of tolerability, as well as what you’ve seen in terms of efficacy? DR PAL: Honestly, Neil, not so different from what you cited there. I think cytopenias, in addition to the GI toxicity, particularly nausea, tends to be an issue. So, I would definitely suggest giving with some nausea prophylaxis on starting with these drugs. I tend to recommend ondansetron for daytime use. Prochlorperazine is useful at nighttime for these patients as it induces a little bit of drowsiness; helps with that, an element of things. The cytopenias come with the territory for prostate cancer as well. Very often times we’ll start with patients who have some baseline anemia. But relative to chemotherapy, I would say that this tends to be relatively straightforward to manage. DR LOVE: So, Joaquim, a question in the chat room from Charles about MSI-high prostate cancer: do you test your patients with metastatic disease for MSI, Joaquim? And have you had any patients that you’re able to treat? Charles, it looks like he has a patient who’s been treated for a couple of years. DR BELLMUNT: So the amount of DNA repair gene mutations in men with metastatic CRPC is like, you see around 11 — close to 12% germline mutations and MSI-high is seen in 2%-3% of these patients. And now that we have options for therapy, I think, after our patients are progressing, and even now germline is indicated in patients even with high risk, localized disease, based on the NCCN Guidelines. So, I think these patients need to be profiled because now tumor mutational burden, we know that there is indication for immunotherapy and finding these DDR mutations is an option to treat these patients. And MSI-high, well it might be an option to treat these patients with olaparib, but, also, you might consider to treat these patients with even immunotherapy. So, now, more and more is known about these genomic alterations predicting response to immunotherapy or olaparib, for example, PARP inhibitors. DR LOVE: So last question about prostate cancer, Monty. We’ve been hearing about lutetium labeled PSMA 617. We’ve some data in Phase II that looks pretty interesting and encouraging, however, we’re about to see a Phase III study that sounds like it’s going to positive. Monty, any thoughts about where we might be heading after we see these data? DR PAL: This is very, very exciting, Neil, I’ve got to tell you. I think this is an eagerly awaited therapy. I think it’s going to be very interesting to see what the activity is like in later-stage prostate cancer versus earlier-stage prostate cancer where we might not potentially see the same degree of PSMA uptake, but it’s just wonderful to add what I presume to be a well-tolerated option. You highlighted that paper in the Lancet from Michael Hoffman, where the drug was juxtaposed against cabazitaxel, and no doubt, a very strong efficacy signal. But from the standpoint of tolerability just seemed leaps and bounds better than cabazitaxel. DR LOVE: So, it’ll be really interesting to see the data and how it impacts your sequencing of therapy. Urothelial Bladder Cancer DR LOVE: Let’s talk a little bit about bladder cancer. We could spend an hour on each one of these topics very easily, and we have many times in the past. But we’ve got a couple of good cases to go through. So, Joaquim, I’d like you to listen to this case from Dr Moon of an 82-year-old man who got put on a pretty interesting trial. Here’s Dr Moon. DR MOON: An 82-year-old, non-muscle-invasive bladder cancer off and on for about 3 to 5 years. And sporadically he’s gotten either BCG or he’s got TURBT. And with COVID he has just not wanted to come in, so the last TURBT was about 9 months ago. He has peripheral neuropathy. He’s overweight. That part is relevant because he doesn’t move around very much. And his creatinine clearance is 45 to 55. He’s at a senior citizen home and gets some aide assistance about that. He’s a retired physicist, and his brain appears pretty active. And so, his urologist, as part of kind of the pre-TURBT that he’s setting up for, got a CT urogram, but now you have significant lymph nodes that’s growing out in the RP. This is urothelial cancer with some squamous dedifferentiation. So, knowing this scenario, ECOG 1 or 2, what regimen selection would you give? Enfortumab, or the ADCs, have been a really big presence in this field. Currently enfortumab is FDA approved I believe in third line, so you’d fail chemo, you fail IO, and it’s there available for you in third line. So, for this particular patient we put him on our first-line enfortumab trial because they’re looking for cisplatin ineligible, which is this guy right here, and the randomization is for enfortumab plus/minus pembrolizumab. And he went on it, he just got the first dose today. DR LOVE: So, Joaquim, of course upfront treatment of metastatic bladder cancer it’s been pretty interesting, particularly over the last year. We saw the maintenance avelumab trial that really had a big impact on practice from what we could tell. I’d like your thoughts about that strategy in the younger patient who’s platinum-ineligible, is that the route you’re going? Are you using avelumab maintenance? And then, what about for patients like this, 82 years old, poor renal function, considered not a candidate for platinum. Went on a trial of enfortumab. But would that make sense outside a trial setting theoretically or in the future, compared to, for example, going on an IO? So, let’s start first with the younger patient with good renal function, Joaquim. How do you generally approach them? Are you using the maintenance IO strategy? DR BELLMUNT: In bladder cancer now, patients with first-line, we need to put the patients into buckets. So, the fit patients, patients who are able to receive platinum-based therapy/cisplatin-based therapy, and these need to receive platinum/gemcitabine, dose-dense MVAC. And then, based on the results of the JAVELIN trial, those patients that do not progress, meaning that those patients that obtain a CR/PR stable disease, then we know that switching to avelumab maintenance, the immunotherapy, this provides a survival advantage in this situation. So that’s the fit space. That may be the standard of care. So, unfortunately, the chemoimmunotherapy first line, the 3 trials that we have conducted recently, there is no role for chemoimmunotherapy as we know. It’s a role in lung cancer or head and neck and other situations. In the second group of patients are those that are considered to be unfit or platinum-ineligible. And when talking to platinum-ineligible, I’m talking about cisplatin-ineligible, so are not able to receive platinum/gemcitabine or dose-dense MVAC. For those, we have 2 options: carbo/gemcitabine if they are able to receive chemotherapy, or immunotherapy if they are testing for PD-L1 positivity. And for that we have 2 drugs that are still approved, and the FDA reviewed that quite recently and still atezolizumab and pembrolizumab in patients with PD-L1 positivity based on the specific score of pembro and atezo is still an option. And obviously, in those patients that receive carbo/gemcitabine, you need to follow the same strategy as the JAVELIN trial where after receiving the chemotherapy, 4-6 cycles, if the patients are not progressing, you need to move to switch maintenance with immunotherapy with avelumab. Because in the JAVELIN study, the JAVELIN 100 was published last year in the New England Journal, so the patients could have received platinum/gemcitabine or carboplatin/gemcitabine. So, in this patient that we’re talking about, this patient, it’s an age patient with poor renal function, so several comorbid conditions, this patient fits here in that space. So, the option of chemotherapy with carbo/gemcitabine, if he’s chemo eligible, or immunotherapy, testing PD-L1-positive could be options. Here in US, the FDA also granted the approval for immunotherapy in patients who were ineligible for any type of chemotherapy, and you don’t need to test these patients for PD-L1 staining. If you have a patient that is 95 years old, renal insufficiency and able to receive even gemcitabine monotherapy, then you can give immunotherapy without testing for PD-L1 positivity. So, the question here is how to decide in a patient to treat with chemotherapy or immunotherapy. And usually, the decision is also — and this is like clinical practice, you cannot give to all the patients the immunotherapy, even if they are PD-L1-positive, because the natural history of the disease, the tumor burden, the performance status matters because we know that immunotherapy in order to be effective, it takes a bit of time. And if you have a patient with a highly aggressive disease being unfit, likely immunotherapy, despite being PD-L1-positive, is not the best option. Also, it was mentioned here the enfortumab vedotin. And we know that there is a Phase II study combining in first line patients previously untreated with metastatic bladder cancer and fit for platinum-based therapy, where the combination of enfortumab vedotin and immunotherapy with pembrolizumab obtained a 73% objective response. And this is really highly promising. And now, this is in a Phase III, despite here it has been mentioned this comparison, EV versus EV/pembrolizumab, but we have now a Phase III trial in first line where patients are randomized to receive enfortumab vedotin plus pembrolizumab versus chemotherapy either with a platinum/gemcitabine or carboplatin with gemcitabine. So, it might be that, in the future, if the trial is positive, enfortumab vedotin plus immunotherapy might jump to the first-line patients, unfit, theoretically, or could be even fit. Who knows? So, initially, enfortumab vedotin nowadays is only FDA-approved based on a Phase III trial in third line in patients. DR LOVE: And I know there’s so much excitement about that combination you mentioned of enfortumab plus IO. We’ll see where that heads. Monty, I’m curious where things stand. We saw the approval of pembrolizumab in non-muscle-invasive disease. We saw some data, a follow-up of that at the GU symposium. Any follow-up to that Monty? One and a half years later, have you been seeing many patients? Any clinical experience with this strategy? Any thoughts about it? And any thoughts about these updated data, Monty? DR PAL: I will say it’s a smaller proportion of my practice and I think that lends itself to being in a tertiary center. A lot of the patients get referred to us for non-muscle invasive disease, have already been through BCG and they’re being referred in specifically for consideration of cystectomy. I have had a number of colleagues in the community who have used this regimen. I’ve used it on occasion myself. I’ve had some reasonable responses. I will say that the data is from a single-arm study. I’d certainly love to learn more about the durability of these responses and whether or not it will last for the years and years that tends to be the trajectory for non-muscle-invasive disease. But so far, I think it’s a reasonable option if a patient cannot tolerate or refuses cystectomy. DR LOVE: So, one other data set I want to ask Joaquim about, looking at adjuvant therapy with IOs. We’ve seen several adjuvant trials. But adjuvant nivo, Joaquim, as a strategy? A hazard rate of 0.7. Actually, hazard rate goes down to 0.53 in PD-L1 patients. We know there was another trial of atezo that wasn’t positive, although they looked at ctDNA and that made it look more positive. Any thoughts right now about adjuvant IO, Joaquim? DR BELLMUNT: That’s an interesting space. And this trial, the CheckMate 274, surprised us all because of the positive results in terms of PFS. I can tell you that I was the PI of the IMvigor010, with a similar design, similar setting, instead of using nivolumab, atezolizumab was used. The trial is now published in Lancet Oncology. And at ASCO GU, Dean Bjorin presented the results of nivolumab. In the same situation — patients who had persisting disease after having received neoadjuvant chemotherapy after surgery, patients that did not receive neoadjuvant but were eligible for receiving therapy because of having lymph node disease or extra bladder extension, ineligible for platinum-based therapy, those type of patients were assigned in this CheckMate 274 trial using nivolumab versus placebo. And this is one of the differences between the other trial. So the other trial was open-label. But this was placebo for 1 year. And this trial, as you have mentioned, has a ratio of .70 in progression-free survival that improves up to a hazard ratio of .53 in patients having PD-L1 is really, really important for our patients. So, from here, this trial, the primary endpoint that was progression-free survival, but people are wondering is this going to impact on overall survival? We will see. And this is going to be one of the most important things to see in the future, if the follow-up leads to an improvement in survival getting nivolumab adjuvant in these patients after surgery. DR LOVE: So, we’re going to go to another case but actually there’s a question in the chat room that relates to this, because the case is the issue of when you get beyond IOs and chemo. So, Vanessa says has a patient with Stage IV urothelial, failed IO and platinum. Did well on enfortumab. Stable for 9 months, but 6 months later has “25 brain mets” and needed whole brain radiation therapy. She’s not sure what to do next. Monty, any thoughts? DR PAL: I think we’re so blessed in bladder cancer because the approvals are really coming very quickly. So, sacituzumab is another antibody drug conjugate akin to enfortumab, albeit with a very different target that one could use in this setting. I don’t know whether or not it actually has satisfactory brain penetration. In a patient like this those, I think that that would be a very reasonable option to consider. DR LOVE: Yeah, that was really interesting when that approval came through. Of course, we’ve been talking about sacituzumab in breast cancer, which is also approved, but then boom, here it is in bladder cancer. Well, let’s hear about another case that really relates to again these late-stage, and of course erdafitinib would be another possibility. I don’t know if this patient has already been tested. But let’s hear about this 65-year-old of Dr Rahul Gosain originally picked up in 2018 and then presents with metastatic disease. Here’s Dr Gosain. DR GOSAIN: She was started on split dose cisplatin. Her GFR was 50, but her renal function further declined, so I switched her carbo and gemcitabine. She completed a total of 4 cycle. And initially I had discussed that, after that, if she has stable disease or responsive disease, I was going to switch her to avelumab, based on the recent data. However, her repeat scans were consistent with more pulmonary lesions and bone lesions, so I switched her to pembrolizumab. I did get a liquid biopsy and she’s positive for FGFR mutation. The other question I would have with someone like this with FGFR mutation, if they were to progress, do you consider jumping on a TKI for FGFR mutation, or enfortumab? Given low TMB score, MSI-stable and that FGFR mutation, for second line would you have considered erdafitinib for second line versus immunotherapy? If you were considering immunotherapy, I have very limited experience with both of the drugs, erdafitinib and enfortumab. What is something that you recommend for community oncologists that we need to watch out for in terms of side effects, overall tolerability? With enfortumab, could you expand a little on the recent data for the skin toxicity that were seen? DR LOVE: So, first, let’s take the pulse of the audience related to sequencing that he brings up. So theoretically, if you have a patient with an FGFR mutation would be eligible for erdafitinib, audience, curious what would come first? Enfortumab or erdafitinib? And then we’ll jump into these questions. And Monty, maybe you can talk about what your experience is in terms of tolerability with these 2 agents? And generally speaking, what you sequence first? Looking at the chat room, I always love it when I see something that’s lose to 50/50 — yeah, like 55 versus 45, so a good chance for you to jump in and cast your vote, Monty. How do you sequence them? And what do you see tolerability-wise? DR PAL: So when you begin with the biology, I truly feel that FGFR3 is a driver in these patients. But I think practically speaking, we have to go beyond the biology to the clinical evidence. And now we have Level I evidence that really supports using erdafitinib post-chemotherapy/post-IO. With that in mind, and with the survival benefit that we’ve seen, it’s hard not to choose erdafitinib as your first. Now when it comes to the practical implications that Rahul was outlining, management of toxicity with FGFR3 inhibitors is complicated. I’ve worked with this class of drugs fairly extensively, in particular with a drug called infigratinib, which we’re looking at in a large adjuvant study, using drugs like erdafitinib really requires very vigilant management of toxicities such as hyperphosphatemia, for instance, which is something you don’t incur with other agents. There are ocular toxicities that you need to be mindful of. And really, you should have an ophthalmologist engaged in terms of following these patients in order to witness those toxicities. And that can sometimes go beyond the scope of what’s feasible in terms of your day-to-day oncology practice. So I do think that enfortumab probably represents an easier drug to manage on a day-to-day basis, in addition to being supported by higher level of evidence in this setting. DR LOVE: So, Joaquim, Rahul brought up the question of maybe you have a patient who has low PD-1, a low TMB. I don’t know how relevant that is in bladder cancer. And let’s say they have FGFR alteration. Any situations where you’d want to use erdafitinib before an IO, let’s say a patient who’s symptomatic and needs a response. DR BELLMUNT: So, I think this point is pertinent. So, nowadays, we know that, based on the genomic profiling in bladder cancer patients, we have this, just to make things easy, these luminal types and the basal types, as in breast cancer. And the luminal types are the ones that are usually enriched for FGFR genomic alterations. And usually, in this type of tumors, it’s believed that, although this is the question there, is that likely immunotherapy is not an option. In the other group, the basal, are the ones who are enriched by squamous histology and those are much more responding to immunotherapy and enriched for PD-L1 staining. So, the case that is being mentioned here, the patient with low PD-L1, low TMB, enrichment for FGFR, is this type of luminal you need to treat with erdafitinib. So, erdafitinib is an option and I want to put here, enfortumab is okay. We have this Phase III trial. But third line Phase III trial being positive with this survival that is like close to 12 months, so this might be a highly selected patient population. So, meaning that we need to carefully take care of selecting patients and give enfortumab vedotin. This is a therapy that is given weekly — 3 weeks and then the fourth you can break. And then we do not have studies on quality of life in this study. So if we have an option of treating a patient with erdafitinib, maybe you may need to consider that the tumor is heterogenous and if a population of tumor cells are responding to erdafitinib, enfortumab vedotin is going to be there. So, I think the adequate sequencing of drugs matters and sometimes maybe if you use enfortumab vedotin, then you will not be able to give this oral drug. Because oral drugs are also very good for the patient despite hyperphosphatemia, ocular toxicity, that you see quite frequently. This is correct, what Monty said, that the Phase III shows a survival evidence, but this is in the setting of clinical trial. I would like to see much more real-world evidence of enfortumab vedotin. DR LOVE: So, we’ll finish out. Here are some of the data we’ve been talking about. This is enfortumab in platinum-ineligible patients. Pretty impressive waterfall plot. Pretty significant response rate. Joaquim was talking about the exciting data with enfortumab plus pembro. Pretty impressive waterfall plot. Let’s talk a little bit about FGFR alterations, a minority of patients with bladder cancer, Monty. Can you talk a little bit about what’s been seen, both in terms of the efficacy but particularly tolerability? And what are some of the issues that come up with enfortumab? And also, you mentioned sacituzumab, where does that fit in now that you have 3 options, sort of in the post-IO platinum space, Monty? How are you going to sequence them? DR PAL: I think Joaquim makes some very relevant points. There are certain tumor types that seem to be enriched for FGFR3 alterations. So, your patients with upper tract disease are likely going to have a higher frequency of this phenomenon. In fact, in that population it may actually be between 40% and 50% of patients that are FGFR3-positive. It tends to be a bit lower if your patient’s tumor is derived from the lower tract; there it tends to be on the order of 15% to 20% depending on which series you look at. So those are some of the pearls that you can look for in the patients’ history to discern whether or not FGFR3 might be relevant. Now in terms of sequencing, I’ll sort of stick to my guns and say level of evidence higher in the context of enfortumab at this moment. So, I’d probably put that ahead of erdafitinib, even in an FGFR3 altered patient. With sacituzumab, and again, I’m going to base this argument on level of evidence, we have a Phase II study which suggests a response rate of around 25%, so if a patient has received enfortumab previously, it’s logical to go ahead and sequence sacituzumab right after that. There really aren’t any other great competing options besides conventional chemotherapy. But in the patient who’s FGR3 altered, I think that perhaps one could consider the sequence of enfortumab followed by erdafitinib, right, because we see a response rate there that’s on the order of around 40% and then follow that up with sacituzumab if the patient remains fit enough. And again, I’ll just reiterate, it’s amazing to me that we’re talking about fifth line therapy in metastatic bladder cancer. So, it’s really been a tidal wave of developments for our patients here. DR LOVE: Yeah, 2 or 3 years ago when we were doing a CME program that included bladder cancer, we were sort of looking around for things to talk about. Now, whoa, we can barely get it through it and we’re barely going to get through it here. But let’s jump onto another topic that’s probably even more complicated and getting more complicated I think almost every day, the management of renal cell cancer. Renal Cell Carcinoma DR LOVE: We’re going to start out with a case from Dr Jeremy Lorber, a 77-year-old man who presented with metastatic disease. Here’s Dr Lorber. DR LORBER: I started him on ipilimumab and nivolumab. He had a partial response which lasted close to 2 years. So my questions are, he’s had a great response to checkpoint inhibitor therapy. He’s only been on nivolumab since early on in his course. Is it reasonable to re-introduce ipilimumab? If not, what would be the preferred agent in second-line for a patient like this? Is there a way to distinguish TKI from TKI? Is cabozantinib better not used in first-line since at least it preserves a later-line therapy whereas one is less likely to use something like axitinib in later line? This patient even at presentation had very limited and asymptomatic metastases. What would be the role for nephrectomy at that point? What would be the role if not at the beginning, after some response like in this patient, or is there never a role for nephrectomy that is justified by data. DR LOVE: So, Joaquim, we did a CME program on management of metastatic renal cell cancer in November and then when I went back and looked at it, I saw that it was completely out of date 6 months later. We had the approval of cabo/nivo. We had lenvatinib/pembro presented at ASCO GU. So, let’s talk a little bit about choice of first-line therapy, Joaquim? And also, how you factor it in based on risk status? I know that patients who present with metastatic disease are automatically intermediate or higher. How do you manage patients with favorable risk metastatic disease, Joaquim? And can you start to dissect out the options that fall into ipi/nivo, TKI plus IO or TKI, Joaquim? DR BELLMUNT: So, starting with ipi/nivo, this trial was done in the setting of patients having intermediate- and poor risk. So that’s the place where ipi/nivo shows the benefit. So, there is no role in patients for good-risk renal cell carcinoma. For the other TKI/immunotherapy, I think that’s — the field is being complicated and crowded and it’s very difficult just to make differences. If you see that lenvatinib/pembro, so the PFS is so exciting. So, it’s like double of what we saw with sunitinib in 23 months. And now, one thing, well maybe pembro/lenvatinib is the best option. But then we go back to ipi/nivo and we say, well, ipi/nivo seems that is where patients have much more durable responses, higher rate of complete responses. So, we need to adhere balance in making decisions in first line, the type of patient characteristics. If you have a patient with intermediate risk, what’s your endpoint? If you are looking for prolonged survival, depth of CR, higher experience, all the time I’m favoring ipi/nivo in these patients. However, now we have not enough experience, and we have no long-term follow-up with, for example, lenvatinib/pembrolizumab. And more is going to come because now the field is moving to triple therapy, so we are going to see trials that are using pembro/lenvatinib plus these HIF-2 alpha inhibitors. We’re going to see other triplets with cabozantinib in first line. So, we have so many options. I think that the experience matters. And we were talking on bladder that we are talking about fourth line, fifth line of therapy, but presently, our patients with renal cell carcinoma are receiving 5, 6, 7 lines of therapy, depending. So there are trials, based on the question of this case that was presented, so what to do after ipi/nivo, progressing after 20 months. So likely, based on clinical trials, cabozantinib might be the right answer. And sometimes we want to change the way we are treating patients, like giving a break on immunotherapy, jumping to TKIs. But I can tell you that some of these patients, rechallenging them later on with ipi/nivo again, I have done that. I have seen response. But, for example, there is the OMNIVORE trial, where they decided just to switch immediately or to add ipilimumab in patients failing. It didn’t show benefit. So, duration of response matters. The type of patient. Disease locations. Toxicity profile. What we are looking for. Age of the patient. So, there are so many disease characteristics and patient characteristics that matter when deciding what to do. I know that I haven’t answered your question because there is no definitive answer what’s the best option in first line with metastatic RCC. DR LOVE: So, if there’s no definitive answer, what we usually do is just ask a whole bunch of people and if they all say the same thing, we figure it’s a consensus. If they say 5 different things, which is what happens when you ask about first-line renal, then it’s a different story. Monty, maybe you can give us the flavor of how you think it through? And also, could you describe a favorable risk metastatic situation. Because, as I listen to people talk, I feel like that’s shifting too. Favorable risk — a couple of years ago I was hearing about TKIs, now I’m hearing a lot of people talking about IO plus TKI in these patients. So, can you describe a favorable risk metastatic situation, Monty, and how you manage it? DR PAL: I think favorable risk is best really assessed by the traditional scoring algorithm by the IMDC, simple characteristics, time from diagnosis to systemic therapy, Karnofsky performance status, and then for laboratory-based parameters. It’s an easy tool. I recommend doing it for all patients. However, Neil, I’m going to try to give you a simple answer. If you follow me on Twitter, I have this long thread of like 17 or 18 tweets that I use to arrive at this. But I tend to be fairly dogmatic. I’m using cabozantinib with nivolumab across the board for the vast majority of my patients. And I’ll tell you why. The IO/IO combination of nivo/ipi doesn’t yield the same response rates and there’s a higher rate of primary progressive disease if you juxtapose that against cabo/nivo. So that’s my number one selection criteria. Then if you go to lenvatinib and pembrolizumab, if you go to axitinib and pembrolizumab and then cabo/nivo, I think across all these studies, impossible to do cross-trial comparisons, all are hitting on response rate, all are hitting on progression-free survival and overall survival. With cabo and nivo, we have distinguishing characteristic of us using a lower dose of cabo frontline at 40 mg, which I think is very well tolerated, and that’s bolstered by the quality of life data, which really seems to favor cabo/nivo as compared to, for instance, axi/pembro, where you actually see a decrement in quality of life over time relative to sunitinib. I’ll also point out too, that with lenvatinib and pembrolizumab, no quality of life data as yet. And lenvatinib is a tough, tough drug. And I’ve chaired a study looking at dose modifications of lenvatinib. But I think it’s challenging to offer patients in the frontline setting, where ostensibly they’ll be on treatment for a long time. So, my simple answer is cabo/nivo across the board for most patients with frontline renal cell. DR LOVE: So, talking about lenvatinib, our gynecologic series have been struggling with pembro/lenvatinib for MS-stable endometrial cancer and the question of dosing. But I’m curious though, Joaquim, how you think through — one of the choice of IO/TKI, one argument or point that I’ve heard people raise, I don’t know how you feel about it, is that “since cabo is the most effective single agent maybe better not to start out with it first line.” Other people say go with what you think is best first line. How do you make the decision if you’re going to use a TKI/IO combination, Joaquim, how do you choose which one? And do you approach the question in favorable risk different if they’re symptomatic versus not symptomatic? DR BELLMUNT: So, as mentioned, I defer a bit of Monty. So, my preferred first line in intermediate-, poor-risk let’s say is ipi/nivo. As mentioned, the survival curves, the flattening of the survival curves is seen with ipi/nivo. That’s something that we not yet have seen with IO/TKI. So, in terms of which one of the TKIs with IO/IO I choose? So here I am supporting Monty that cabo/nivo is, like, surprisingly doing well in terms of quick response. And because we have much more experience in managing cabozantinib on dose adjusting, and then sometimes holding the drug, reintroducing the drug — well, the same as with axitinib, but as mentioned, the quality of life data that Monty has mentioned favors the use of cabo/nivo. So, I prefer that to — sometimes I’m reserving even this combination for second-line therapy in some patients. So now the second line, cabo is the option monotherapy. Sometimes in patients in third line, I have been using cabo/nivo. And if the patient received immunotherapy first and then receive other TKI that was not cabo for whatever reason, right. So it’s cabo/nivo. I think it’s a good option in the combination. I have no experience with pembrolizumab/lenvatinib. I know lenvatinib/everolimus, that is another combination. It’s treated, managed. And this is a combination that, despite being approved in second line, I have been using that in third and fourth line of therapy. So there is retrospective data now on how to sequence all these drugs. So, just answering your question, cabo/nivo would be my preferred option. DR LOVE: So, we’re going to go onto the last case, another patient of Dr Moon, a 43-year-old woman. And Monty, I’m going to ask you to respond to it. But first, I want to let you know there’s a case in the chat room, Monty, that I also want you to respond to from Venue, 70-year-old man, poor-risk clear cell. Progressed on upfront ipi/nivo. Second line cabo. Now 6 months later progressing on cabo. So, Venue wants to know what’s next? So just keep that in the back of your mind, Monty. I’ll let you address that after you hear this case from Dr Moon of the 43-year-old lady. DR MOON: This is a young patient, 43-year-old Latina woman. Cough, actually, and it was lung mets. So, diagnosed RCC, found a big primary lesion, about 11 cm, when I first saw it. Because she’s young I want to get her to a true durable CR. So she went on ipi/nivo. She actually did relatively well. The fourth one was held and ultimately never given because she had like a terrible, terrible colitis and it resolved on steroids. And she went on nivo maintenance. And eventually we stopped at about the year and a half mark, not that there’s great data in that, but I think COVID kind of happened, and she was feeling fine. She did not get all the way to CR because you can still see some small dots, but they haven’t grown for about a year or so. So, we just went with that. So my question would be, so here you are with a really young woman, would you have selected a double-IO regimen versus one of the currently available TKI/IO. DR LOVE: So, another issue that comes up in both of these cases is surgical removal, of nephrectomy, Monty. You can comment on that. So, first of all, let’s go back to the case from the chat room. Ipi/nivo, second-line cabo. What’s next? DR PAL: And I’ll bring up something that you mentioned earlier which is that there’s this premise that maybe we will save our most effective agents for later. Unfortunately, in kidney cancer, although we’ve got a long lineage of therapies we can use, very oftentimes, by the time you get out to the third- and fourth line setting, the patient’s performance status declines and options are limited. So I’m always in favor of using your best options upfront. And part of the reason why I support using cabo/nivo as first-line therapy. If you have patient like the one proposed in the chat room who was on nivo/ipi and then goes on to cabo as a second-line option, until recently I was really using lenvatinib and everolimus as my preferred option. I will say that if the patient is frail, as many of these are in third-line setting, I would really like to start considering tivozanib more often. This is a drug that has a potent-specific VEGF inhibitor that really has significant activity, as we demonstrated on the TIVO-3 study that we just published in the third- and fourth-line space. So, I think that that’s an agent that’s far better tolerated in general than lenvatinib and everolimus. And really great data for it, in fact, post-immunotherapy in another really sort of relevant current context. So tivo might be option for this patient. DR LOVE: Any comment about the issue, and I’m going to ask you about this coming Plenary presentation by Dr Choueiri, on adjuvant pembro in renal cell. Should be pretty interesting. So, first of all, Monty, do you know anything about this trial? Any thoughts or expectations about this study? Also, in the chat room, Sam wants to know is there still a role for high-dose IL-2? DR PAL: So, I’ve got to tell you that I’m chairing a similar study looking at adjuvant atezolizumab in this setting. We finished accrual. So, I’m hoping that the results for adjuvant pembrolizumab are strong because I think that bodes well for this adjuvant atezolizumab study as well. Based on what was issued in the press release, I’m anticipating that this study may really shake up our algorithm. And we’re going to have to start thinking about how we treat those individuals who are reasonable candidates for adjuvant therapy, and it may shift our horizons in terms of frontline treatment significantly. DR LOVE: Final comment, Monty, about nephrectomy in the age of all these new agents. I know there’s a trial looking at delayed nephrectomy. But right now, clinically, how do you approach this question, Monty? DR PAL: I’ll say the same thing that I tell our fellows, if there’s an absolute indication for nephrectomy, either paraneoplastic syndromes, bleeding or pain, that patient has to go to the operating room, right, no question about it. If the patient, on the other hand, has disease that’s intact and you feel that you can just jump right into systemic therapy I would do that and really, as the medical oncologist, make that your priority. Use surgery as a bit of an afterthought. And then consider enrolling onto the trial that you’d mentioned which is called the PROBE study. It’s being run by SWOG and its randomizing patients after they get going on a couple of cycles of treatment and have disease stabilization, to either nephrectomy or not. Until we sort of replicate these study designs, in the context of frontline immunotherapy we’re never really going to know the right answer. DR LOVE: So, I remember one of the last live meetings we did was ASCO GU the year before, and an area of great contention relates to this last thing I want you to comment on Monty, again from the chat room from Sam, is there a role for high-dose IL-2 nowadays? DR PAL: I’m going to say likely not. That population of patients that we always considered for high-dose IL-2, ie, those patients with low disease burden, maybe just pulmonary metastases, young age, no brain mets. These are patients that are going to just as well, if not perhaps even better, in the context of VEFG plus IO with a regimen like cabo/nivo, for instance. I would suggest that we should shift away from that. I will say, I’ve been involved in the PIVOT-09 study, which is a trial looking at pegylated IL-2 in combination with nivolumab versus sunitinib or cabozantinib. So, that’s very much akin to the design of many of the frontline studies that we’ve seen recently. If we’re going to use IL-2, it’s going to probably be in this different, more sophisticated fashion. But I don’t think we’d go back to the days of high-dose IL-2 for those patients. DR LOVE: Joaquim, I’ll give you the last word. DR BELLMUNT: So I can provide some input in high-dose IL-2 because in the institution where I’m working, well, I’m there since 2 years, but Dr McDermott has huge experience with high-dose IL-2 and still, we are receiving patients because this is the first immunotherapy treatment that was able to provide long-term durable response, although it was in a low percentage of patients. So, it was still in highly selected, as Monty mentioned — highly selected, lung-only disease, young patients. In this third line that we have been discussing, we sometimes receive patients for high-dose IL-2, although it’s not the best space. But it’s a tough regimen to use, but still there may be a very narrow, tiny space for these patients. Introduction DR LOVE: We’re going to talk about GI cancers for the next hour, 4 in particular. This is a Real World Oncology Grand Rounds. We’re presenting 48 cases today from the practices of general medical oncologists and getting some input from clinical investigators. Today, we’re going to be focusing right now on GI cancers. We have Dr Wells Messersmith from the University of Colorado and Dr Eileen O’Reilly from Memorial Sloan Kettering Cancer Center. And as we’ve been doing all day, we have cases that are going to be presented by video. I met with these docs ahead of time, recorded their cases. Colorectal Cancer DR LOVE: So we’re just going to jump in and start with the first case and then we’ll chat with the faculty. We’re going to talk about colorectal cancer. We’ve got a couple of cases there. This is a patient of Dr Jeremy Lorber, a 74-year-old woman who presents with metastatic disease, interestingly picked up with colon cancer from a screening stool DNA test but found to have some pericecal adenopathy and 3 liver mets. She’s both MSI-high and with a BRAF V600E mutation. We’ll get the thoughts of the faculty, but here’s Dr Lorber. DR LORBER: I started her on pembrolizumab which she tolerated without issue. After about 3 months of therapy she had a repeat CT which showed close to complete resolution of all liver metastases and the adenopathy near her cecum. And she went for combined hemicolectomy and metastasectomy. Two out of the three lesions in the liver were no longer present on MRI of the liver. One of them was ablated. The hemicolectomy actually had a complete pathologic response and no evidence of tumor. Now that she’s had a great response and resection and no evidence of disease, is there an optimal duration of therapy after surgery? Is there a role for ctDNA or any other assessments? DR LOVE: So, Wells, we used to make up poll questions like this and then here we have the actual situation. We would present it as theory, but here it is, a patient who needs a response, has liver mets that are thought to be resectable but is both MSI-high and BRAF mutated. So first of all, any thoughts about how you might approach this situation? This patient obviously had a great response to pembro, but would you have considered chemo plus IO in this situation, Wells? And any thoughts in general about managing patients with MSI-high and BRAF mutations? DR MESSERSMITH: It’s a very interesting case. First of all, getting a 74-year-old through a hemicolectomy plus liver resection is good workup by the surgical team. So, there are a couple of things that jump out. So, first of all, when you have this oligometastatic disease where you’re trying to figure out how to sequence things, you really want to carefully coordinate with your surgical team because you don’t want too much of a response where they can’t actually find the lesions. In the 2021 NCCN Guidelines, we actually put in that you can use immunotherapy in this situation and that was really for the first time. Previously, we hadn’t put immunotherapy into something like this. And the thinking is, is that the response rates are so high, and patients have a benefit. As you mentioned, and I’m sure we’ll talk about this in a little bit, the 177 trial showed that during the initial few months you actually have a little bit more progression with immunotherapy, and then the survival curves flip. I think we’ll be looking at those in a little bit. So chemotherapy would have also been reasonable in a situation like this. But for a 74-year-old you’re trying to get through liver surgery, I think it makes a lot of sense to start with the immunotherapy. And we’ll see what the results from the ATOMIC trial are. The ATOMIC study is looking in Stage III patients. We won’t know how much we can extrapolate to Stage IV. But the use, in this case, it’s atezolizumab in addition to FOLFOX in the adjuvant setting and the atezo is continued for 1 year which kind of gets to the duration of how long. We don’t know how long we should use immunotherapy in this situation, but if you want to follow that study for instance, you would give it for approximately 1 year. DR MESSERSMITH: So the BRAF, just to point out the biology of BRAF, even though it’s such a tremendous driver, it seems to be wiped out by the MSI-high. So, in this case this patient probably has a hypermethylation of MLH1, which causes the loss of MLH1 and PSM2 because those heterodimerize. And if you look across really all of the MSI-high studies, whether you have BRAF or not really doesn’t seem to affect response. So, in this case I tend to focus on the MSI part of it rather than the BRAF. DR LOVE: So, Eileen, I don’t know how often you see patients who have both BRAF and MSI-high, but I would guess maybe they might end up getting pembro in a more typical situation. What do you think about in terms of second line and when do you bring in targeted therapy, for example, encorafenib, with EGFR antibody in those patients? DR O'REILLY: I think it’s a great question and it’s one that’s being actively research is what to do for this subset of patients. So, for this individual, as I think Wells was alluding to, the sort of typical phenotype would be a person with a right-sided tumor already who had hypermethylation and not a germline etiology for the mismatch repair deficiency. In that setting, the go-to, too, for me would immunotherapy and would favor, too, consideration of a year of extrapolating from the ATOMIC study indeed. So, with regard to the targeting of BRAF, I think that’s second line. I see those drugs being somewhat more toxic and perhaps not quite as efficacious and also not having the same durability in response that we see when immunotherapy works very well. And I think that’s a very interesting space. And looking at building BRAF targeted therapy plus immunotherapy, that’s a question that’s being actively worked at, and other combinations such as PARP inhibitors with immunotherapy following BRAF targeted treatment. So we’re going to see more carving out of additional subsets in this space in colorectal cancer. DR LOVE: So, Wells, in the more typical situation with the patients with BRAF mutant disease, or MSI-stable, what type of targeted therapy do you use and in what line of therapy? And what do you observe in terms of efficacy and tolerability? DR MESSERSMITH: So, like Eileen, I generally go second line and above. I use an EGFR targeting monoclonal antibody and typically in combination with encorafenib. And what I’m finding in practice is that the patients seem to have an initial benefit, but they do get resistance like Eileen said. So that’s why I would have, for an MSI-high, favor immunotherapy just because of the duration. DR LOVE: So, let’s move on to another case. This is a patient of Dr Dayyani, a 60-year-old woman with metastatic MS-stable colorectal cancer. And you can see interestingly she has a high TMB of 35.4, although she’s MS-stable. Goes through FOLFOX, cape/bev, FOLFIRI and then gets into the what’s next line where you often think about regorafenib, TAS-102, but in this patient also pembrolizumab because of the high TMB. Here’s Dr Dayyani with his questions. DR DAYYANI: I think some emerging data tell us that introducing the regorafenib sooner than later might have actually a benefit over fourth line plus. But with the newer data of a randomized Phase II of TAS-102 with bevacizumab showing progression-free survival benefit over TAS-102 alone, how would the discussant put these 2 pieces of information in perspective, TAS-102 plus bev as third line versus regorafenib single agent as third line? And how would they prefer to sequence those? I did a quick circulating tumor DNA; she was known to be KRAS mutated and microsatellite stable with a relatively high TMB of 35.4. So, when I saw this the question came up okay, is it reasonable to try pembrolizumab due to the high TMB score? DR LOVE: So, Eileen, can you talk a little bit how you think through the question that’s been out there for several years, sequencing of regorafenib, TAS-102. Also, his question about adding bev to TAS-102? We’ve seen some interesting data over the last year or two that suggests that might be an effective alternative. And then again how you factor in the fact that the TMB is high, Eileen. DR O'REILLY: Yes, and I think all great questions and a very interesting case. I’m very curious about the TMB of 34 in this setting and I wonder what’s driving that. We’ll maybe come back to that in a second and address the sequencing issue first. So I think regorafenib and TAS-102, relatively similar in terms of their efficacy. And one reason that you might consider a sequence of regorafenib first, perhaps if the person had done well with regard to the anti-angiogenic strategy and continuing regorafenib would be part of that paradigm and that may be one consideration. I don’t know that I personally sense this so much, but there are some believe that the durability of responses on regorafenib may be a little bit longer and again might speak to using that before TAS-102. On the counterpoint, in terms of TAS-102 and bevacizumab, the data do look intriguing and certainly suggest that that’s a very real alternative. So I think at the end of the day either one of those would be reasonable. And if there’s access and it’s appropriate, I would favor giving TAS-102 plus bevacizumab as opposed to the single agent. To address the TMB high, so the disease agnostic indication would support using pembrolizumab in that setting, although from what we know, the expectation of benefit is pretty low in microsatellite-stable colorectal cancer. So, while it may be something the patient might ask a lot, perhaps I would keep that in the background and try to understand a little bit more about the genetics of the tumor to support the rationale for pembrolizumab beyond what was shown. DR LOVE: Wells, here are some of the — we’re not going to show all the slides that are in the deck, a lot of these are just for reference, but I’m curious what you think about this strategy of adding bev to TAS-102? Have you done that? And any thoughts about sequencing TAS-102 or TAS-102 bev with regorafenib? Maybe you can comment a little bit about how you approach dosing of regorafenib, Wells? DR MESSERSMITH: So I think the person who presented the case was referring to the REVERCE study which had about 100 patients and was looking at this this sequencing question of regorafenib versus cetuximab, so it was like regorafenib, then a cetux-based therapy plus/minus irinotecan or vice-versa. Important to remember, that one included some right-sided tumors, and they only initially were looking for KRAS Exon 2, so just be aware of that. But it was a pretty impressive difference of 17 versus 10-ish months. And so, from my standpoint, that’s more hypothesis-generating. I’d be curious to see if there’s any confirmatory data on that, given that it’s a fairly small study. I think this interaction with bevacizumab and sort of 5-FU drugs is impressive. And once again, we see a very nice efficacy. And again, in 2021, TAS-102 and bevacizumab was added to the NCCN Guidelines. So, that’s on there as an option. And it’s not a homerun. It’s one of these progression-free survivals of 2 months, but it looks pretty impressive. In terms of dosing the regorafenib, for a patient who’s fit, I start at 120 and then try to work my way up to 160. And for someone I’m pretty concerned about or may have had trouble with TKIs in the past or something like that, I’ll start at 80 and see how high up I can go. And that seems to be a better route in terms of actually being able to keep patients on the drug. Some hints of actually better efficacy but maybe that’s just because you don’t blow people out of the water and you’re actually able to continue to treat them. DR LOVE: So, Eileen, getting back to the MSI question, one of the things that’s come up recently in a couple of our webinars is the question of adjuvant therapy in the MSI-high situation. In the past we sort of heard that if it’s Stage II, 5-FU doesn’t seem to be effective. But what do we know about Stage III disease, and are there trials looking at adjuvant IO in that situation? Would you consider pembrolizumab in a patient with multiple positive nodes who has MSI-high, Eileen? DR O'REILLY: Yes, a great question, very practical one. So, Wells mentioned this, the ATOMIC study has been underway and it’s about 60% accrued now. This is an Alliance trial that’s evaluating FOLFOX with or without atezolizumab in MSI-high Stage III colon cancer. So we’ll need a few more years to get the answer from this, but I think it’s a very open question. It doesn’t include, which is intriguing to me too, it doesn’t include an IO-only arm. That’s, I think, out there in the adjuvant setting in colon cancer, whether that’s going to be something that we should be thinking about. So ideally, one would see if the patient could participate in this trial and that ultimately is the soonest way to answer the question. But if there were not an option for whatever reason, would one consider for a Stage III MSI-high colon cancer using IO or chemotherapy/IO off study, I think it’s open. I would say yes, but that’s not, of course, the correct view in the absence of definitive data. DR LOVE: So, does that mean you’ve done it? DR O'REILLY: No, I haven’t done it. DR LOVE: So, Wells, I’m curious whether you face that situation. And another question, Wells, which is, talking about renal cell cancer where there are like 4 IO/TKI combinations that they argue about. They’re all extremely effective. We haven’t really seen that happen with colon, but a couple of years ago we saw some interesting data with regorafenib plus IO. Where did that land? And is there any future, lenvatinib/pembro for IO/TKI in MS-stable disease? DR MESSERSMITH: That’s a great question. And it’s been a frustrating aspect of our field because it really goes all the way back to atezo/cobi, I don’t remember that study. But basically, straight out of Phase I, they had quoted this response rate of 27% or something, 26%, and launched right into a Phase III and it ended up being a negative trial when compared to control. I think one of the control arms was regorafenib. So right out of the gate we had this incredibly positive, interesting Phase I that went to Phase III and then kind of crumped. And there’s been some data with regorafenib and nivolumab, that was also quite promising. And then it turns out as the company and investigators looked at it more, it seemed to be more in patients with lung-only mets. There’s definitely a hint of activity there but we just don’t know who’s going to benefit. And I’m actually running a couple of investigator-initiated trials trying to get to the bottom of that and to try to figure out how the immunomodulation of the TKIs is impacting these patients. But certainly hasn’t been the homerun. And most of the Phase III, Neil — the Phase III trials have basically been wound down and we haven’t seen the final publications. Hopefully, we’ll get some more information coming up at ASCO. But that was all the rage about 2 years ago and then it just kind of petered out because they just didn’t see the same activity they were hoping to see. DR LOVE: Yeah, that was pretty disappointing. Gastric, Gastroesophageal and Esophageal Cancers DR LOVE: All right, let’s move on and talk about gastroesophageal cancer which, in terms of complexity, is now ranked number 1 by general medical oncologists for confusion, at least from my point of view. So, I’m going to give you two a few minutes to see if you can straighten us all out. So we’re going to start out with another case from Dr Dayyani, a 60-year-old man, well you’ll hear the history — he presented with locally advance disease. Got FOLOFOX, concurrent chemoradiation, with carbo/paclitaxel, then went to surgery. Here are his questions about this case. DR DAYYANI: We decided to do concurrent chemoradiation with FOLFOX, and ultimately, he had a good response. So we were able to do a laparoscopic and thoracoscopic esophagectomy, and pathology showed a yp tumor in situ (Tis) ypN0. Ten months later he’s now suddenly admitted with large pleural effusion, dysphagia, ascites, anorexia, hypercalcemia to 14; really, really acute presentation. I remember the outside emergency room doctor called me at 10pm on a weekend saying this gentleman is here. So now he had fulminant recurrence. So they stabilized him, treated the hypercalcemia. His PD-L1 CPS score was 15%, microsatellite stable. So, what do you do? Do you treat him with single-agent pembrolizumab? Do you give him paclitaxel? Or would you think about combining both in terms of treating this patient? DR LOVE: So, Wells, I’m curious about your thoughts about what you would do in this situation, but also kind of looking back when he had the initial therapy for the localized disease and he did have ypTis disease, whether you would have thought about a checkpoint inhibitor at that point? And what would you be thinking about at this point, Wells? DR MESSERSMITH: So I would have been thinking about a checkpoint inhibitor actually, although it’s interesting, Neil, in that study, and this happened to me a few times, so unfortunately, I’m familiar with that protocol. If you didn’t have a T1, so if you actually look at the schema for the trial, you had to have a ypT1. I’m not sure the Tis would have been allowed. And I had a patient who had a complete response who I wasn’t able to put on that study. But certainly, nivolumab in that situation would be a consideration after the CheckMate 649 trial. So, certainly at this point in time, you probably would have given this patient a checkpoint inhibitor post-treatment. The problem with this case at this point is that it’s a very fulminant presentation. And so, because it takes longer for immunotherapy to kick it as it were, I would be pretty concerned as to whether or not you have time right at this moment in time to use an immunotherapy. So I would be looking more towards the paclitaxel as mentioned. I might also think about FOLFORI. That would be another option. And it would be reasonable to add immunotherapy in that situation because we know that in the first-line setting, especially now that this patient is naïve — because remember, now we’re going to have all these patients who have gotten checkpoint inhibitor in the adjuvant setting are now going to relapse, right. So now we have to figure out how we’re going to use checkpoint inhibitors in that situation and if it’s been more than a year, do you use it again or at some point in time? It’s going to get a lot more difficult. But for this patient, checkpoint-naïve, I would think strongly about using it with cytotoxic chemotherapy, try to get this disease back under control. DR LOVE: Eileen, any comments about this clinical situation? And would you be thinking about ramucirumab in addition? DR O'REILLY: I agree with chemo plus immunotherapy. If we look at the randomized study that addressed this question, immunotherapy was actually inferior in the first number of months to chemotherapy in the high CPS setting. So, I think this disease needs to be stabilized but it is very appealing to combine the two to address both the CPS and to address the need for urgent disease control. So that would be the strategy that I would take here and then, perhaps if response is stabilized maybe to consider dropping the chemotherapy at a later timepoint. DR LOVE: Wells, can you comment, we’ve talked about a couple of these studies. Here’s the New England Journal paper in resected gastroesophageal cancer, looking at adjuvant nivolumab. Any comments about what was seen here and how it affected your practice, Wells? DR MESSERSMITH: Well, it’s one of these situations where there’s certainly benefit. It’s not a homerun. It’s not curing everybody. You have to be sort of realistic about the amount of benefit that you’re seeing there. But the curves do seem to flatten toward the end And we’re basically using it standardly at this point in time. And as I said, we’re going to have a new population of patients who relapse having had IO in this situation and what exactly we should do with those patients is unclear. DR LOVE: So, let’s ask the audience a question here. So, audience, you’ve got a 65-year-old patient with MS-stable metastatic adenocarcinoma of the esophagus and the PD-L1 CPS level is 0. What would you be thinking about in terms of treatment in this situation? And Eileen, I’m going to ask you how you approach first-line in metastatic adenocarcinoma of the esophagus. And how, if at all, you factor in PD-L1 level. The most common answer in the audience is FOLFOX. A minority are saying either pembro or nivo plus chemo. How do you think that one through, Eileen? DR O'REILLY: I think in the HER2-negative space with a CPS 0, FOLFOX is certainly a standard of care and that would be a good choice. In a way, esophagogastric has obviously been very exciting in this last 6 months with all the data and the approval that we’ve seen. And it’s gotten perhaps a little bit easier in that now checkpoint inhibitor use in frontline therapy can be justified independent of CPS. I think it’s worth remembering that most of the benefit for sure comes for those with CPS higher, 5 and above, and in one setting, 1 and above, but we know, like with chemotherapy, there’s a degradation in terms the benefit is present to. So, I think this is practical, part of the licensing authority and it would support consideration here of giving chemo plus an immune checkpoint inhibitor. But I also think for CPS 0, frontline, chemotherapy on its own remains a very reasonable option. DR LOVE: Just kind of curious, Wells. I think a lot of people were surprised that the FDA approval didn’t really specify PD-L1 levels so now you have the option. What do you do, Wells? DR MESSERSMITH: Neil, I can’t think of an example where NCCN Guidelines or ASCO Guidelines were more restrictive than the FDA. I can’t remember a single example of that in my career. But I agree with Eileen in this situation, that it’s approved in the situation for first line use. I would just have low enthusiasm. As you and I have talked before Neil, I’m always shocked how all of these autoimmune diseases that I didn’t really pay much attention to in the past are coming out of the woodwork. So, if there’s any hint of a contraindication, I wouldn’t use it because I think with a CPS 0, the chances of survival benefit aren’t great. But in our practice, we’ve pretty much standardly used it, we just have very low enthusiasm with a CPS 0. DR LOVE: Let’s go on to another case. This is from Dr Del Rosario, a 49-year-old woman with HER2-positive metastatic gastro-adenocarcinoma, also with a PD-L1 level, a CPS of 5. So this patient initially got FOLFOX/trastuzumab. Here’s Dr Del Rosario discussing the case. DR Del ROSARIO: She was initially treated with FOLFOX and trastuzumab. My questions for the panel, on progression, would immunotherapy be on the table because she had a PD-L1 CPS score? And my next question, if she did progress, do we need to rebiopsy to demonstrate HER2 positivity? And if she was HER2 positive, can we continue anti-HER2 or can we use fam-trastuzumab-deruxtecan? And the follow-up question to that is, if we did use fam-trastuzumab- deruxtecan, what adverse events should we be monitoring given that this is a relatively new drug? In terms of the adverse event of interstitial lung disease, how can we monitor that? Would it just be through symptoms such as a dry cough? Or is there any recommendation on routine imagine such as chest x-rays or a CT chest? DR LOVE: Let’s put a question to the audience. So, audience, you have a patient with metastatic HER2-positive MS-stable gastric cancer, as we just discussed. We’re going to just say in this situation the CPS is less than 1, sort of remove that out of here. And the patient has gotten first-line FOLFOX/trastuzumab and second line, paclitaxel/ramucirumab. I’m curious, audience, what comes next? We’ve seen some interesting data with TAS-102, but also, we have other options out there, now trastuzumab deruxtecan. We’ll see what the audience thinks. And Eileen, overwhelmingly, the audience says T-DXd which, of course, Dr Del Rosario just referred to. Any thoughts about how you generally approach this situation, Eileen? And I’ll even backtrack into second-line therapy. DR O'REILLY: Well, I think in third-line therapy, the decision is relatively straightforward. We have data from the recent gastric study evaluating trastuzumab exatecan, which is T-DXd, and that has shown a high response rate in the high HER2/3 overexpressers and the ISH-positive, so very exciting signal and that’s now been moved to second line in terms of an ongoing randomized Phase II study compared to chemotherapy. The question on monitoring and toxicities, and I think the main one that we’re alerted to with this drug is the interstitial lung disease. This is insidious and it can sort of emerge over a period of time, but it can be serious, and I’ve seen this in a different setting, not in gastric cancer, but cough, any shortness of breath, we clue our patients into promptly report those symptoms. And I think our radiologists now are very attuned to this for many reasons. We use a lot of drugs that can cause pneumonitis with inflammatory disease in the lungs, with checkpoint inhibitors, with this class of agents, and with TKIs in some settings. So, any hint of that on imaging or any hint of early symptoms I think is a warning sign that we need to stop, monitor, consider steroids and evaluate. DR LOVE: So, just curious, we see now T-DXd was actually approved in HER2-positive gastric adenocarcinoma in January. Maybe you can comment a little bit about your vision about T-DXd is exactly, and particularly what we’ve seen in terms of efficacy? DR MESSERSMITH: Neil, it’s very interesting. These antibody drug conjugates were really proposed back in the ‘80s and ‘90s, and it’s taken a long time. And one of the reasons is that that sort of purple part there, the linker, the linker chemistry has been very complicated and then also the payload. So, obviously, we know trastuzumab is a good antibody but a lot of the prior antibody drug conjugates, the warhead, that kind of toxic payload, would either come off too easily, in which case it’s basically a systemic drug, or it wouldn’t come off easily enough. And, until recently, they really couldn’t dial in the consistent ratio between the antibody and the warhead, the number of warheads that are on those antibodies. So, the field was kind of stuck for a while but now we’re suddenly seeing more and more of these trials coming out. And what I thought was really fascinating about the gastric, it’s not approved for it at this point in time, but it’s interesting, it kind of gets to the question do you need to rebiopsy? And we don’t. And if you look through the trial, you’re allowed to use archival tissue for eligibility. So, we do not rebiopsy. But what was interesting is, you still see some responses, not as many, not as much activity, but in 2+ FISH-negative or 1+, which is very interesting. It just tells you that as long as there’s some target there, that drug might have some efficacy. And getting back to the lung toxicity, we don’t do any kind of special monitoring outside of just asking patients about their symptoms. And remember, it was seen on a median of 80 days. And so, by 80 days, most of the time you’re going to have gotten a scan. And like Eileen said, you’re going to hear from your radiologist, if they start seeing infiltrates, you’re going to hear about it most likely because we have so many drugs that can cause these reactions. So, I think we’re not doing any special studies other than having a very low threshold to get a chest x-ray, etc, if a patient has any complaints. DR LOVE: So, again, the waterfall plot looks pretty impressive. We talked about the ILD which has been seen in all these cancers. Another thing I wanted to ask both of you about was T-DXd in metastatic colorectal cancer. And Eileen, even though it hasn’t received approval, I’m kind of wondering why, but in any event, any thoughts about T-DXd? And how often do you see HER2-positive colorectal cancer? And what are your thoughts about T-DXd? Have you used it? Would you like to use it? DR O'REILLY: No, I haven’t in colorectal cancer but in terms of frequency, so about 5% plus/minus, colorectal cancer will be HER2-positive, typically left-sided tumors and typically RAS wild-type and that’s the group usually application rather than mutation. And in in this setting, there’s a number of drugs now that have shown promising activity T-DXd also, based on the study that you just showed us there looks very active as well and I think is clearly going to go into development in earlier stage colorectal cancer. So, yes, so an exciting space. Small subset, but real subset, and definitely new options. DR LOVE: So, Wells, it never fails to surprise me what will pop up on my phone in the morning about FDA approval. When I saw this one I was sort of scratching my head a little bit. So pembro and trastuzumab and chemo, any comments, Wells? DR MESSERSMITH: Actually, this comes out of Eileen’s institution. So, the head of GI program, Dr — I always mispronounce it, Eileen… DR O'REILLY: Janjigian. DR MESSERSMITH: Janjigian. Right. So, she had presented a really impressive data set with basically a 100% disease control rate and 90% response in a prior study looking at the combination of chemotherapy plus trastuzumab plus pembrolizumab. So, they then launched a follow-up study. And I haven’t seen the results of that study yet. There’s a number of publications about the study design, but like you, I went through my cell phone about the approval. And so, hopefully we’ll see the data soon. But given how promising the initial experience was, I think it was 27 patients, if I’m not mistaken, I’m hoping it will be a very positive trial. And again, as with other immunotherapies, the hope is that the tail will flatten and that we’ll see these really nice, prolonged responses. DR LOVE: So, Eileen, any comments on this? But also curious about TAS-102, both alone and being studied now and reported in combinations. Where does that fit in your algorithm of management of metastatic disease, Eileen? DR O'REILLY: Yes, and maybe just one other thought of what we were just talking about in terms of the trastuzumab/pembrolizumab study with chemotherapy in the frontline setting. So that was a preplanned analysis that led to the FDA approval based on very high response rates. So, very much in support and in line with the original single-institution experience and exciting, as Wells was saying. We’ll hopefully see the data very soon in terms of the details. But clearly another combination that’s likely to become a standard in the frontline. So, going back to TAS-102, it’s active, right. We have fluoropyrimidine in GI malignancies. We know that from the colorectal cancer world. And David Ilson and Eric Van Cutsem and colleagues have looked at this in third-line esophagogastric malignancies and demonstrated very low response rate, small survival advantage. So, yes, it’s an option for patients and we use this in that setting. Hepatocellular Cancer DR LOVE: So, we’re going to move on now and talk about hepatocellular cancer. I mean there’s almost like no part of oncology that we don’t have a lot going on, and there’s a lot going on with HCC as well. We’ll jump in there with another case from Dr Dayyani, a 59-year-old man who has a history of hepatitis C, cirrhosis, esophageal varices, and HCC. You can see the patient presented with abdominal pain. Had a hemoperitoneum from HCC rupture. I’m curious whether you’ve seen that. Gets treated with TACE and other local therapies and actually ends up on the IMbrave150 study of atezo/bev. Here’s Dr Dayyani. DR DAYYANI: 59-year-old gentleman, hepatitis C, multiple rounds of transarterial chemoembolization. And at that time, we had IMbrave150 open. So, he was consented on that trial and was randomized to the atezolizumab/bevacizumab arm. At around 16 cycles, we had to start holding his bevacizumab repeatedly for advanced proteinuria. In February 2020, he came off for recurrent Grade 3 proteinuria. The question is for a patient who had atezo/bev, didn’t tolerate it, but he’s technically TKI naïve, do I switch him to a TKI given the fact that he had proteinuria? Or do we continue on one of the approved checkpoint inhibitors? DR LOVE: If he were not on the trial, what would you have done? DR DAYYANI: I would have kept him on atezolizumab. DR LOVE: So, Eileen, I’m curious now it seems like atezo/bev, there was actually an Asian study of a similar combination showing similar results. Seemed to have moved in firmly as first-line therapy. I’d be curious whether you have ever seen a severe problem with proteinuria like this and what you would do in this situation? DR O'REILLY: I think it brings up a few important points and maybe just to go back to the first one of presentation with acute pain and HCC. It’s a classic one, rare, but for rupture, and those patients need to be treated very emergently with embolization which was done and probably saved that individual’s life. So back to the question of proteinuria. So, I haven’t seen this specifically in HCC but for sure in colorectal cancer. And yes, occasionally you have to stop bevacizumab or anti-angiogenic therapy for that complication. For this gentleman, I would favor just continuing PD-L1 therapy with atezolizumab on its own. We don’t know that much in terms of whether there’s likely to be a difference between PD-1 and PD-L1 in HCC, they haven’t been compared head-to-head. And we don’t have single-agent PD-L1 data in HCC. But if this person has benefited, I don’t see why not in terms of that being that being option. In the absence of that, yes, we’d probably be able to continue single-agent PD-L1, would probably have gone to pembrolizumab as a single agent — we’re waiting additional data from Asia, but based on the original approval in the second line, this isn’t exactly a second line setting, but it would be justifiable. And just given the varices, etc, I’d be a little hesitant TKIs and would keep those in the background for this particular patient. DR LOVE: So, Wells, I’m curious, actually it’s only been I think about a year, year and a half since we saw the atezo/bev data, what your experience has been? Are you seeing responses? Does your experience line up what’s been seen in the trial? And in particular, whether or not your group is maybe moving away from some situations where they would use local therapy, such as TACE, to systemic therapy, such as atezo/bev now that we’re actually seeing some response? DR MESSERSMITH: I mean both of those are great points. Yes, I’ve been using atezo/bev really since its approval, and I’ve had very good experiences with it. Patients seem to tolerate it quite well. Sometimes I have to delay the bev a little bit while I’m getting varices banded or things like that, you are supposed to do a scope before starting just for the concern on the varices and bleeding. But thus far, it’s been very active. And I can tell you any patient who’s had one of the TKIs and experienced those toxicities, most of them are incredibly relieved with the lack — the comparative lack of toxicity with this combination. And it’s been quite active. So, I’ve been very impressed. And my clinical experience has borne out what was seen. In terms of the sequencing of therapy, indeed word is sort of slowly leaking over to the interventional radiologists that they can refer sooner than after the 20th TACE when they find lung lesions at the bottom of the scan. So we’re trying to remind them that we have more and more effective systemic therapies and I think it will be interesting to see some of these studies looking at combinations to see how best to sequence, how best to combine local therapy with systemic therapy. But it is interesting how often I’ll see a consult and the patients had many, many procedures and no one’s imaged the chest or the pelvis until it’s kind of seen incidentally. So that’s something that we talk about in our multidisciplinary conferences. DR LOVE: So, Eileen, the instant the IMbrave data came out, it also created a real question about what’s second-line therapy going to be because almost all the agents we’re using were not tested in this situation, usually tested after sorafenib. Let’s see where the audience is in terms of that. So, audience, you’ve got a 65- year-old patient, Child-Pugh A, PS0, first-line atezo/bev. What’s second line? So now it’s 18 months later, we’re going to say the AFPs up, just so you can include ramucirumab as a possibility. What’s your usual second-line therapy in a patient who responds to and then has disease progression on atezo/bev? And we’re going to get into a case in a second where this actually came up, this is an 80-year-old patient. And Eileen, when I look at the audience response in terms of second line, it looks like it’s cabo, number one, lenvatinib not far behind it. Some ipi/nivo. Ramucirumab. How do you think through second-line therapy in an 80-year-old, for example, Eileen, after atezo/bev? DR O'REILLY: So you’re right, it’s gotten complex, and I guess it’s a good problem to have that there’s, in relative terms, a luxury of choices. So, we sort of think about if a person’s had a checkpoint inhibitor first, then TKIs are second. And for most people, I think Dr Messersmith was saying the tolerability isn’t generally as nice as compared to immunotherapy for most people who don’t feel anything related to immunotherapy. But cabozantinib, regorafenib would be an option. Ramucirumab if the AFP is greater than 2 – 400, and a combination immunotherapy would all be options. I would probably think about maybe lenvatinib, but at a lower dose in an older person — 12 mg is the dose that’s FDA-approved in HCC, but smaller, older patients, we start at 8 and maybe that would be decision point. But you can argue for any one of these. And we’ll have more and more data of what’s happening in the second line as we see some of these frontline studies reading out over the next year to two years. DR LOVE: So, speaking of having problems on lenvatinib, let’s hear about an 80-year-old case that we sort of based this on. This is a patient of Dr Jeremy Lorber, an 80-year-old woman who presented with unresectable HCC. She had a pleural effusion and she was losing weight, 15-cm primary with satellites. And she actually got atezolizumab/bev first line. Here’s Dr Lorber. DR LORBER: This is an 80-year-old woman, was diagnosed with an unresectable hepatocellular carcinoma. I started her on atezolizumab and bevacizumab. She had some response for about 9 months, but then had symptomatic progression thereafter. She was started on lenvatinib in second-line. She was quite small and frail and had issues with stomatitis and nausea and was dose-reduced really to the lowest dose, and then developed what was eventually attributed to the lenvatinib sort of severe ulcerations on her shins, and sort of desquamation that required hospitalization for a short period of time. The lenvatinib was stopped and I had a discussion with her and her family if she is willing to try other agents that may have similar toxicities but unclear, and I started her on dose-reduced cabozantinib which she started in the last few weeks and has not had any issues thus far. So, with atezolizumab and bevacizumab establishing its role in first-line, where does that leave the remaining treatments? What is best to use in second-line? DR LOVE: So, Wells, any comments about this case? Any thoughts about how you generally approach second-line therapy? You mentioned about the dosing of lenvatinib. Also, where cabo fits in? DR MESSERSMITH: Like Eileen says, what I do is go back to what they’ve gotten already and then try to see what targets have we not covered or where has it been the greatest amount of time. I agree, in an older I would start at a lower dose of the lenvatinib at the 8 mg, I’m not sure what this patient was dosed at. I’ve never seen skin ulcerations from that drug. I guess if I had had that kind of reaction to a TKI, I might have thought about trying something different. But hopefully the cabozantinib will work out for this patient. And as we get into later lines, I might have thought about ipi/nivo in someone like this, basically trying to juice up the immune therapy and stay away from the TKI in case the skin problem might recur, especially if she got hospitalized. But because all these things have just been approved, we just don’t have a lot of experience with how things turn out as things are sequenced. I do use cabozantinib second line. But when someone got hospitalized because of the TKI side effect, I might be a little bit careful about using that. I don’t know if Eileen agrees. DR LOVE: What else would you be thinking about? DR O'REILLY: I think ramucirumab would be another nice choice in an older person, well tolerated, elevated AFP. And that might strike a strategy of eligibility in this setting. And reserving going to back to any additional TKIs until later, so probably keep cabozantinib in the background. But also, maybe going very gently with the dosing with ipi/nivo in subsequent line settings. Pancreatic Adenocarcinoma DR LOVE: So let’s finish out talking about pancreatic cancer. And we’re going to start out with a patient with localized disease. This is an 80-year-old woman who presents with jaundice, weight loss, pancreatic mass in the head of the pancreas with biliary dilatation. And her germline testing was negative. Here’s Dr Chen with her questions about this case. DR CHEN: Very nice 80-year-old female. She is considered to be operable. My questions are first about the benefit of neoadjuvant therapy followed by surgery versus upfront surgery followed by adjuvant chemotherapy. DR LOVE: What’s the follow-up with the patient? DR CHEN: We discussed FOLFIRINOX versus gemcitabine and nab paclitaxel and we decided to go ahead with the gemcitabine and nab paclitaxel. So, she currently has undergone cycle 1. And there are some additional questions after the initial treatment is that would surgery versus radiation after neoadjuvant chemotherapy to be a good option, in her case especially, given her age? And also, some additional questions would be if her somatic BRCA was positive or if NGS testing shows that she’s HRD-positive, would there be emerging data for PARP maintenance? DR LOVE: So, we’ll get to the PARP question in a second, but Eileen, first let’s talk about neoadjuvant chemotherapy in patients with what appears to be resectable disease, both younger and older patients? And then her question about follow-up local therapy, surgery versus radiation. DR O'REILLY: I think great questions and one a very active discussion at this time, what’s the standard of care for somebody with a resectable pancreas cancer? And I think it’s surgery or adjuvant therapy, that would be the default, versus neoadjuvant with a shift in favor of neoadjuvant. The attraction, of course, being the early delivery of systemic therapy in a systemic disease by nature. For an 80-year-old, I think one would be a little leery of modified FOLFIRINOX and would probably favor here gemcitabine/nab paclitaxel in that neoadjuvant intent. And we have support for this in a way from the SWOG 1505 study which looked at perioperative gem/nab paclitaxel or modified FOLFIRINOX, not comparing to each other but compared against historical controls of 3 months of chemo, surgery and an additional 3 months. And they were more similar than different with, if anything, waiting to gem/nab paclitaxel. So, yes, I think for many reasons that’s a very rationale choice. The question about radiation in resectable pancreas cancer, I think there’s not a lot of enthusiasm there in the preop setting, and that patient would go directly to surgery. It’s more if the patient ended up having locally advanced disease might radiation be a consideration for definitive local control, and I think all the data suggests no. But some more recent data is revisiting this question. We have further, how should I put it, maybe confusion coming from the Alliance trial that was presented at the GI cancer symposium which looked at modified FOLFIRINOX with or without SBRT in borderline resectable pancreas cancer and suggested that there wasn’t a value to the routine inclusion of SBRT. So, a lot of happening in this space. And just to also put in a plug for Alliance trial, which is addressing resectable pancreas cancer and addressing the sequence and timing of modalities, so comparing surgery plus adjuvant, being the traditional arm, versus neoadjuvant modified FOLFIRINOX followed by surgery and limited adjuvant. So that’s an open question. DR LOVE: So, the last issue and case that we want to talk about, this is a 79-year-old woman with pancreatic cancer and a BRCA germline 2 mutation. It’s really interesting when you see a strategy that’s used in different tumor types, how people think through things and maybe start applying one thing from another. We’re going to see a huge presentation of the use of adjuvant olaparib in breast cancer. We’ve already seen great data in ovarian cancer. This is an interesting case where a pretty creative approach was used and he’s very open about asking you all what do you think about it. Here’s Dr Dayyani. DR DAYYANI: Really nice 79-year-old lady, but robust, known to have BRCA2-mutated breast cancer, germline, had bilateral mastectomy and prophylactic oophorectomy many, many years ago, 5 cm mass in the central head of the pancreas. Main duct dilation and 180-degree encasement of the superior mesenteric vein. Ultimately, we kind of strategized to induce her for about 3 months with platinum-based chemo, in this case FOLFOX. And at that time, then tried to switch her to a PARP inhibitor. The first one available at that time was olaparib. I have to say she did tolerate it relatively well given her age. Nine months into her treatment, no progression, good response, remains unresectable. She received 33 Gy and had such a good response that we could actually take her to surgery about a year after her diagnosis. And path was a T1aN0. I think clearly trying to extrapolate to nonmetastatic to see whether the discussants think there might be additional benefit of trying to further achieve a cytoreduction by PARP inhibition that might then enable a better resection, or R0 resection, as we saw with this lady. DR LOVE: So, Wells, pretty creative approach, a 79-year-old lady. Any thoughts here? DR MESSERSMITH: So it’s a very interesting case. First of all, I definitely agree with using a platinum in this case. We just talked about an older patient where you might favor gem/Abraxane over FOLFIRINOX, and in this case using a double but making sure you have a platinum there I think definitely right call. And we are seeing this — some patients who are initially thought not to be resectable, over time became resectable, so-called conversion therapy, in pancreatic cancer. And of course, these days with the superb surgeons that are at all these specialized centers, encasement of the SMV can usually be reconstructed and even arterial reconstruction these days. So, it’s kind of amazing what’s going on. In terms of the use of PARP inhibitor neoadjuvant, that’s definitely, as you said creative. I have not done that. Yet, I can see the temptation especially an older patient. because of the POLO trial which did not show an overall survival benefit, but did show a progression-free survival benefit, and certainly there’s tolerability there. And Dr O’Reilly and others have been involved in designing follow-up studies so that we can try to get a sense of what is the best way to use these in a perioperative setting. Right now, that’s really not known. DR LOVE: So, Eileen, just kind of curious looking back at the POLO trial where the approval came out in the sort of the maintenance situation, we see a pretty significant benefit. Of course, these patients, the other arm didn’t get randomized to maintenance chemo, which is something bring up. I’m just kind of curious right now, Eileen, first of all, what abnormalities will get you to use a PARP inhibitor? Obviously, BRCA germline. What about BRCA somatic? What about other germline, other somatic? And how do you use it? Do you always use it as maintenance, Eileen? DR O'REILLY: All good questions. And just to add to the last patient, there’s been an ECOG study just activated looking at olaparib against placebo in the adjuvant setting, so we’re kind of excited about the OlympiA data and look forward to hearing that providing, I think, even more rationale for this. So back to POLO in the advanced disease setting and what genetic alterations would support the use of a PARP inhibitor. So, the FDA approval is in germline BRCA, but we have increasing — small numbers, but increasing reports in the literature showing value in somatic BRCA alteration. We have just published in JCO recently a single-arm study looking at rucaparib in the maintenance setting that had responses in somatic BRCA alterations. So, oncogenic somatic BRCA alterations I think are real and confer essentially equivalent benefit to germline alterations, in BRCA alterations in pancreas cancer. I think PALB2 is high up on the list, so somatic or germline BRCA1/BRCA2 with PALB2 are the core things. I think beyond that is still a very open question. With ATM, probably being the next most common one, but a lot of discussion as to whether ATM really does confer HRD and prediction for benefit for a platinum or PARP inhibition. That’s something that’s being looked at in a lot of studies. So, the other big questions on the table are building off of POLO is evaluating plus or minus immunotherapy. SWOG have an ongoing study. So that’s a key one, looking at olaparib with or without pembrolizumab just in germline BRCA1 and BRCA2, so the same core group as POLO was looked at. And with regard to the challenges of the POLO control arm, I think that’s going away. It was compared to placebo and not compared to chemotherapy. But nonetheless, I think looking after a lot of these patients there’s a big attraction to switching off of chemotherapy and the flexibility that an oral agent provides. I think with acceptable quality of life for most patients is a compelling reason, and platinum and cumulative 5-FU or even irinotecan get progressively wearing for people over time. DR LOVE: Do you ever use olaparib monotherapy, Eileen, as opposed to maintenance olaparib in advanced metastatic setting? DR O'REILLY: So, we do. Mostly if they’re platinum-sensitive or it’s been a long time since they’ve had platinum and maybe recur with small volume, relatively asymptomatic disease, I think that’s a perfect setting for going directly to a PARP inhibitor. The response rates are about 20% with PARP inhibitors. Chemotherapy, response rates are higher. So, somebody with symptomatic bulky disease, I think chemotherapy is still going to be your go-to, and platinum is probably the targeted agent of choice in BRCA-related pancreas cancer. So it’s hard to see that it’ll be an initial drug that will be used, but in an older person or in subsequent line of platinum-sensitive diseases, then, yes, I think olaparib is very reasonable. Introduction DR LOVE: We’re going to talk about AML and MDS with Drs Erba and Komrokji. Dr Harry Erba is from Duke University and Dr Rami Komrokji is from Moffett Cancer Center in Tampa, not far from us here in Miami. And faculty, as everybody knows, basically we’re making rounds with a bunch of general medical oncologists, mainly from the Medical Oncology Association of Southern California, presenting cases here today. And here are the cases we’re going to talk about with you. Myelodysplastic Syndromes DR LOVE: I want to start out talking about MDS. And I’m curious, Harry, if you’re going to take a more global look at MDS, it seems like there’s more happening in the last couple of years. We’re going to get into some of the specifics, but any sort of broad-brush strokes, about what’s been going on with MDS over the last couple of years, Harry? DR ERBA: So there has been a lot of activity, as you alluded to, of promising new agents, both targeted therapies, but also immunotherapies being developed in that space. Having said that, my impression of the current lay of the land is, there’s a lot of promise of what might be coming, but unfortunately, the number of treatments that are directed, the underlying disease state, remain limited, the IMiDs, lenalidomide and the hypomethylating agents. And then there’s luspatercept specifically for ring sideroblasts. I think I would rather defer to my colleague, Rami, whose actually led the way in the development of many of these new agents, for his perspective on what’s coming. But when I’m in the clinic, I still have a very limited armamentarium for my patients with MDS. DR LOVE: So, Rami, in addition to sort of a broad stroke of what’s new, also curious whether there are any myths or misperceptions you think that are out there in the community — I’m not going to say mistakes, but I know you see second opinions all the time. Any sort of things that you see people doing in the community maybe they could have done more optimally? DR KOMROKJI: So, I agree with Harry. I think there’s a lot of promising drugs in clinical trials that hopefully will translate to benefit. Obviously, indicate we got the first drug, the luspatercept approved, so that hopefully will be opening the gate. But to your point, we do see different things that happen at different steps of the disease course. I think first to stress on the bad news is, in many cases that’s straightforward but we obviously still see patients unfortunately, that did not have MDS, treated for MDS, or had MDS for a long time and were not treated. I think now it’s almost becoming standard to integrate molecule testing. So, I would emphasis need to check molecular status and obtaining next-generation sequencing for somatic mutations. In terms of treatment, we do still see some of the things that have been used for a while such as very liberal use of hypomethylating agents early in the course of the disease in the lower-risk MDS patients. Where, in reality, there is no need to use that option that early on. In the higher risk, still optimizing the use of hypomethylating agents, the right time of assessing the response. And obviously, thinking of allogeneic stem cell transplant in the higher risk, that’s something we don’t think of often in community. And knowing that the age limit had really extended in patients that have good functional status and no comorbidities up to probably 75, to consider transplant. So those are the main things I encounter usually in my practice. DR LOVE: So, let’s get into some cases here bring this into the real world, so to speak. We’re going to start out with a 73-year-old man who’s a patient of Dr Jeremy Lorber. The patient had ring sideroblasts and multilineage dysplasia. Here’s Dr Lorber commenting on the case and some questions for you all. DR LORBER: He was typically very healthy and active but presented with progressive fatigue that was interrupting his daily swimming and was found to be pancytopenic, borderline leukopenia, anemic, and a bone marrow biopsy was performed which was consistent with myelodysplastic syndrome with ring sideroblasts. Referred him for evaluation for allogeneic stem cell transplant. The evaluation was that he’s not a great candidate. Their center’s policy is for patients with a TP53 mutation not to treat with transplant. So he was started on decitabine. And he actually has had, through the present, complete normalization of his counts and he’s returned to his normal swimming routine. So, if and when, and it’s more of a question of when he loses his response, what is the next best therapy in a patient who has high-risk myelodysplastic syndrome? It seems that the pipeline for MDS after being somewhat dry for many years is more enriched. What is the most promising agent in the pipeline? Is there a role for treating MDS patient either up front or at progression like this patient with the addition of venetoclax, similar to an AML patient? DR LOVE: So, Rami, a lot of questions there. Can you comment a little bit on some of the things he brings up, including the issue of venetoclax HMA in MDS? DR KOMROKJI: So this is an interesting case. I would like to highlight first that obviously ring sideroblast subtype of MDS, we think of it commonly as a good subtype. But that’s the case especially when the myeloblasts are less than 5% and an absence of presence of complex karyotype and p53. Commonly, ring sideroblasts are associated with the SF3B1 somatic mutations, so that’s the genotype most frequently seen. But in cases where it’s not, it could be seen in the setting of increased blasts. And there is association actually in patients that have more than 5% myeloblasts, the ring sideroblasts — we’ve published that there is association with p53. So, this patient has a complex karyotype, p53 mutation, considered higher risk. And, unfortunately, those patients with p53 are probably the most harder to treat, to the point made that usually transplanting those patients, if they got to transplant with a detectable mutation, the outcome had not been optimal where the majority of the patients would relapse within a year. So, we follow the same policy. We try to clear the mutation if we can prior to transplant, rather than taking somebody with a detectable or higher allele burden of the mutation. So, I think the referral to transplant was very appropriate. If the patient was responding to decitabine, I think that would be an opportunity to think of the transplant or reconsider the transplant before losing the response. In general, patients with p53 mutation, the general theme of it that they do probably better with hypomethylating agents than intensive chemotherapy. So, decitabine was a very appropriate choice. And actually, they sometimes respond ever better than patients that don’t have p53 mutation in terms of upfront, but inevitably, as mentioned also, they all will relapse. In terms of active therapies for p53, they are mostly in the investigational arena at this point. There is a drug called magrolimab, which is an anti-CD47, that actually will bind CD47, which is a receptor that prevents the macrophages of eating the cells, so require the don’t eat me signal. And by blocking that, it will allow the macrophages to engulf the leukemia or MDS cells. It’s been tested in Phase I and II and currently in Phase III. The magrolimab seems to be agonistic of the p53 mutations, so the responses have been seen similar in patients with p53 or not. There is a drug that we were working on call APR246, that’s a p53 modulator. But unfortunately, the first results from the Phase III did not show superiority to azacitidine alone. But we are trying to look at if there are certain subset of patients that benefit from that. and there is oral formulation of it that’s moving into trial. Regarding the venetoclax in MDS, there are some early Phase I/Phase II, as well as a case series, including our case series published. The outlook looks promising in the upfront setting and also maybe as an add-back strategy in some patients. Probably the benefit, in my view, highly in patients that are going to transplant, prior to transplant. It’s still not approved in that indication. The only thing that I would highlight that in AML patients, patients with p53 don’t seem to derive most of the benefit from venetoclax. When we look at the data in AML, there was no difference in the overall survival between patients that got aza versus aza/venetoclax that are p53 mutant. So, unless somebody is hoping for a higher response as a bridge to transplant, I don’t commonly use venetoclax in the patients with p53 mutation. DR LOVE: Any comments on oral decitabine, and the cedazuridine/decitabine formulation, Rami? DR KOMROKJI: So, obviously, that was approved recently by the FDA, added to our options of treatment. It’s basically equivalent to IV decitabine. They did the studies nicely, where patients were randomized between either IV decitabine or the oral decitabine and then with a cross over. And the bio-equivalency is almost 99%. So this is an oral option available for patients. The FDA label approval is for patients with MDS, intermediate and higher risk, as well as CMML. It does not include AML by the FDA label. So, it’s an option for patients to get oral treatment. Obviously, doesn’t remove the need for monitoring those patients. The myelosuppression expectations are very similar to the IV decitabine. But it can be an easier option and one could envision that down the road we’re going to have completely oral regimens for treating with a high-risk MDS or AML for such example combination of oral decitabine and venetoclax. And at times where the COVID, where patients didn’t want to come a lot for clinic visits, having taking the pill at home was welcomed by many patients. There is oral azacitidine that we’re probably going to be touching, based on the oral azacitidine is not equivalent to the subQ or IV decitabine and bio-equivalency, while the oral decitabine is very, very similar to the IV decitabine. DR LOVE: So, Harry, I’m just kind of curious, and Rami mentioned the fact that this is not approved in AML, but if you could, would you use it with venetoclax in AML, oral decitabine in this combination? DR ERBA: Those studies are ongoing now to look at the safety, but the only reason why you might expect that there might be some issue with safety or efficacy is if there’s some interaction when both tablets are taken at the exact same time by mouth. But otherwise, you would expect the same degree of myelosuppression based on the pharmacokinetics and the schedule of the 2 drugs being the same. I think that would be something I would consider in my patients after they’ve achieved a response to parenteral hypomethylating agents and venetoclax. And I do it that way for maybe three reasons. Number one, it can take some time to get the prior authorization and a copay assistance that’s often necessary for a drug like oral decitabine with cedazuridine. And in AML, you want to move quickly. The second is I don’t have to worry quite as much about compliance when I’m giving IV, of course you’re giving oral venetoclax, but at least you know the patients getting the decitabine early on because they’re coming to clinic. I think the third most important is that when I start therapy high-risk MDS or for patients with AML, it’s typically because they have significant clinical effects of bone marrow failure and are requiring transfusions and are at risk of febrile neutropenia. So we do have to watch those patients very closely anyway and check blood counts at least — in my practice at least a couple of times a week, waiting for them to respond. So, yes, later on I think is something reasonable to do, obviously off label, because it’s with AML as a maintenance and in combination with venetoclax. But I do think it’s something you can offer to, especially an older patient who wants to maintain a quality of life of life after they’ve achieved a remission and are tolerating that combination of therapy without significant myelosuppression or complications. DR LOVE: So, Rami, I want to go back to magrolimab. It’s so hard for docs in practice to sort of get a feel for new drugs that are coming out, particularly in terms of their efficacy. I’m curious, I mean is this an agent you’d like to have available right now, Rami? Do you feel like you’ve seen enough that you’d like to be able to use it? Have you seen patients yourself who benefit? And anything else you want to say about the fascinating mechanism here? DR KOMROKJI: So, this is data from David Sallman from our group and we’ve worked with many patients to those Phase I/Phase II studies. There is no doubt that at least the experience we’ve had in the Phase I/Phase II had been very promising. And so, as we just discussed briefly, that it’s a monoclonal antibody that targets a receptor called CD47 that would be able to block the macrophages from attacking the cells and by blocking that, we’re allow the macrophages again to engulf or attack the leukemia and MDS cells. So, it’s in a point a macrophage immune checkpoint inhibitor. In turns out that in MDS as well as in AML, that CD47 is overexpressed and is associated with worse outcome as one would expect. So, the drug targets that. In the Phase I/II trial, the responses, compared to historical azacitidine, had been very promising, where around almost 90% overall responses were observed, complete response rates exceeding the 50%. Keeping in mind with aza alone, we expect overall response around 50% historically and somewhere between 15% to 20% response. So, this looks promising. The other part, as I mentioned, in terms of somatic mutations, we know certain somatic mutations are associated with worse outcome with hypomethylating agents such as ASXL-1 predicting less responses, or as we just discussed in the case presented, the presence of p53, magrolimab seems to be agonistic of all the somatic mutations. And the responses have been seen across in MDS and AML in patients with p53. In terms of tolerability, the treatment in general is very well tolerated. There is on-target hemolytic anemia that is observed in the first cycle where we titrate or escalate the dose. That’s because the mature red blood cells express the CD47, so it’s an on-target effect but obviously, one should monitor carefully for that. Other than that, it really doesn’t add much myelosuppression to azacitidine. And it’s now already the study, a Phase III there. And we really hope that this will translate to a benefit because, as Harry mentioned earlier, we’re really at unmet need to have more options for our patients, especially the higher-risk group. DR LOVE: So, one final question about MDS, Rami, can you comment on luspatercept a patient with low-risk MDS? DR KOMROKJI: So, luspatercept, as I mentioned, was the first drug to be approved in 10 years. It’s approved by the FDA for patients with lower-risk MDS with ring sideroblasts and transfusion dependent. The drug is a monoclonal antibody, fusion trap 14, that will bind and neutralize ligands of TGF beta pathway that tend to be important in what we call a determinant erythroid differentiation. So, erythroid differentiation maturation goes into different steps. The first steps are dependent more on erythroid stimulating agents, while the later steps are regulated by other mechanisms, including some of those TGF beta ligands. So, the drug will bind those ligands and release that block on the determinant erythroid differentiation. In this study, the MEDALIST, it was a randomization with placebo and obviously, the primary endpoint was met where almost 30% to 40% of the patients achieved transfusion independency with the drug. It’s a subcutaneous injection given every 3 weeks and generally well tolerated. There is some fatigue with it in the first few rounds, some joint pain and aches. But in general, less than 5% of patients discontinued because of side effects. No evidence of disease progression or AML acceleration. In my experience, and when you look at the data, the maximum benefit was really seen for patients with what we call a low transfusion burden, those patients that are not getting a lot of blood transfusions. So we try to use it earlier on after ESA failure in patients with ring sideroblasts. Would the benefit be just for patients with ring sideroblasts? I don’t think so. The early studies suggested that there could be responses in non-ring sideroblasts, but that’s subject of clinical trials. There is an ongoing clinical trial called the COMMAND that’s randomizing all low- risk patients with MDS between erythroid stimulating agents such as erythropoietin or darbepoetin versus luspatercept. And there are also some studies on the way in terms of combination with the treatment. Newly Diagnosed Acute Myeloid Leukemia (AML) DR LOVE: Well, let’s move on and talk about AML now. And Dr Amanda Blackmon has a 40-year-old woman. Harry, I’d like to hear your thoughts about this case. Here’s Dr Blackmon commenting on the case and her questions about it. DR BLACKMON: This is a 40-year-old female with no comorbidities who presented with bruising, found to have AML. Her bone marrow has FLT3-TKD and translocation of (8;21). She was treated with 7+3 and midostaurin and is in CR1. The question is should we transplant this patient population? Is gilteritinib being used in front-line treatment? In FLT3-ITD mutations, is FLT3-ITD low an indication not to transplant a patient? If this patient were elderly with AML, with a FLT3 mutation, what is the front-line approach for treatment? DR LOVE: What have you been using? At your institution, how do they approach older people with AML nowadays? Something like azacitidine and venetoclax with the addition of a FLT3 inhibitor? Or do you just do the hypomethylating agent with the FLT3 inhibitor? DR LOVE: Any questions you have about the use of HMA venetoclax in older patients? DR BLACKMON: In elderly patients who have cytopenias from their AML, do you dose reduce the venetoclax? Would you decrease the number of days of the hypomethylating agent? Do you choose decitabine or azacitidine at the time of diagnosis? DR LOVE: So, Harry, a ton of questions there. Maybe you can start out with a little bit of an overview of FLT3 AML and your thoughts about this case? DR ERBA: This is a great case and it brings up a lot of points. And it’s being presented as a case that wants me to focus on FLT3 mutated AML and quite frankly, I don’t think that’s the direction we should be going in this patient and I’ll come back to that. But to answer your question, about a third of patients with AML will have an activating mutation of the FLT3 tyrosine kinase. Most of these are internal tandem duplications. About 5% to 10% will be these tyrosine kinase domain mutations. In terms of prognostic impact, it’s clearly the ITD and especially at higher allelic burden that is associated with a worse outcome in AML. However, we’ve also learned that there’s clearly an impact of other mutations that are often present in this subtype that can also help to determine outcome. For example, data from Elli Papaemmanuil, published in the New England Journal, showed that the impact of having a FLT3 ITD was really only seen if patients had concomitant mutations of DNA methyltransferase 3A and nucleic phosphine. And it shouldn’t be surprising that other mutations affect this outcome since FLT3 is a very late event in leukemogenesis. But in terms of the prognostic impact of the TKD is really much less certain. However, having said that, Dr Blackmon is right, midostaurin, a first generation Type 1 FLT3 inhibitor and gilteritinib, a second generation also Type 1 inhibitor, are both active against both the ITD and the TKD mutation and through use of those drugs, they’re agnostic to the type of mutation. So, let’s look at the data that led to the approval of the midostaurin and that really was the international RATIFY led by our friend and colleague Rich Stone up in Boston. And in this study young patients, under the age of 60, like this patient, who had AML with either a FLT3 ITD or TKD mutation were randomly assigned to standard 7+3 followed by HIDAC with or without midostaurin, so midostaurin or a maintenance for 2 weeks following the chemotherapy and the induction and the consolidation. There was no difference in CR rates by protocol definition. We don’t really have any data on whether MRD-negative remissions were maybe improved. But there was clearly an improvement in survival with a 22% reduction in the risk of death at 4 years from about, I think it was 54% down to 40 something percent with placebo. So that was the basis of the approval, older patients. There was data from Germany using midostaurin in older patients that looked promising, compared to historical controls, in terms of event-free survival and an acceptable toxicity profile. So, the label is age agnostic for both. Having said that, what’s really the important target here in AML? What’s driving the biology? And I really think that’s the question that we need to focus on for this patient. In the RATIFY trial, only 22% of the patients actually had a FLT3 TKD mutation, but more importantly than that, only 5% had a core binding factor translocation 8;21 or infusion16. And so, we’re extrapolating a very large study with about 700 patients that were treated, the benefit being seen there down to a subset of patients that accounted for less than 10 patients with both 8;21 and a TKD mutation. In this patient, I would have focused more on the presence of a core binding factor translocation, the 8;21 or inversion16. The way I approach AML in a young, otherwise fit patient for intensive chemotherapy is I first look at what is the goal of therapy? And I don’t want to miss the opportunity to cure patients with standard intensive induction and consolidation. And we can clearly do that, especially in certain subtypes: the favorable-risk patients, core binding factor leukemias, and those with nucleic phosphine mutation without FLT3 and biallelic CBFalpha. In those subsets of patients, I may not need to think about sending that patient to allogeneic transplant in first remission. I think the totality of the data strongly supports in a patient with core binding factor leukemias to include gemtuzumab ozogamicin in a dose and schedule we could talk about in a second. The major reason for this is a meta-analysis of over 3000 patients treated with chemotherapy plus/minus gemtuzumab ozogamicin showed a survival benefit, not just remissions, relapse free survival, but a survival benefit. In the meta-analysis, it was improved from 55% at 4 years to 75% at 4 years. And so, I would have given her gemtuzumab. And then you’d have a long discussion about what dose, what schedule. Quite frankly, that’s one of the difficulties with using gemtuzumab, the anti-CD33 antibody drug conjugate. The approval was based on multiple different studies, including the alpha French study with the fractionated dosing. What I do is I give standard 7 + 3 and on day 4 I choose to give 3 mg/m2 or a capped dose of 4.5 mg of gemtuzumab, a single dose. It gives my pharmacist time to get the gemtuzumab into the hospital. Gives me time to get back the core binding factor FISH. But I’ll be honest with you, when I look at patient, I’m looking at FLT3 but I’m also looking at the results of that FISH analysis to drive the decision about giving gemtuzumab. And in a patient who gets gemtuzumab with standard induction and consolidation, I actually don’t consider them for transplantation. I think what Dr Blackmon is alluding to is the concern from a number of studies that the presence of receptor tyrosine kinase activating mutations and core binding factor leukemias is associated with a worse outcome. And I think the story is so much more complicated than that. There’s a difference between the ITD and the TKD. There’s a difference in how these mutations interact with 8;21 versus inversion16. There’s an effect of the allelic burden. And most importantly, there’s an effect of the concomitant mutations again, where it’s been shown by some that it’s the presence of cohesin mutations or chromatin modifying mutations like the spliceosome mutations that really impact negatively in the presence of a receptor tyrosine kinase mutation. And finally, what I think is going to be most important determining for a patient like this or any patient with AML about whether they should undergo stem cell transplant in first remission is, instead of all this baseline risk stratification, we get the most important data and that is the sensitivity to whatever regimen we’re choosing, intensive chemotherapy regimen, by looking at measurable residual disease, in this case we have a marker by RT-qPCR of the Runx1, Runx1T1 fusion. And so, there’s a lot of data out there that you can use to at least monitor a patient, look for depth of response, and help make that determination about whether to transplant in first remission. I think I’ll a breath there. I know she had other questions. DR LOVE: I was going to say I love talking to you guys about AML and MDS. I could listen all day long and maybe pick up a quarter of it. But, anyhow, hopefully, people out there are picking up more. But let’s get back to the other question that Dr Blackmon had, I’m actually going to put out here to the audience, and Rami, you can respond to this question after we see what the audience said. How do you approach an older patient not eligible, a 78-year-old patient, for intensive chemo, intermediate-risk AML with FTL3 ITD mutation? So, Dr Blackmon brought up a bunch of possibilities that could be considered. And it looks like actually Rami, the most common answer in the audience is just straightforward HMA/venetoclax. We see HMA/FLT3 by a smaller number and all 3 of them together, HMA/venetoclax and FLT3 by another group out there. So the most common just HMA/venetoclax. Rami, how do you approach AML in a patient with a FLT3 who’s 78 years old? DR KOMROKJI: So that’s a good question as well. And I don’t if we have one answer, that you probably see different opinions about this. In terms of the HMA/venetoclax combination there is no doubt that it’s active. The response rate was high. The responses were not as durable as other subtypes, for example, like the IDH1/IDH2 mutant, those patients derive the longest response from the HMA/ven, all the MPNs. The FLT3 ones had a little bit less response. But definitely an improvement over the use of hypomethylating agent. In terms of the combinations of HMA and FLT3 inhibitors, I think there are several ongoing studies. The data with the midostaurin, those are small studies; that they did seem to historical comparison seem to be very promising. There was some recent data, also I think with the gilt upfront that did not meet survival advantage. And partly because also those patients, we have to start thinking of sequence of therapies, that they could get the FLT3 down the road. So, I think the mainstream now is probably considering hypomethylating agents/venetoclax. However, those that choose the triplet combination is also very interesting. There is data coming out from MD Anderson looking at combinations of gilt, ven, HMA, that looks very promising. Obviously, this is going to be a myelosuppressive combination and some of the dosing we have to figure out on study. But I think that’s where we are going to be moving to. Do I do it in practice? No, not yet. I’ll probably stick either to HMA/ven, or I don’t think it’s totally unreasonable to do HMA/FLT3 inhibitor in this setting. DR ERBA: If you don’t mind, can I add on to that? DR LOVE: Sure. DR ERBA: I agree with everything that Rami has said. I don’t disagree with it. But in terms of a practical approach for people out there seeing AML, I told you in the young patient that I’m looking for a curative path, maybe not even including transplant, just with chemotherapy, I do use the cytogenetic and mutational data, FLT3 and the FISH analysis. In the patients who I look at and I know they’re not going to be able to tolerate intensive chemotherapy and I’m going to use HMA/venetoclax, I don’t think we need to wait for any of this mutational data. I agree with Rami, we could see outcomes that differed based on subsets, IDH1/IDH2, MPN doing very well in terms of response and duration response. FLT3 and TP53, also having very high response rates; it’s the durability that is short. But in that situation, the question is, but do I have something that I know is better? And the answer, in my mind is, is no. So, if I have a patient that I don’t think I’m going to give intensive chemotherapy to because of fitness or comorbidities or patient wishes, I don’t need to wait for all of that fancy data unless I have a clinical trial. In terms of his comment about the combination, I agree with the very little data from midostaurin, no randomized data. In terms of gilteritinib, there’s the top line result from the LACEWING study of aza/gilt versus azacitidine alone showing no survival benefit. And I think what that really brings up is what Rami alluded to and that’s the sequencing of these drugs that we can now do. So my typically older patient, I’m going to start with HMA/ven and have Plan B ready. If they relapse with FLT3, that’s when I’ll give them gilteritinib. The one exception that I use for the combination is in a patient with relapse disease or an older patient that I don’t think could get intensive chemo but might be able to get to transplant, I think the data from MD Anderson suggests we get deeper responses. The problem with those deeper responses is that although they’ve reported an 85% response rate, the vast majority of those are what we call morphologic leukemia-free states, meaning you don’t see the AML in the marrow, they showed MRD-negative remissions, but the counts don’t recover. So, for the 78-year-old, they need counts. They need counts to be able to survive and have a good quality of life. For the 60-year-old or 70-year-old or even 75-year-old that I’m trying to get to transplant, it might appease my transplant colleagues who are telling me to get rid of measurable residual disease. So it depends on what I’m going to do after the initial therapy that helps guide the triple combination in my mind. DR LOVE: This is patient of Dr Hatim Hussein, a frail 85-year-old man with AML who actually gets treated with decitabine and venetoclax. Initially diagnosed in 2019 with MDS, got ESA for that, but then presented with AML earlier this year. Here’s Dr Husain. DR HUSAIN: So, he's currently getting his decitabine/venetoclax. And he's tolerating it pretty well with normal blood counts. The patient is doing well but one of the things that we wanted to discuss is, what the panel thinks about the next line of therapy, when and if it’s needed? And then lastly, this patient did receive epoetin alfa for the MDS. I heard about some recent data with luspatercept and more information about that would be really helpful. Where are we at in terms of oral considerations for they hypomethylating agents I think would be fantastic. DR LOVE: Do you think if this man were able to get oral decitabine or azacitidine, in terms of his particular situation do you think it’d be advantageous? DR HUSAIN: Yes, I think it actually would be. It would be very helpful to have that. He is frail, a frail person. He’s 85. And so, I think that it would be a nice thing for him. DR LOVE: So, Rami, we talked about a couple of these issues already, but what about what follows HMA/venetoclax? Anything out there, or palliative care? DR KOMROKJI: So this is obviously the case, a classical secondary AML progressing from MDS. And I think the choice of therapy is reasonable. Maybe also to cover a part we didn’t cover in the prior case is the dosing, and that’s an important issue. And the subtle differences from what we are used to do with hypomethylating agents, that the combination of decitabine/venetoclax is pretty myelosuppressive upfront particularly. So those patients will need a bone marrow reassessed within a month. Historically, with hypomethylating agents alone, we repeat the bone marrow after 4 to 6 cycles sometimes. But with venetoclax the dosing in the first cycle is the full dosing, usually 400 mg daily, but if patients are on some prophylactic antibiotics, we dose reduce them accordingly. At the end of the month we repeat the bone marrow. And that’s very important because in the majority of those patients will get profound myelosuppression, a hypercellular bone marrow and no blasts, and in that setting we need to back off the treatment, hold both the decitabine as well as the venetoclax, and once we get some count recovery we restart and often what we are doing is really we are backing off the dose of venetoclax in those patients. Nobody knows the exact time and dosing, but some people think somewhere between a week to 3 weeks of venetoclax, or even dose reduced, would suffice after you get into that remission status. So those are important points to keep in practice. Please re-evaluate those patients earlier on. If one continues several cycles of venetoclax may get into profound neutropenia or cytopenias. In terms of the luspatercept, in the lower risk MDS we covered that. Obviously, if those patients had ring sideroblast type they would benefit in terms of anemia. There is no indication at this point or data to suggest that it will alter the natural history or prevent the progression to acute myeloid leukemia. In terms of the next step, that gets challenging. The group from MD Anderson started putting data out there on outcomes after HMA/ven failure and that’s been a challenging group. I would say, in general, our approach, obviously is there’s a clinical trial to consider those. And always look at the molecular profile for those patients. We do repeat, if the patient’s had a NGS panel done upfront, we will repeat it at the time of the relapse because every now and then we’ll see a clone that emerged or subclone that has a mutation that could be targetable, for instance something like IDH1 and IDH2. There are oral drugs available. Sometimes there are some targets that we use drugs even off label to go after that. Short of that, going after a targeted therapy, I think the options are really limited after HMA/ven failure in this setting. DR LOVE: So, Harry, I don’t know about you, but I kind of lost track of time. I was looking at this paper thinking that was last summer. It seems like about 5 years go. But anyhow, maybe you can comment a little bit on these landmark data, both in the VIALE-C and VIALE-A study and what your key takeaway was. This is the VIALE-A study. Anything you want to say about that, Harry? DR ERBA: Yes, I think what’s important here is, the FDA approval came out before this publication based on the Phase I/II data looking incredibly promising with the promise of having the VIALE-A data to support an accelerated approval, which was on November 2018. So, we have been using it for a while. I think what’s most important about those survival curves is not only the difference in median survival, with an improvement in median survival you could see from about 10 months up to about 15 months, but more importantly that, if you look at all the censor marks out there between 18 and 27 months, it’s remarkably different between the 2 arms. If you go way back to the AML 001 study of aza alone versus conventional care regimens, the median survival, there was a trend for improvement in median survival, but those curves by 24 months were back together again at about 10% to 20%. So of course, we don’t know if this is curative therapy. We don’t think it is. But we do really seem to be improving the outcome of these patients. And the benefit, as you can see here, was seen across subtypes. I made the comment about p53 in FLT3, although the remissions are not as durable and survival was not better with the venetoclax-containing regimen than aza alone, the response rates are important. And that’s an important consideration because the second most important thing besides the increased response rate, is the timing to responses. Rami alluded to two thirds of patients get a response and two thirds of those are after cycle 1 and most of the remaining are after cycle 2. So we have to look early to know how to hold the venetoclax and not start the next cycle until they have count recovery. So, I think that really is critically important here. So, this has really changed the standard of care. I haven’t treated so many 80- and 90-year-olds with AML in my 30-year history as I have in the last 2 years since this regimen is available. And having said that, I am very tuned into quality of life for these patients. I think moving to an oral regimen may help with that quality of life, but they can often get into a response and tolerate these drugs for prolonged periods of time. DR LOVE: Really, what an amazing advance. Rami, any thoughts about IDH? One of the most dramatic examples of benefit here is in the IDH subset. We didn’t talk very much about the use of IDH inhibitors. Any thoughts about how these data affect your practice particularly older patients with IDH mutations? DR KOMROKJI: So, just going back to the case, I applaud the doctors for treating those patients because even until now, sometimes we see reluctancy in treating older patients with AML. Obviously, with good intents, sometimes not to harm those patients. But unfortunately, leukemias are going to affect the quality of life. And data are clear from even the pre-venetoclax era that patients that get treatment do better in terms of survival, in terms of quality of life, and even the short-term mortality actually is better with treatment than no treatment. And I think adding the venetoclax for patients that are older is appropriate. In my practice I see them tolerating it. That goes back to the key point that Harry and myself were trying to stress is the monitoring for those patients. Now the IDH1/IDH2 subset is obviously an interesting group. In the subset analysis from that study in the New England Journal, those patients drove the most durable responses and high responses from the aza/ven. We know that for both patients with IDH1 mutilation or IDH2 mutation drugs approved by the FDA, enasidenib for patients with IDH2 mutation, as well as ivosidenib for IDH1 mutation. The studies looking at combination aza IDH inhibitors, again in the upfront setting, have not translated to an overall survival advantage. Again, going back to the same point that in my mind it’s the sequence of those therapies. The data with aza/ven is really very promising and very strong in patients with IDH1/IDH2 mutation, but I think those patients should definitely be considered for that. Very high responses, very durable responses. Are there settings where I would consider single-agent IDH inhibitors in leukemia treatment? In cases like this where patients have history of MDS, if they were on prior hypomethylating agents, and particularly for a long time, HMA/ven becomes obviously less appealing option. So for some of those patients a single agent IDH inhibitor could be the frontline therapy for patients with AML. But to be honest, with that strong data with aza/ven for patients that had no prior HMA, I think, in my mind, it should be the frontline choice for treating those patients. DR LOVE: So, Harry, of course there was also the VIALE-C trial with low-dose ara-C, less excitement, less use of low-dose ara-C in the United States, but they still did see a benefit. And I’m just kind of curious, are there situations where you use this strategy, particularly in the situation Rami just brought up which is the patient previously treated with HMA for MDS. DR ERBA: That’s a great question and there was a trend for improvement in survival, as defined by the primary endpoint analysis of VIALE-C, but it didn’t reach statistical significance. But with further follow-up the did see a survival benefit as you might expect. I mean the only thing that really keeps me from using low-dose cytarabine is just logistical issues in our own practice, which may vary from place to place. I mean if a patient can get low-dose cytarabine at home and do self-injection, it’s clearly much more convenient for the patient. So, I wouldn’t discount that as an option. And then, as we’re waiting for more data on oral decitabine or even someday, oral azacitidine with venetoclax. So, I think it goes on to just support the overall benefit of adding venetoclax. In terms of a patient who’s on a prior HMA, you’re right, the VIALE-A in the Phase I studies excluded patients who had had a prior HMA. The VIALE-C did not exclude those patients. And in the Phase I study, there were about 24 patients actually, who got ara-C with venetoclax who had been on prior HMA. The overall response rate was about a third. Almost all of them were CRis. So, yes, I mean it’s something that you could do, but I’ll be honest, I’m not really certain if it wouldn’t be just as easy to continue the HMA and add in venetoclax if a patient progresses. Of course, there’s not data to defend that, but, logistically, it’s an easy to thing to try. And I’ve clearly seen response. The only other place I would consider for an IDH mutated patient, IDH1 or IDH2, to use ivosidenib or enasidenib, would be potentially a patient who wants to get all oral therapy and not come in for anything parenteral. And the second is, Courtney DiNardo presented some interesting data at EHA, and I think it’s now been published, that in the patient’s getting aza with ivosidenib, there seemed to be neutrophil count recovery really early during cycle 1, which I have actually seen in my own patients. So, if you have an older, very infirm patient with an active infection let’s say, getting them back neutrophils more quickly during cycle 1 might be the way to go in that situation. But otherwise, I agree with Rami, it’s hard to walk away from what we see in the IDH mutated patients getting either HMA or low-dose ara-C with venetoclax. Secondary AML DR LOVE: So let’s finish out. I want to talk about secondary AML. We have a couple of cases that docs have questions about, beginning again with Dr Husain who had a 65-year-old man who developed AML while receiving therapy for adenocarcinoma of the lung. Here’s Dr Husain and his questions about this case. DR HUSAIN: He did get cisplatin/etoposide and radiation. And one of the confusing things is the latency. This was only 3 years ago, so it's a little bit weird in the sense that some of the genomic changes on the bone marrow suggest more of an alkylating kind of response with the monosomy 7. This new diagnosis of AML that really speaks to some of the complexities with treatment-related AML. What is new in treatment-related AML? What are some new therapies and approaches, prognostic and genomic characteristics that can help us understand what therapeutic strategies may be applicable for a patient? My colleagues had brought to my attention a new medicine, CPX-351. Can you please tell us a little bit about this medicine, and the pros, the cons and its applicability in this case? DR LOVE: So, Rami, any thoughts about this case? DR KOMROKJI: So, obviously, secondary AML is a collective term we use to include both AML proceeding from MDS, as well as therapy-related AML. In this case, by temporal correlation, is probably labeled as therapy-related AML, those typically are around 10% of the AML/MDS cases. As we successful treat more solid tumors, we are seeing more patients obviously develop this, unfortunately. The points raised by Dr Husain are very valid. There are 2 types of therapy-related AML, one we call Type 1, typically with alkylating agents, classically will see the chromosome 5 or 7 abnormalities, and with a latency of 5 years plus, they go into lower-risk MDS, then the progress. And Type 2, which is usually related to topoisomerase with shorter latency such in this case, and typically like the 11q23, the MLL gene rearrangement. However, I think in practice we do see those cases that develop, they don’t follow the book exactly. A question always had been, why do patients develop this? And if you look at the data for patients, for example, or autologous transplant after myeloma or non-Hodgkin lymphoma, the risk is pretty high and sometimes even, you don’t see a plateau of the risk of therapy-related AML/MDS. In patients getting adjuvant therapy for breast cancer, around 1%, somewhere, will get therapy-related AML/MDS. In the past, we used to think that there are different pharmacogenomics for the treatment or drug metabolism. In the last few years we’ve learned a lot about this CHIP, clonal hematopoiesis of indeterminate potential, that many of those patients already have acquired some somatic mutations or a first event in clonal hematopoiesis. Our group and the MD Anderson group published almost the same time, data showing that those patients that had evidence of CHIP and those common mutations like TET2, DNMT3A, that if you sequence 100 people walking in the street above age of 70, around 20% of them will have them as part of senescence of the cells where you get some clonal hematopoiesis. If you look at those patients, the risk of developing therapy-related AML or MDS was 12-fold higher. So, it’s almost like a two-hit theory that those patients already had some clonal hematopoiesis and with further chemotherapy you select those clones and get subsequent mutations. And in my mind, although we didn’t translate that to practice yet, that would be something important for people that treat solid tumors in the future, if the absolute survival benefit of an adjuvant therapy, for example, is 3%, but then you find that those patients have a CHIP and they be at 10% risk of therapy-related AML/MDS, that may change our benefit-risk estimate for recommending those treatments. Now, in general, patients with therapy-related AML or secondary AML/MDS do worse than primary de novo AML and that’s primarily or mostly driven by the cytogenetics. Most of those patients, 70%, 80% of them will have complex karyotype, highly enriched in p53, chromosome 7 abnormalities and M5 abnormalities and so forth. And the best outcomes for those patients obviously is with allogeneic stem cell transplant. In terms of the management, obviously we follow still the same algorithm. We decide, are those patients for intensive chemotherapy or not based on disease features as well as patient comorbidities and functional status. For patients that can’t receive intensive chemotherapy, CPX-351, as mentioned, is a drug that was approved by the FDA for this setting. So, what’s CPX-351? It’s really a daunorubicin/cytarabine that’s liposomally packaged in a certain molar ratio, 5:1 of cytarabine to the anthracycline that will allow better delivery and better leukemia kill cell, more uptake by the bone marrow and a little bit more prolonged exposure of the leukemia cells to the drug. It went through Phase I/Phase II trials that suggested that the maximum benefit or potentially the signal of benefit was in patients with secondary AML, including those coming from MDS, or therapy-related. And the Phase III trial focused on that group of patients, randomized to 3+7. Response rates were higher. The short-term mortality was less. And overall survival was better with the CPS-351 compared to the 3+7, particularly in patients that were HMA-naïve that had never had exposure to hypomethylating agents before. And what’s intriguing to me is the data about CPX-351, particularly in the setting of transplant. So those patients that proceeded to transplant seemed to do very well when the bridge or the induction regimen with the CPX-351, the responses seemed to be deep. And that’s the hypothesis, that maybe we are achieving a better MRD-negative status with that. So, compared to even patients that went into remission with 3+7 and got transplant, the curves with CPX-351 post-transplant looks promising. It’s also the same, even patients that did not proceed to transplant, it looks like the outcome for those patients is better. Dr Lancet updated the results. And it looks like almost at the 5 years, there’s around 20% survival with the CPX-351. So, currently, by the label, by the NCCN Guidelines for patients that have secondary AML, if they are fit for intensive chemotherapy, that’s where we think of using CPX-351. DR LOVE: So, let’s finish out with one more case. This is from Dr Lorber, a 74-year-old man who actually got CPX-351. Here’s Dr Lorber. DR LORBER: I ended up starting him on the liposomal daunorubicin and cytarabine. He got induction. He did require a short hospitalization for a neutropenic fever, but unfortunately, as of a week ago, he actually recurred with cutaneous manifestation of his AML even though his peripheral blood did not have evidence of a recurrence. DR LOVE: What did the cutaneous stuff look like? DR LORBER: It looked like sort of dark gray nodules mainly on his back and some on his extremities. I plan to use probably HMA and venetoclax regimen. For this patient that is transformation to AML, what would be the most appropriate therapy given that he is somewhat elderly. Is liposomal daunorubicin and cytarabine worth the extra toxicity versus the other option which would be an HMA agent and venetoclax? DR LOVE: Any questions you’d like to throw out there about using HMA venetoclax? DR LORBER: Yeah. So, there’s always the problem of initial cytopenias often from their underlying disease. There’s different strategies that I’ve heard in terms of managing it, in terms of either dose reductions, holding, changing cycle duration, having venetoclax not given every day, and is there an optimal strategy? DR LOVE: So, Harry, I’ll give you the final comment. I should have mentioned, this man had prior MDS that was treated with ESA. Any comments about this case? Also, the cutaneous disease without any marrow abnormalities, have you seen that, Harry? And also, his question about dose modification of venetoclax? DR ERBA: So, we definitely see relapse of AML in extranodal sites, the skin being one of the most common, called leukemia cutis. It may accompany at the same time, systemic relapse or it could be isolated, or the systemic relapse would come later. But it’s treated, whether it’s a primary manifestation of AML or at relapse, it’s treated the same way with systemic chemotherapy. In terms of this patient, you really need to look at the goals of care. He’s 74. He’s otherwise healthy except for his atrial fibrillation. He’s had MDS. And now he has progressed into a secondary AML. And the question that he brings up is would this be a patient that I would think about for CPX-351 or liposomal daunorubicin/cytarabine? And I definitely would, but it would be after a very thorough conversation with the patient about his goals in life, and if he wanted to pursue therapy with curative intent, then I would consider giving him CPX-351 and getting him to an allogeneic transplant in first remission. Now a question came up on the last case about any molecular predictors in patients with treatment-related AML and I’ll stick to how about in CPX-351? Coleman Lindsley from Boston looked at about two thirds of the samples from the Phase III study at baseline to see if there were any genomic predictors of outcome. Now, he only had enough data on either group of mutations like the mutations associated with secondary AML which are the spliceosome mutations and the chromatin modifier mutations, or single mutations like FLT3 or p53. Let me just focus on the data he presented for the secondary AML type mutations with the chromatin modifiers in spliceosome mutations like the UTAF1 that this patient has, that was a subset of patients in his presentation that clearly showed a survival benefit compared to 7+3. So, unlike p53 where there was no benefit compared in terms of survival. So, I think that would be a very reasonable option for this patient. If I was using HMA/venetoclax, I think this is the most important thing that listeners have to get out of our presentation and others on this combination. If we’re going to see the same outcomes that were seen in the trials, we need to follow what the investigators were meant to follow. You do a bone marrow at day 21, as early as 21 to 28. Less than 5% blasts you hold venetoclax. You allow count recovery. You can use G-CSF. And then you start the next cycle when counts have recovered to an ANC of over 500 or 1000. And in subsequent cycles, I reduce the dose of the venetoclax. So, if it was only 21 days to get in remission, give 21 days in the second cycle, not 28 days because it only took 21 to get in remission. And if they had prolonged cytopenias then during cycle 2, for cycle 3 I will give on 14 days. And as Rami said, with each cycle I’ll go down even 7 days of therapy. No one knows how many doses you need, but I would continue both agents together. And I don’t reduce the daily dose in an effort to get around myelosuppression. I reduce the daily dose based on drug-drug interactions, but not to try to get around the myelosuppression.
Introduction
DR LOVE: We’re going to be talking about lung cancer. This is Real World Oncology Rounds. This is our 10th year working with the Medical Oncology Association of Southern California. We’re usually hanging out in Santa Monica at the Fairmont Hotel with that great tree out front, but, well, we’ll just have to keep that in our mind today as we finish out talking about lung cancer. Here’s where we’ve been today, starting earlier this morning, finishing up today with lung cancer. We have a great faculty, Dr Ross Camidge from the University of Colorado and Dr Ben Levy from Johns Hopkins. We have a bunch of general medical oncologists who’ve been presenting cases all day long. I worked with them over the last few weeks to record these presentations and present them to you today. We have a whole bunch of them we’re going to try fly through in the next hour, so we’re going to just jump right into this, and we’ll talk to the faculty in a second. Localized or Locally Advanced Non-Small Cell Lung Cancer (NSCLC) DR LOVE: But let’s start out with this first case from Dr Sandip Patel. This is a 57-year-old woman with locally advanced non-small cell lung cancer who actually got concurrent chemoradiation, consolidation durvalumab, but interestingly, as you’re going to hear, presented with a complication sometime after she completed therapy. Here’s Dr Patel describing the case and his questions. DR PATEL: She got concurrent chemoradiation with weekly carboplatin/paclitaxel followed by consolidation durvalumab for a whole year. And she did great on her scans, there was no evidence of disease recurrence. Her cough got better. She had a good quality of life, and she actually had a couple scans that showed no evidence of cancer even after she completed her therapy. However, all of a sudden, she presented to the emergency room about 6 months after her last dose of any immunotherapy with a blood sugar of 650 and a creatinine of 4. This presented as DKA. She was acidotic. Our concern was immune-related Type 1 diabetes, and so she did in fact have anti-beta islet antibodies develop. She remains on insulin to this day. DR LOVE: I’m curious how easy or difficult it’s been to control her glucose with the insulin? DR PATEL: It’s been very difficult. We’ve had our endocrinologists involved. So I’d be curious to hear from the investigators what they would do after the acute crisis of the DKA had been managed and the patient is on a stable insulin regimen. DR LOVE: Any questions about the use of durvalumab? DR PATEL: I’d also be curious if the timeframe in which one typically starts durvalumab after completing radiation. Some suggest if you start within 2 weeks maybe those patients do better. DR LOVE: So, Ross, any thoughts about this? Have you seen Type 1 diabetes as a complication of immune therapy? If so, what’s it been like to manage these patients? How long? When does it occur, usually while they’re on treatment? DR CAMIDGE: So, I haven’t seen it, but I mean it’s certainly been recorded. I mean any ‘itis’ you can get as a consequence, and as we see in this case, and after you’ve stopped the immunotherapy. So, it’s particularly kind of iniquitous that you an unmask something and it takes a while to sort of clinically manifest. I mean I think you just have to work with the endocrinologist to try and control it. DR LOVE: So, Ben, any comments — now it’s been a couple of years since we saw the PACIFIC data, now it’s become really a part of clinical practice. What are some of the issues that come up? Dr Patel was bringing up the issue of the timing for starting therapy. A lot of times these people are having residual problems form their chemoradiation. How long do you feel comfortable waiting? And any other issues that have come up in this setting that you want to comment on? DR LEVY: I think the timing has been one of the things that have been discussed quite frequently and clearly, in the trial, you had up to 42 days to give durvalumab post-concurrent chemoradiation. And a lot of patients can’t start right away. They need some time to recover. There are times that I will wait past the 6-week mark to give them durvalumab if they need more time to recover. Tucked away in the Appendix of the trial was that patients did the best if they started durvalumab within 14 days. Now, that may be more indicative of the patient population that was able to receive durvalumab within 14 days, a fitter patient. But nevertheless, for me, I try to really start them within 2 to 3 weeks. One of the issues that also comes up, do you need a CAT scan post-concurrent chemoradiation? Does that really guide your therapy? We want to at least evaluate for stable disease, so we do a CAT scan within the 1- to 2-233k mark post-concurrent chemoradiation just to make sure that they have stable disease and then from that point on, schedule them for durvalumab if they’re ready to go. DR LOVE: So, Ross, again it’s been a couple of years since we’ve had this strategy out there. I’m curious what you’ve seen in your clinical practice. One of the initial concerns with pneumonitis, we know you can get that with a checkpoint inhibitor, you can get with chemoradiation, you can get that with COVID, obviously. I’m curious whether you’ve had situations where you saw pneumonitis and was it always clear what it was from? How you manage it? DR CAMIDGE: Well, I think one of the clues is the radiation-related pneumonitis is still going to have some geographical limitations on it. I think a classic, sort of autoimmune pneumonitis is going to be much more bilateral and everywhere else. So, that would be a clue as to what it is. Certainly, also the timing. We know that radiation pneumonitis usually peaks about 3 months form the end of the radiation. I personally haven’t seen it that much as a kind of deal-breaker. I think the biggest burden is when we started to do this, we were giving the treatment every 2 weeks and you got to know your patients really well because they were coming in, but I think we now have some more relaxed dosing schedules that we can use. DR LOVE: So, Ben, how are you thinking through the issue of patients in the unresectable locally-advanced situation who have targetable mutations? EGFR? ALK? Obviously, we have the big adjuvant osimertinib trial that’s been out there for a year, really changed the way people, I think, think about targeted therapy. We’ll talk in a second about the use of checkpoint inhibitors in the adjuvant setting. But do you still use the durvalumab approach in patients, for example, with EGFR mutations? Do you ever think about following it up with osimertinib? Later on? What about the issue of the patient who relapses after durvalumab? And the question of increased toxicity with targeted therapy after an IO? DR LEVY: All great questions and my decision-making is often predicated on a lot of extrapolation, extrapolation “cubed” maybe. We know from the subset analysis for the EGFR-positive patients in the PACIFIC trial, those patients did not derive a benefit with consolidative durvalumab versus placebo. Small numbers, exploratory analysis, and has to be approached with caution. But then comes along, the ADAURA trial which shows, at least in the resected Stage III setting, there is a benefit with adjuvant osimertinib versus placebo. I will tell you, and this is not yet approved, and you could go to 4 different thoracic oncologists and they can tell you 8 different things in this setting. For patients that have EGFR mutations who receive concurrent chemoradiation who are not resectable, I will consider, instead of giving the durvalumab, giving them osimertinib. And then the question becomes, well how long? These are all unanswered questions. I feel like the best drug for that patient with an actionable mutation is a genotype-directed therapy and not immunotherapy. It becomes a slippery slope however, because you start — Neil, you’re asking about different alterations like RET and ALK and can we do the same thing, and I’m not there yet. And again, I don’t know if I’m necessarily right, but I do feel that the patient’s best chance at survival is not with consolidation durvalumab if they have an EGFR mutation, and one should consider consolidation osimertinib. Again, there’s some insurance and payor issues we have to get through, but that would be my first choice. DR LOVE: And not to get too far off the topic, but obviously this does lead into the issue of the ADAURA trial, and at this point, Ross, you hear a lot of widespread acceptance of using, at least in the patients who are eligible for the trial, osimertinib. Is that what you’re doing? But also, the question of are we going to wait for the RET trial, the ALK trial, the BRAF trial, or do we just go ahead and make — I mean in metastatic disease we had to go through this with EGFR and the IPASS and then everybody just started using targeted therapy upfront. Do you think that’s going to happen in the adjuvant situation, Ross? DR CAMIDGE: I don’t know. I think ADAURA, there’s probably more time spent talking about ADAURA than actually you’d ever see a patient. Remember that these are not patients who are usually smokers. They’re not picked up with early stage disease as often. And so, despite the fact that ADAURA is licensed, I can think of zero patients I’ve actually seen, and I have a lot of targeted therapy patients that would actually fit the criteria for ADAURA. Just to go back to what Ben said, the subset with EGFR mutations in the PACIFIC trial was not statistically significant. There was a trend. And we know that there’s the occasional EGFR patient that does benefit from immunotherapy. Remember, in PACIFIC we have an overall survival benefit and we don’t have that in ADAURA. We have a sort of promissory note that we’ve improved disease-free survival and maybe that’s going to be a benefit. So actually, in my patients with an EGFR mutation, I would give them the consolidation durvalumab; if they had a lot of toxicity, I probably wouldn’t lose a lot of sleep about stopping it. In terms of whether I would then give them adjuvant osi, I probably wouldn’t. I will offer it to patients who meet the criteria for ADAURA. But this is the beginning of the story, not the end of the story. And so, all your comments about other driver oncogenes, that could be the beginning of a balloon expanding out there, but when we get data on ADAURA showing perhaps no overall survival advantage, will the balloon collapse down again? DR LOVE: I guess, on the other hand, it’s nice to avoid CNS mets. Of course, we saw dramatic decrease there. But maybe your point about survival is well taken. But I can’t even keep straight all the adjuvant IO trials we’ve talked about today, Ben, both recently presented and about to be presented, and here’s another one that Heather Wakelee has at the ASCO meeting IMpower010. Ben, any thoughts about this? Do you know anything about the data? And any thoughts about what it might lead to? DR LEVY: I do know a little bit about the data. I think that we’ll see it when it gets presented. I look forward to people’s impressions. I think we’re hungry. We are hungry for novel therapies in the adjuvant space to help cure patients. And Ross brings up a good point, can we use DFS as a surrogate for OSS and can we look at other endpoints as well? I look forward to seeing the full data set. I look forward to potentially, at some point, using something other than chemotherapy. I mean keep in mind, right now in the adjuvant setting, depending on the data you look at and depending on the meta-analyses, adjuvant chemotherapy provides anywhere from a 5% to 15% survival advantage compared to nothing at 5 years for resected lung cancer, depending on the stage, and I think we need to do better. And hopefully, perhaps this trial and others, even looking at the neoadjuvant chemo IO, will change our calculus and they’ll be some clinical adoption based on what the results show. DR LOVE: So, it will be interesting. It’s interesting how the melanoma people processed it. You saw adjuvant IO and adjuvant BRAF come out at the same time there. And then started to realize IOs can cause permanent problems, even though generally patients tolerate it well. So, Ross, it’s going to be interesting to see this data. Any thoughts about it’s going to take for you to think about using an adjuvant IO, Ross? Are you going to again need to see survival benefit? DR CAMIDGE: Well, there’s an element of kind of academic hypocrisy here, which I’m about to espouse, is, that in the same way that the toxicity for an IO can continue even when you stop the IO, I think we believe, or at least I believe, that the efficacy might also benefit. Whereas for a TKI, I have zero evidence that benefit continues when you stop it. And that’s my biggest worry about adjuvant TKI, is that sure, you’re kicking the can down the road, and that maybe useful in and of itself, but it’s really hard to imagine, unless you’re kicking it so far down the road that the control group is dying off that it’s really going to change OS. For immunotherapy, even though it’s still DFS and so, there is where the hypocrisy comes in, somehow the mechanism of action makes me believe that that’s more likely to deliver on the promise of overall survival. DR LOVE: Wow, really interesting thought there. Newly Diagnosed NSCLC with No Actionable Mutation DR LOVE: Well, let’s talk about metastatic disease in the patients without actionable mutations. And we have a case from Dr Jeremy Lorber, a 66-year-old man who presents with metastatic adenocarcinoma of the lung, PD-L1 60%, TMB 14, but very symptomatic, malignant pleural/pericardial effusion. Interesting that he actually chose to use pembro alone even in this very sick patient. Here’s Dr Lorber. DR LORBER: This is a 66-year-old man who presented to the hospital with a very symptomatic, malignant, pleural and cardial effusion. His PD-L1 was 60%. I started him on pembrolizumab. He had a complete response lasting over 2 years. At 28 months, he developed some progression of the primary mass, and also developed a single vertebral metastasis. Questions would be, if he changes to a second-line therapy, should checkpoint inhibitor be continued as part of it? He is undergoing radiation to the vertebral metastases and he was changed from pembrolizumab to pembrolizumab, carboplatin and pemetrexed, as I did not want to completely abandon the checkpoint inhibitor, given he had good response and he did not have rapid or massive progression. It was one metastasis and slight progression of his primary mass. DR LOVE: So, Ben, any thoughts about this case? He kind of bit the bullet and went with pembro and the patient did well. Any thoughts about how you think through the patient with elevated PD-L1 level, Ben? And also, about this thought he has, this patient had a great response for a couple of years with pembro, of adding in chemo and keeping the pembro going? DR LEVY: Yeah, we’re in a data-free zone here, but clearly, we have 2 choices in the elevated patient PD-L1 patient population as defined greater than 50%. Single-agent pembro or KEYNOTE 189 regimen of carboplatin, pemetrexed and pembrolizumab. I’d love to see this patient in my office just to look at them and understand what their wishes and desires are. What their fitness level is. I would say in about 60% of my patients I use single-agent pembro, 40% I use the triplet therapy. A lot of this depends on disease burden, patients not wanting to be on chemotherapy. The other is what do you do when patients have progression, and this case highlights how heterogenous progression can be. And this also is where eyeballing the patient and seeing them would be really important to me. This, to me, sounds like oligoprogression, 2 sites: the original mass that’s growing slightly, I think he said, and a new mass. So, this is where we partner with our radiation oncologist. Depending on how big the mass is, could they radiate both if they’re not that large and continue the pembro? Could they radiate both and add in chemo to pembro? Or could they radiate one and add in the chemo and not give pembro? In my practice, given that this patient had a CR, I would feel — again, not a lot of data — I’d probably continue the pembro and add on chemo if we’re truly going to make a therapeutic switch. But some of this would be predicated on my discussions with the radiation oncologist and what they felt they could radiate safely and effectively. DR LOVE: Interesting. Well, let’s flip over the to the opposite situation and audience, I want to ask you, so you’ve got a patient, 65 years old, no targetable mutations, metastatic non-squamous. PD-L1 of zero. What are you thinking about in terms of therapy for a patient like this? It looks, Ross, like the audience is almost — 75% say carbo/pem and pem. I’m looking for ipi/nivo, not very much. And then chemo plus/minus bev. But not too much ipi/nivo, mainly carbo/pem and pem. Ross, how are you thinking through low PD-L1 cases like this? DR CAMIDGE: Yeah, that’s what I would have done, too. There was no statistically significant PFS advantage in the low PD-L1, but there was an overall survival advantage with a hazard ratio of .52 or something like that. So, I mean it clearly works in this group. The ipi/nivo is a really interesting idea, and I think it’s perhaps an idea of just messaging how not to develop a combination drug. It was kind of like ipi/nivo is going to be great in those with high PD-L1. No, just look at the ones with low PD-L1, which isn’t actually part of the license. And I think ipi/nivo is a drug combination kind of looking for a target patient population. Until somebody really does a head-to-head study that allows us to compare it to a KEYNOTE 189 regimen, I don’t know where it fits in. DR LOVE: So, Ben, I recall I was doing a webinar with you and Suresh Ramalingam and we had an interesting discussion about ipi/nivo, but a press release came out with the son of ipi/nivo or daughter, durva/tremelimumab. Maybe it’s going to be another first-line option. I don’t know if it there’s 12th or 13th — I’m losing track of how many IOs and combinations are available. Any thoughts again about the anti-CTLA4 and anti-PD1 combination? What are situations right now where you’re using it, Ben? Do you use it also with chemo, the SLA approach? And what do you think about these new data coming out with these 2, durva and treme? DR LEVY: I just don’t know if this is going to be that impactful. I agree with Ross, I’m just not sure who that right patient is for dual checkpoint blockade. We looked at high TMB and then pumped the brakes. And then we’ve looked at a lot of different potential biomarkers. The combination strategy is toxic. And everyone has different stories or anecdotes on the toxicity of dual checkpoint blockade. I have not had a good run when I’ve tried this. I believe that carboplatin/pemetrexed/pembrolizumab is a well-tolerated regimen that has shown consistent survival advantages across PD-L1. So, I’m just not using dual checkpoint blockade and I don’t know who that patient is. I want to piggy-back on one thing Ross said, which is, I’d love to see a trial, maybe even a Cooperative Group trial comparing the KEYNOTE 189 regimen to dual checkpoint blockade to help definitely answer this question. We may need to look at — be mindful what endpoint we’re going to look at, but that to me would help because at this time I’m not real sure who that patient is. NSCLC with an EGFR Tumor Mutation DR LOVE: Well, let’s go on and we’re going to talk about patients with targetable mutations. And Dr Patel has a 47-year-old woman, metastatic adenocarcinoma with EGFR exon 19 mutation, but multiple, more than 50 brain mets, but is asymptomatic from the brain mets. Interestingly, the PD-L1 is 50%. Here’s Dr Patel talking about the case and the question he has about it. DR PATEL: For this patient, she was working in a cognitive task. She wanted to avoid anything that would interfere with that, and she was asymptomatic from her brain metastases. I’d love to hear from the investigators for a patient who’s asymptomatic but with 2 to 3 CNS metastases, what is your preferred strategy? DR LOVE: So, what happened with this patient? DR PATEL: In terms of her cough, better within about 2 weeks. We got an MRI 1 month after initiation of osimertinib and basically, she only had 2 lesions left, and they were all smaller than they were before. And so, the decision to continue osimertinib with close surveillance was made, and I actually to this day am visiting with this patient. She’s doing very well. DR LOVE: How long has it been? DR PATEL: It’s been almost 3 years now. I’d love to hear what their preferred management strategy around paronychia. So, for her, inflammation of her nailbed was the main side effect that she struggled with. And then rash. I think broadly, it’s the dermatitis, which includes the paronychia, and the diarrhea that are probably the two most problematic chronic toxicities, though they can be managed. And it’s important because these patients are likely going to be on therapy for a long time, given how effective this entire class of therapy remains. DR LOVE: So, Ross, what’s your paradigm for managing brain mets, those that require whole brain versus those that you could treat with SRS? Not just with patients with EGFR, but patients with targetable mutations, RET, ALK, BRAF? Do you use the same paradigm for all these and what is it? DR CAMIDGE: So generally speaking, if the patient is asymptomatic, and particularly if you think they have a reasonably high chance of having a targetable abnormality, a never smoker or a younger person, I would wait. I would try and get the radiation oncologist to stand back and wait until we have the molecular result. If they’re symptomatic, I think that’s a much harder call, maybe even manage it with steroids. It depends there, honestly, whether they’re talking about whole brain radiotherapy or SRS. If it’s contemplating whole brain radiotherapy, like in this case where there’s 50 brain mets, if there’s any way I can just sort of delay that decision until I have the molecular result back, it’s so important. Because as Dr Patel mention, these patients will live for years and they will long enough to experience the side effects of whole brain radiotherapy. So, the short answer to your question is if you can get the result, if the patient is asymptomatic, absolutely I will try the targeted therapy, unless it’s a drug that I know isn’t going to get in the brain like crizotinib. The other situation is if the patient is symptomatic, would I even consider the TKI, or maybe if I had the information in hand. Often, I have to tell you, I’ve had ALK patients who maybe I knew they were ALK-positive for other reasons and then they present with brain metastases that are symptomatic, I can get them responding before they can get in to see a radiation oncologist. DR LOVE: Yeah, and we had a case recently where the radiation oncologist said, hey, this patient didn’t have NGS and actually held off radiating the patient until they had that information. So, Ben, Dr Patel brings up the issue of tolerability of EGFR TKIs, of course osimertinib much better tolerated than first generation, but now, particularly when we start thinking about adjuvant, as we’ve talked about with the ADAURA trial, patients getting treated in the adjuvant situation for a long period of time. Any comments on what you do see with osimertinib, and particularly his thoughts about paronychia and dermatologic issues, Ben? DR LEVY: We’ve been blessed to have these next generation EGFR TKIs for what we use to have with first generation TKIs, less rash, less diarrhea, less paronychia. Overall, the next generation TKIs, specifically EGFR-directed TKIs, are extremely well tolerated. Now, we do occasionally see rash. We do occasionally see some GI upset. Very manageable. And I do have a couple of patients with paronychia who’ve been on osimertinib for quite some time. In our experience, interestingly it’s been the longer they’ve been on. It the more likely they are to develop it. We’re seeing this, not as an early toxicity, but maybe later on. We’ve had to get creative with some of our patients. You can give warm compresses. You can give topical steroids. You can give topical antibiotics. But we’ve gotten a little bit outside the box with some of our management, doing more recently tea tree oil. I’m not endorsing it. It’s just something that has worked in mainly our patients, soaking the tea tree oil with warm water has seemed to do the trick. Again, there’s not a lot of published data on this. But overall, just taking a step back, this is an extremely clean drug in hitting its target and having very little toxicity. That’s not to say it’s not there. But certainly, the days of dealing with the rash and diarrhea from the first generation TKIs and the awful paronychia in some of these patients, I think we’re much better suited now with these newer drugs. DR LOVE: So, audience, think about your typical patient with non-small cell lung cancer. You’ve got a patient who’s had a resection. This is Stage IIB, has an EGFR exon 19 deletion. In general, what kind of adjuvant strategy are you going to use for a patient like that? Are you going to use chemo and not use osimertinib? Are you going to use osimertinib and not use chemo? Or are you going to use chemo followed by osimertinib? Or some other strategy? And Ross, we’ve asked this question many, many times and one of the things that’s really interesting, and it’s interesting how it changes over time, thinking back to last summer when we started. So, 62% of the audience says chemo followed by osi. But 33% of the audience says osi alone and no chemo. Any thoughts about that answer, Ross? DR CAMIDGE: So, if it was your mom or my mom, let’s say I want to cure you. This is what we’re going for here. So where is the thing that we have data to increase the cure rate? Chemotherapy. So, unless there’s some major contraindication to chemotherapy, that’s the thing you should start with. And osimertinib, as I say, we’re going to give it olaparib based on this kind of promise that we believe it might improve overall survival. Why would deny that chance to your patient. But we have to wait and see. So, absolutely, chemo, I think, is a given. I would be really worried about giving osi alone. One of the studies flew under the radar just before ADAURA came out, was one of the CTONG studies, and in that study there was erlotinib or gefitinib, I can’t remember which one, given for 2 years versus placebo. Nobody got adjuvant chemotherapy, and nobody was cured. The disease-free survival didn’t turn out into an overall survival advantage and the fact that nobody got adjuvant chemotherapy, all of these people relapsed. So that’s a big warning sign for me. DR LOVE: Well, that’s what we always hear from investigators. I will say the numbers are starting to shift. Last summer, it was more like 50/50, so it’s starting to bump a little bit. But I understand the numeracy of what people are thinking about, you see such a huge impact on disease-free survival with osi, and granted you have survival benefit with chemo, but it seems more modest. But anyhow, we have lots of controversies in oncology. A couple of other things I want to get into before we get to the next case. So, Ben, a lot of questions about exon 20 insertions and whether or not we’re going to find any agents that are going to be affected. Can you talk a little bit about this alteration, how often it’s seen? And what amivantamab is and what we know about its efficacy? DR LEVY: So not all EGFR mutations are the same. Clearly, the most common are the sensitizing 19 and 21, which make up around 80% to 90% of all EGFR mutations. Exon 20s are a little less common, making up maybe 5% of all EGFR mutations. And they historically have been very difficult drugs. If you look at some of the data with first generation TKIs and even second generation TKIs, we really haven’t had a lot of meaningful responses or durable responses, although some anecdotal data suggests that some drugs, some of the TKIs may work. We’ve got this new drug now, it’s a bispecific EGFR MET antibody. And we’ve seen some of the data early on. I think we may get a little more data soon, showing meaningful and durable responses with this. This is a weekly IV infusion. It does have some toxicities. But the response rates look encouraging. And if you compare the response rates to what we’ve seen in other TKIs, it looked better, again, cross-trial comparisons. This trial was looking at patients that were EGFR exon 20 who had received prior platinum therapy, so this was not an initial treatment strategy. This was in the platinum refractory setting. But the responses are, again, meaningful, I think higher than we’ve seen before. I can’t remember the actual number, whether it’s 40% to 50% with this drug, and I think because of that, we’re going to get an approval with this drug, perhaps in the next 6 to 12 months. And this is a win. I think we’ve tried in a lot of different ways to target exon 20. We’ve looked at TKIs. We’ve looked at high dose osimertinib. And I think this drug probably has the most traction in this molecular niche. DR LOVE: So, I’m going to say sort of related, not too far away in the genome, is the issue of HER2. And Ross, we’ve already talked about trastuzumab deruxtecan a couple of times today in our breast cancer session and in our GI session about gastroesophageal and colorectal cancer. But of course, we also have data, but not yet FDA approval, of T-DXd in HER2 mutated in overexpressing non-small cell lung cancer. Ross, what’s your take on this? The waterfall plot looks pretty impressive, but what’s the bottom line in your point of view? Is this something you have or would like to use in your patients? DR CAMIDGE: Well, let’s break it down. So, I think just in the HER2-overexpresing, so we’re just looking at protein levels, we’ve got a response rate that looks exactly the same as everybody else’s antibody drug conjugate, about a 20% response rate. So that’s nothing to write home about. It’s great if you’ve got that, but there’s a gazillion other alternatives for antibody drug conjugates. I think what was really surprising was this sort of 60% response rate in those who have a HER2 mutation in their lung cancer. And the question is why? And it’s probably two-fold. So one is, when you have an antibody drug conjugate, one where you can become resistant as your sort of shed the epitope and stop making it. If you happen to be addicted to that, maybe that’s not an option for you, maybe you also have a lot more of it on the surface of your cell. The other thing is we know from other examples that different oncogenic-driven subtypes of lung cancer differ in their sensitivity to cytotoxics. We know that gene rearrangements tend to be exaggerated sensitivity to pemetrexed. There were early studies with EGFR mutant and sensitivity to taxanes. So, it may just be that the underlying biology of HER2 mutant lung cancer happens to be particularly sensitive to the TOPO-1 warhead which is involved with this drug. DR LOVE: So, Ben, any thoughts, particularly about HER2 mutant disease. I see you all when you have a targeted agent that has a response rate 50%, 60%, you guys kind of bring it up into the first-line setting. This has in the mutant patients, response rate around 60%. Ben, would you like to use it? Have you used it? And also, any thoughts about the issue of interstitial lung disease in these patients? DR LEVY: I think this is a class effect that we’re seeing with these antibody drug conjugates, interstitial lung disease. It looks like most of them are Grade 1 or 2, but certainly something that we need to keep a lookout for when we’re giving these drugs. I’ve been blessed to be able to give these drugs as part of a clinical study for our HER2 patients, and these responses are real. I would love to use this drug first, if I could. I think we need to use our best drugs first. I think this drug, while it does have toxicities that we need to be mindful of, the response that we’ve seen in our clinic mirror what we have in the data — these responses happen relatively soon, and they can be durable. And the drug is reasonably well tolerated. So, we’re hungry for new drugs like exon 20 in the EGFR. We’re hungry for HER2 drugs. We’ve looked to target this mutation for a long time, and this seems to be the best drug. When you do cross-trial comparisons, this by far is the best data that we have so far. So, I would love to use it first, if it gets approved at some point. Metastatic NSCLC Harboring Other Mutations DR LOVE: Well, let’s talk about some other targetable alterations and targeted therapy. We have Dr Ranju Gupta has a 61-year-old man with a RET fusion, PD-L1 is 0. TMB 3. Here’s Dr Gupta. DR GUPTA: By that time, we had this selpercatinib that was approved for RET fusion mutations in lung cancer. So, we started. We were like all right, awesome — he has RET/RET fusion, we have a targeted agent now. We started him on the regular dose of 160 mg, and he developed uncontrolled high blood pressure. I mean we just could not get around it. He also developed significant swelling in the legs. Initially he was very drowsy. He was sleeping like 18 hours a day. And then kind of we reduced the doses of the selpercatinib. We even gave his doses at one point, 40 mg daily. His drowsiness kind of resolved, but his blood pressure was still not controlled at all. So, we finally kind of stopped that. So, this is my first patient with this kind of targeted treatment. I’m asking how to manage this pedal edema and drowsiness? I know that there is a medication, pralsetinib, that also can be used in these patients who have RET/RET fusions. We are trying to get it, but any discussion about that medication vis-a-vis the selpercatinib as far as the toxicity and all of those issues is what I wanted to get from this case. DR LOVE: So, Ross, it’s just amazing talking to general medical oncologists, how often they use drugs for the first time. Like she said, she never used it before. We don’t know what to expect. Try to ask you all what do we know? We have strange situations where, edema, profound drowsiness. Have you seen anything like this? And again, is this a class effect with these RET drugs? DR CAMIDGE: So, the hypertension, it’s not really a class effect, but both selpercatinib and pralsetinib also hit VEGFR2, and so that’s really probably the cause of the hypertension. It sounds like this guy had a very exaggerated response to this. And the drowsiness is not particularly commonly reported. The edema obviously could be related to a gazillion different things. So, some of that is also going to carry over with pralsetinib. It’s not a RET effect, but pralsetinib also has VEGFR2 effects. So, I think one has to go into that with your eyes open. In terms of the drowsiness, because that’s not clear, that may not occur with the pralsetinib. But one of the things I want to pull out here is there’s a little bit of a kind of ruby in the dust that may have been overlooked. So, this particular patient got 1 cycle of carbo/pem/pembro and then sort of bailed out because of an autoimmune side effect. But remember that the gene rearrangements, ALK, ROS1, RET, NTRK, have exaggerated sensitivity to pemetrexed. That arrow is still in the quiver and could be used, obviously without the immunotherapy, to sort of bridge this patient and let everything settle down. DR LOVE: Hmm, really interesting. So you’re saying that applies to all these fusions. I’m trying to remember the first one I heard that discussed with, I think — was it ALK, in terms of pemetrexed? DR CAMIDGE: Yes, we discovered that. That was me. So that was ALK. It was then replicated within RET and ROS1. NTRK I don’t think has a big enough data set. But it’s something fundamental about the gene rearrangements. DR LOVE: Wow, that is really interesting. So, here’s another case, this is from Dr Mohamed has a 71-year-old woman with metastatic adenocarcinoma with a MET exon 14 skipping mutation but MET amplification also. PD-L1 95%. Here’s Dr Mohamed. DR MOHAMED: Her lung was obstructed, so I had to do some palliative radiation to the right upper lobe lung mass. In the meantime, the radiation doctors actually decided to do the SRS to the brain, there are 2 small lesions there. My question, if she really didn’t have that obstructive mass, should I have just went with target therapy without doing brain radiation? And does the capmatinib would work on the brain by itself? Or that’s not like one of the target therapies that would cross the blood brain barrier and affect her brain lesions. The second thing was PD-L1 of 95%, is that somebody that should have been considered for immune therapy? Or target therapy will proceed that as first line? Actually, I started her on the capmatinib. I’m keeping the PD-L1 in my pocket for now for the future. DR LOVE: And how’s she doing on the capmatinib? DR MOHAMED: She’s doing very good. She is tolerating it fine. She started gaining some weight. The question is does the MET have the same status like the EGFR and ALK regarding immune therapy? Should we have really treated with immune therapy? Or should we have still considered capmatinib as the drug of choice? DR LOVE: So, Ben, so many questions there. And I’ll add on there, what about MET amplification? Is that an indication to use an agent like capmatinib? We’ve talked before about brain mets, does the paradigm apply here as well, Ben? DR LEVY: Well, let me just say that I know my lane and if you want to ask anyone about MET amplification, based on some recent data that the person to really answer that would be Ross. I’ll start with MET exon 14 skipping mutations and what’s the ideal first therapy. And I think, based on the data that we have, both from the VISION trial and the GEOMETRY trial looking at tepotinib and capmatinib respectively, these are the ideal drugs to start. And in this case, I think that what we’ve learned, at least from small subsets from both of these papers, is that these drugs do cross the blood brain barrier and they can control disease in the brain. At least in the capmatinib data, we saw response rates in the brain in small numbers of patients of 60%, 70%. So, for a patient with an untreated brain met, or untreated brain metastases that’s not symptomatic, I would apply the same paradigm I do for EGFR, I would probably give that patient a targeted drug and hope that it controls the disease above the neck and below the neck. In terms of the value of immunotherapy, I think we’re still trying to learn. I mean there’s been some early hints that immunotherapy may not be the best choice, at least single-agent immunotherapy may not be the best choice for MET exon 14 skipping mutations. I’m going to refer the question about MET amplification though, because Ross has discovered a lot of things and one of the things that he has led is this whole concept of MET amplification as a biomarker. I’m not trying to push it, but he may be able to answer that a little bit better. DR LOVE: Okay, Ross, go for it. And also, this question of IOs? Does that apply to all targetable therapy, all targets, like BRAF, for example, also? DR CAMIDGE: So, let me do the IO thing. So, I think there’s still undiscovered heterogeneity in MET exon 14. On a very simplistic level we know that it can be a classic never smoker driver oncogene, in which case the PD-L1 is probably meaningless, and I suspect those patients don’t respond. But you also get MET exon 14 in heavy smokers, just as you can get BRAF mutations and KRAS mutations. So, the concept of all driver oncogenes not responding to IO I think is too simplistic. And as we add certainly MET, BRAF and KRAS, you might want to consider the smoking status of the patient when you’re interpreting the PD-L1. To come to the MET amplification story. So, in the context of MET exon 14, about 20% to 30% of people have some degree of MET amplification. You don’t need to worry about that, you can just work with the MET exon 14. But MET amplification alone can be driver all by itself in the absence of an underlying MET exon 14. And the challenge there is how do you measure it and where do you put the cut point –- it’s not like a mutation that’s there or not; it’s a continuous variable. And I think we’re doing a lot of work behind the scenes. I think people have shown the gene copy numbers of 6 or 10 using next-generation sequencing assays or MET/CEP7 ratio using cellular assays like FISH of sort of 4 or 5 seem to produce response rates about the same as MET exon 14, about a 40% to 50% response rate. I think it’s the beginning. I think, certainly for NGS in the future, we’re going to probably be able to finesse exactly what that gene copy number with some other bioinformatics, how narrow is the peak of amplification? The narrow it is and the higher it is, the more likely that that’s truly driving the cancer. DR LOVE: Well, let’s move on to another case, this a patient of Dr Gigi Chen with a ROS1 fusion. Here’s Dr Chen. DR CHEN: She was started on the crizotinib as well as denosumab for bone metastasis. Her symptoms really improved very rapidly. Her shortness of breath improved. She’s now walking a couple of miles a day and feels much, much better. However, 9 months later she had mild headaches and we repeated MRI of the brain and this actually showed a new brain lesion, 3 mm in size, in the left parietal lobe as was a 2 mm lesion in the right frontal lobe. Her systemic disease is very well controlled. So the question is what is the next step? Would it be best to change to a different tyrosine kinase inhibitor versus chemotherapy in this patient who has had brain progression only? And what would be the best choices in terms of the TKIs? DR LOVE: Ben, any thoughts? DR LEVY: We’ve got a couple, I’ll say one that you can potentially reach for in your shelf, which would be lorlatinib. There is data post-crizotinib for ROS1 rearranged lung cancer with lorlatinib showing that can elicit responses and there can be responses in the brain. I would say probably the drug that’s going to need to be on everyone’s radar is a drug called repotrectinib. This is a drug specifically designed to go against some of these secondary solvent front mutations from crizotinib. We’ve been fortunate to be part of some of the studies looking at repotrectinib and very meaningful activity. We had some initial presentations a couple of years ago at ASCO and some updates, but this is a drug I think that will likely play a role again in the next 6 to 12 months post-crizotinib in patients that are ROS1 rearranged. So those would be the two potential options. Every one of our patients who’s ROS1, on crizotinib, who develops resistance and has disease progression, we do consider them for the repotrectinib trial. DR LOVE: Ross, did you want to say something? DR CAMIDGE: Well, if I recall, Ben, this is a patient who is only progressing in the brain and that may just be a brain penetration of the drug rather than acquired resistance. So, the other thing on the list could be entrectinib, which is essentially CNS penetrant crizotinib. DR LOVE: Would you ever start with entrectinib, Ross, if you could? DR CAMIDGE: I actually do now. So, there was a brief period of time where people said if you don’t have brain metastases start on crizotinib. If you do, start on entrectinib. And then I thought that was overly complex and I actually start everyone on entrectinib now. DR LOVE: Well, this is a pretty good case that would support that idea. Okay, let’s go to another case, a 62-year-old man with a BRAF mutation. PD-L1 of 80%. We have lots of cases of people who get their PD-L1 back, get it like a result of 80%. The oncologist gets all excited and treats. And then the NGS comes back, and that’s what happened here, and it came back with a BRAF mutation. Here’s Dr Morganstein? DR MORGANSTEIN: He was just recently started on carboplatin, paclitaxel and pembrolizumab. In these patients who have BRAF mutations, V600E mutations, is BRAF targeted therapy first line? And how imperative is it to get your molecular studies done first before you start treatment? And this is the second time it’s happened to me that I found a targetable mutation after somebody has been treated. So, I’d be interested in the investigator’s opinion. IOs we know don’t typically work in classic driver mutations, EGFR mutations, ALK mutations. I’m unaware if that’s the same in BRAF mutations? Is BRAF considered a classic driver mutation, and should I be concerned about the efficacy of immunotherapies in this? When I use BRAF, what is the standard of care, dabrafenib/trametinib? So, when we use this? And what’s the expectation of BRAF-directed therapies? Is it like we see with EGFR mutations or ALK mutations, or are the responses shorter and less deep? DR LOVE: So, Ross, what do you do with patients who are highly symptomatic from their disease? You don’t have your NGS back, but maybe they’re a nonsmoker. You’re concerned they might have a targetable mutation. You have the whole issue of giving TKI after an IO and the question of whether or not, or the fact that they may have increased toxicity. Any comments about what you do in that situation? Will you give an IO or hold off until you get the NGS? DR CAMIDGE: So, in a patient who’s a never smoker that I think there’s a reasonable likelihood but they’re so symptomatic I need to do something because they can’t wait for that result, I’d probably start with carboplatin and pemetrexed and maybe keep the IO for cycle 2 if they turned out not to have a driver. This particular case obviously was a heavy smoker, which illustrates the point we just talked about, that BRAF is kind of a bit of a paradigm breaker because it’s a classical driver oncogene, has about a 60% to dabrafenib/trametinib. But they may also have a lot of immunogenicity, and they may also respond to chemoimmunotherapy. So, I think this was actually the right thing to do, to start the patient on chemoimmunotherapy. The other thing is, dabrafenib/trametinib is not a walk in the park in terms of side effects. So, I’m totally fine with keeping that as a second-line option here. DR LOVE: Interesting. So, you wouldn’t have switched him then to the dabrafenib/trametinib. You would have kept the chemo/IO going, Ross? DR CAMIDGE: Yeah, absolutely. DR LOVE: So, I’m curious Ben. Ross was referring to the tolerability issues with dabrafenib/trametinib. Can you talk about your experience? What you see? What you do about it. And how much of a problem it is? DR LEVY: I’ve been fortunate. I really haven’t had a lot of toxicities. Clearly, patients can develop rash, diarrhea. There’s this pyrexia that can occur when they start. I have not seen any of that. I’ve got 3 patients currently on that regimen. They’re there. It needs to be looked for. I have a 91-year-old on the combination, which is pretty incredible. And so, the toxicities are there and there are some classic TKI toxicities, the pyrexia we need to be mindful of. I would say that probably fatigue is there. But I’m sometimes unable to sort out how much of that is coming from the therapy versus their lung cancer. But to me, and the patients that I’ve had, it’s been reasonably well tolerated. Is it as tolerated as some of the other TKIs we have? Probably not. But nevertheless, I’ve been able to keep my patients on it for a reasonable amount of time without too much toxicity. DR LOVE: So, Ross, last Fall we saw some first-line data from lorlatinib which has been approved. And the data were also published. Curious where we are today, Ross — where you are today with first-line therapy of metastatic ALK? Lorlatinib is out there, brigatinib, alectinib are 3 common choices. How do you sort that through, Ross? DR CAMIDGE: I think this has actually been an amazing journey because we’ve gone from TKIs better than chemotherapy. Next-generation TKIs are better than first generation TKIs. And if we go back even to something like osimertinib, we quickly move to first-line use of that agent rather than sequential use if you develop T790M, because we worry that we wouldn’t be able to give sequential therapy. ALK has actually moved even far beyond that. The median survival for patients with advanced ALK-positive lung cancer is pushing 8 years now, and some people are way longer than that. And suddenly, the idea that PFS is king just because PFS and overall survival were relatively close is starting to break down. Now why does that matter? Because in general, lorlatinib has a hazard ratio that’s noticeably lower than most of the other randomized studies versus crizotinib where they had hazard ratios of about 0.5, lorlatinib is about .28. And so, the question is why wouldn’t we start everybody on lorlatinib? Well, lorlatinib comes with a whole bunch of side effects. And suddenly, you start to think well, I want to keep this patient alive and well for years, maybe I don’t need to start with the big guns. Maybe I can play catch-up later. And there are zero data that sequence actually matters. And so, we actually had a really fun head-to-head between myself and Ignatius Ou in JTO arguing the pros and cons of starting on lorlatinib. I should say I was the con. And it’s interesting, very few people I would say are actually jumping on board with lorlatinib because some people have had really nasty side effects. It alters the patient in terms of their thinking. They have significant weight gain. And if you can keep that until later and just play catch-up when this is only a fraction of the total life span of the patient, why not. DR LOVE: Alectinib versus brigatinib, Ross? DR CAMIDGE: So, given the choice, because I actually think you can use brigatinib after alectinib and it’s very well tolerated in my book, I actually still start people on alectinib and then I go onto brigatinib. It has about the same efficacy as lorlatinib post-alectinib. It’s got about a 40+ percent response rate, depending on who you’re giving to, and it’s better tolerated. And then lorlatinib for me is a third line, although I am actually rebiopsying and profiling and redirecting people based on the science. Extensive-Stage Small Cell Lung Cancer DR LOVE: Alright, so one more case. This is again Dr Patel, a 63-year-old man with extensive stage small cell. Here’s Dr Patel talking about the case and his questions about it. DR PATEL: This is a former smoker, nice response to induction chemoimmunotherapy, carboplatin/etoposide plus a PD-L1 inhibitor, with shrinkage in the lung and liver, clinically doing well. Really for the faculty the question is what is the next step that we can do to help this patient against this very tough disease. With small cell lung cancer one of the fears is brain metastasis. This patient did not have any at baseline. And so, whether we take a prophylactic strategy with prophylactic cranial irradiation or MRI brain surveillance. This patient was still working and very much opted for MRI brain surveillance. DR LOVE: So, one more question for the audience. I want to know, in general, what’s your second-line therapy for extensive stage small cell in patient who starts out with chemo/IO. What’s next for second-line therapy? And the audience, Ben, I’m seeing mainly lurbinectedin, lurbi, so to speak. A little bit of topotecan. Some ipi/nivo actually. How do you approach second-line therapy in this situation, Ben? And also, any comments about the CNS prophylaxis. And also, consolidation radiation therapy which is another topic that comes up. DR LEVY: I’ll take the easy question first, which is what’s the role of PCI, I believe this extensive stage small cell lung cancer patient. And we had some really early data 15 years ago, suggesting a survival advantage with some newer data suggesting a lack of survival advantage. So, we do not routinely offer PCI for our extensive stage small cell lung patients. We partner with the radiation oncologist, but we do MRI surveillances every 3 to 4 months. I think PCI in a patient with extensive stage small cell is cruel and unusual punishment. There’s a lot of neurocognitive side effects that we’ve seen in our patients and because of that, I don’t routinely offer PCI for my extensive stage small cell lung cancer patients. Limited stage is a little different. In terms of what to do when patients develop disease progression on chemo/IO, clearly, we’ve been stuck for quite a while. We’ve been using the only FDA-approved drug that’s out there is topotecan. I have not been using that. And then more recently, obviously with lurbinectedin showing a response rate of roughly 35%, 40% in platinum-refractory patients with extensive stage small cell lung cancer. Lurbinectedin, unfortunately in a Phase III trial did not show a survival advantage. Now, there were some questions about the combination, they used lurbinectedin in combination with doxorubicin. The dose of lurbinectedin was 2 mg and the single-agent dose was 3.2 mg/m2. So the ATLANTIS trial did not show a survival advantage. Nevertheless, I still think for a fit patient I will try lurbinectedin. It is not for the faint of heart. The cytopenias are real. The fatigue is real. So we have to be very careful. But in the absence of other options, I think it’s worth a try for patients who are motivated. DR LOVE: So, Ross, any comments? Any experience with lurbi? Is it something that you utilize? DR CAMIDGE: I mean it’s interesting how it got licensed on the basis of single-arm response rate which is I think a reflection of that appetite for something new in small cell, but it’s not a walk in the park. It’s another cytotoxic and honestly, for the last 40 years, we’ve known a whole bunch of cytotoxics work in small cell. Honestly, what I actually give my patients second line is weekly paclitaxel. It’s pretty well tolerated. Just a tiny word, Neil, if I may on the PCI. There is actually a Cooperative Group study which his call MAVERICK. I have no idea how they came up with that acronym, but it’s a cool name, which is PCI versus observation. And so, if you can enroll people in that study, it’s in a cancer center near you. |