ASCO Highlights and More: Investigators Review Recent Data Sets and Provide Perspectives on Current Oncology Care (Webinar Video Proceedings)
ASCO Highlights and More: Investigators Review Recent Data Sets and Provide Perspectives on Current Oncology Care
Proceedings from a daylong multitumor educational webinar in partnership with the Texas Society of Clinical Oncology, featuring key clinical presentations and papers in breast cancer, chronic lymphocytic leukemia and lymphomas, gastrointestinal cancers, genitourinary cancers, gynecologic cancers and lung cancer. Featuring perspectives from Drs Thomas A Abrams, John N Allan, Deborah K Armstrong, Arjun Balar, Virginia F Borges, Harold J Burstein, Robert Dreicer, Justin F Gainor, J Randolph Hecht, Corey J Langer, Krishnansu S Tewari, and Sonali M Smith, moderated by Dr Neil Love.
Introduction DR LOVE: I’m Neil Love from Research To Practice, and welcome to ASCO Highlights and More, as our clinical investigator faculty talk about what happened at ASCO, and we make rounds on patients from the Texas Society of Clinical Oncology. We’re covering multiple tumor types; starting out with lung cancer, then GU cancers, and you can see where we’re heading. We’re going to be seeing a whole bunch of cases. Almost 50 cases will be presented today by general medical oncologists in community-based practice from the Texas Society of Clinical Oncology that today we’re working with for the first time. Interesting that they’ve been together now since 1988, a long time. We’re starting out talking about lung cancer. We have Dr Justin Gainor from the Mass General Hospital here, and Dr Corey Langer from the University of Pennsylvania will be joining us today. Here are the general medical oncologists in community-based practice that’ll be presenting cases for us today. Drs Gainor and Langer will be talking about the cases, but in particular we’ll also be talking about happened at ASCO. We’re going to present more than 60 papers from ASCO today. We asked the faculty to put 1 slide for each paper except for Corey, of course, had to do 2 or 3, but that’s Corey. But in any event, just the bottom line of what’s important about the paper. We’re just going to give them 2 minutes to talk about it, and then we’re going to move on. Just a little bit of a tasting menu of the ASCO meeting. Here’s where we’re heading. And this will really be the way we’re going to be doing this for the 6 one-hour webinars. We start out with some cases, then we’re going to go to ASCO highlights, then more cases, and then finally we’ll go back with ASCO highlights again. These are the papers that Corey and Justin will be covering today. Again, just to introduce you to these things. We could spend lots of time talking about that, but as always we’re going to move things along fairly quickly. Before we get started, just to kind of go back to the faculty. From the point of view of lung cancer, Justin, if you had to pick out 1 or 2 papers that were presented at ASCO that really caught your attention, anything you want to comment on? DR GAINOR: I would say 2 papers, the first being IMPOWER010, the demonstration of PD-1 pathway blockade, a randomized study in the adjuvant setting, clearly, I think, is going to be a gamechanger. And then the sotorasib data. This is a KRAS G12C inhibitor. We’ve seen that data before, but it’s really in the context that we now have an FDA approval. So I think highly relevant to the clinical practitioner. DR LOVE: So Corey, we’re going to be talking about a bunch of new adjuvant IO trials today. There’s one in renal cell. There’s another one in esophageal/gastroesophageal, another one in bladder cancer that we’re going to have to sift through early reports. Any comments, again Corey, what caught your attention at ASCO in terms of lung cancer? DR LANGER: I agree wholeheartedly with Justin. The two most important papers, I think, are the ones here, which I’ll cover briefly. And he’ll be covering, I believe, the sotorasib KRAS G12C. A couple others. We’re finally looking at pathways and treatments for TKI-resistant EGFR mutated lung cancer, with very viable agents now, that will ultimately change the therapeutic landscape. DR LOVE: So one more thing before we get started. When we think about ASCO, Justin, we think about last year’s ASCO, which of course was virtual. And from the point of view of lung cancer the big story last year was the adjuvant osimertinib study. Now it’s been a year. Initially there were people trying to digest what was going on, but it kind of seems like now things are settling in. And we’ll talk a little bit more about that. But any comments on what this past year’s been like since we saw that landmark trial being presented last year, Justin? DR GAINOR: It’s a good point, and I think ADAURA has come up even more now in the context of IMPOWER010. There have been a lot of comparisons between the two. In my own practice I have been using adjuvant osimertinib, particularly in patients who are high risk, so the Stage II and Stage III patients. So I do think ADAURA was a practice-changing study, and it will continue to be discussed in forums like this as we see more and more adjuvant data and more and more discussion of integrating targeted therapies into earlier stages of disease. DR LOVE: Corey, one of the most common questions we’ve gotten from oncologists over this past year is what do they do in the adjuvant setting. They’re testing patients who are going to surgery. What do we do when we find ALK? What do we do when we find RET? Are we going to have to wait for adjuvant trials or can we make that leap? Any thoughts, Corey? DR LANGER: I’m not quite sure I’m ready to make that leap yet. I think at this point, particularly for node-positive disease and for tumors greater than 4 cm, I think chemo is still the standard. You have data, as Justin’s pointed out, for osimertinib with ADAURA, and for this year assuming we get an approval for atezolizumab in node-positive, PD-L1-positive patients. But ALK, ROS1, I think we’re going to need some additional trials. Cases from the Community — Non-Small Cell Lung Cancer, Small Cell Lung Cancer DR LOVE: Okay, so let’s start making rounds here today. As I mentioned, we’re really excited to see all these great cases today. But I want to start out by kind of getting the audience involved. And audience, here’s a question I want you to think about. We actually sent these questions out to the audience ahead of time, and we have more than a hundred responses to all these questions. So we’re going to approach polling a little bit differently today. I just want you to think about how you would answer these questions. So the first question is what are you doing right now when you have a patient with metastatic disease, no targetable mutations, and a TPS of 0. And I can tell you, and Corey you’ll find this interesting, that by far the most common answer was the carbo, pemetrexed, and pembrolizumab triplet. But we get into that with this first case from Dr Apuri. This is a 69-year-old man with a heavy smoking history, presented with some dizziness and shortness of breath and was found to have an adenocarcinoma of the lung with liver and brain mets. The patient had to receive whole-brain radiation therapy and also received carboplatin, pem, and pembrolizumab triplet. Here’s Dr Apuri with her questions about the case. DR APURI: He’s a 69-year-old. He has an 80-pack-year history of tobacco use, presented with dizziness and progressive shortness of breath. He had a left lung biopsy, which did come back positive for adenocarcinoma of the lung. And unfortunately, secondary to his dizziness, he did have an MRI of the brain which showed multiple brain lesions, metastatic lesions, for which he was started on whole-brain radiation. He did receive his first dose of carboplatin, pemetrexed, and pembrolizumab. He’s doing relatively well right now. I would like to know if they would recommend to use ipi/nivo combination in somebody who is on active steroid therapy and just completed radiation. And how would it impact the efficacy of the treatment? And would the penetration through the blood/brain barrier be more significant than the chemotherapy/immunotherapy combination? DR LOVE: So Justin, this a challenging situation here, and a lot of people think about ipi/nivo from their experience with melanoma and how well it works in the brain. What do we know about the impact of these various regimens in the brain? And what about her point about you have a patient who has these brain mets, they’re on corticosteroids, how does that affect the efficacy, particularly if you choose an all-IO regimen like ipi/nivo, Justin? DR GAINOR: I think that’s a fabulous case. It brings up so many different discussion points. You’re right that the question of using nivo/ipi comes up based on the melanoma experience. And in lung cancer we have far less prospective data, and most of the pivotal studies require stable treated brain metastases. We have one prospective study by Sarah Goldberg and Harriet Kluger at Yale looking at just pembro monotherapy in patients with untreated brain metastases. And that showed roughly similar response rates in the CNS versus extracranial disease, but we really don’t have comparisons of nivo/ipi versus PD-1 monotherapy in lung cancer done in a perspective fashion. The question here though is in a patient who has low PD-L1 expression, on steroids, what is the impact of steroids. This was actually looked at by the Memorial group in a retrospective analysis. They looked at patients who started immunotherapy, on baseline steroids, and showed that those patients had worse outcomes. Now lots of confounding there, right? Those patients who are on baseline steroids are going to be sicker. They have more brain metastases, commonly have a worse performance status, so it’s hard to pick that apart. Subsequent studies looked at 10 mg equivalent. If you’re on above 10 mg prednisone equivalent you do worse. So for me, taking a step back, the patient’s already had a definitive therapy for their CNS metastases, being whole-brain radiation, which is also a tough therapy, right? So I would lean towards using a triplet therapy of carboplatin and pemetrexed, which has also has CNS penetrance, and pembro for that patient. DR LOVE: Corey, I also want your response to this case, the other side of the coin, the patient with a high PD-L1 level. This is a patient of Dr Prakash, a 65-year-old man, as you can see PD-L1 level of 95%, multiple liver mets. Here’s Dr Prakash’s question. DR PRAKASH: I thought about that initially, should I do the doublet immunotherapy combo? Should I do monotherapy with pembrolizumab, for example, or should I just stick with chemoimmunotherapy? DR LOVE: What kind of symptoms was he having? DR PRAKASH: Just generalized malaise, fatigue, abdominal pain. DR LOVE: And what was it that led you to use the ipi/nivo? DR PRAKASH: Yeah. So in a young, healthy patient I thought if I’m going to use this doublet on anybody this might be the perfect candidate. DR LOVE: Any questions you have that you’d like to hear them address? DR PRAKASH: In a patient with lung adenocarcinoma with high PD-L1 expression how do you decide who to treat with a doublet immunotherapy regimen versus mono immunotherapy versus chemoimmunotherapy? DR LOVE: And you said so far it’s been 2 months, no problems? DR PRAKASH: No problems. No toxicity, and actually clinical response. I have not scanned him yet, but good response clinically. DR LOVE: So again, Corey, I’m curious about your approach, PD-L1 negative and PD-L1 95%. A lot of docs have this feeling that ipi/nivo in a patient who can tolerate it, more is better so to speak. So how do you approach treatment, metastatic disease, Corey, high and low PD-L1? DR LANGER: Well, I’ll start off with this case. PD-L1 quite high. I think our standard is still single-agent pembro based on the 024 trial, which showed a major sustained PFS and survival advantage compared to standard chemotherapy. We are currently involved in the INSIGNA trial nationwide through the cooperative group, which is comparing the KEYNOTE-189 regimen, specifically in nonsquamous, to single-agent pem/carbo/pembro versus pembro, with crossover to chemo either alone or continuation of pembro beyond progression in the group that has a PD on single agent. So I think that’s a critical agent. If that trial’s available, I would encourage that. We all need Phase III trials comparing ipi/nivo to pembro. I have no a priori reason to believe that ipi/nivo’s necessarily better than single agent The patient’s sick, and really it’s a clinical decision. I’ll generally refer to the histology, appropriate chemo plus pembro. If it’s relatively low tumor burden, not too symptomatic, perhaps an older patient, pembro alone. Again, we have no biomarkers that will differentiate the 2. For the PD-L1 0 or low it’s almost always histology-specific chemo plus pembro, although some of my colleagues, particularly in the Delaware Valley, for PD-L1 0 are starting to use ipi/nivo in that population, especially in squamous cell. And that’ll be brought up when we look at the 227 and 9LA data. DR LOVE: So we’re going to take a quick look at a case with small cell as well. And first, this is a question we asked the audience. You can, again, think through how you might answer it. What’s your usual second-line treatment for small cell? And interestingly, by far and away, I think it was 70% of the audience lurbinectedin. Here’s the next case we have. This is a case I’ve been looking for. I’ve been asking people for a long time now what do you do when you have somebody who has a paraneoplastic syndrome. Do you give them IO or not? Well here it is. This woman actually presented with Eaton-Lambert syndrome. They couldn’t figure out for a while what was going on. Eventually they did. She also had SIADH, and so Dr Martins was in a real dilemma about whether to use standard therapy by adding an IO onto chemo in this situation. And here’s Dr Martins. DR MARTINS: This is a fascinating case. We had a long talk. She’s a smart lady, and I said you’ve got two autoimmune complications, and so it’s very risky to do checkpoint inhibitors. But with full knowledge of the fact that without this really nothing else was likely to work she agreed to do it, understanding the risks. So we gave her nivolumab and ipilimumab. And at the time I wrote this up she was doing fine, but I literally saw her in the office today. She said she’s gotten a lot weaker. She’s having to use a walker again to walk around. So I’m worried that she’s actually having autoimmune toxicity now, which actually wasn’t even present just a few days ago, but it came up all of a sudden over the weekend, probably within 7 days of immune therapy. So that’s what we’re facing now. On the other hand, her sodium is 131, and it has been a reliable marker of her disease progression. In other words, it tends to drop every time she relapses. There is a new drug called lurbinectedin, which I have not used yet. Would they have used lurbinectedin in this case ahead of immune therapy? And knowing that her last 2 chemos she had less than 1 month response to either one before we moved onto that. DR LOVE: So before I ask Justin what he thinks about this case. You all say that second-line therapy is lurbinectedin. I’m curious, have you used lurbinectedin, yes or no? I’m curious what fraction of the audience has actually used lurbinectedin. And while we’re waiting — and actually it looks like almost half the audience has already used lurbinectedin, which is pretty interesting, I guess a commentary that small cell’s not rare. Justin, though, what do you think about this case in terms of what happened with her SIADH and with her Eaton-Lambert? DR GAINOR: Tough, tough case. I’ll start with that. In looking at patients with autoimmune disorders at baseline we know from retrospective analysis that our team did with colleagues at Memorial and Dana-Farber, if you look at patients who go into PD-1 monotherapy with baseline autoimmune disorders we found that about 50% will develop either a flare in their underlying autoimmune disorder or a new immune-related adverse event. That was several years ago, and I think now as we’ve gotten a bit braver in rolling these drugs out, I think those numbers are closer to 70%. So in this patient with a paraneoplastic syndrome, a severe kind of neurologic paraneoplastic syndrome, I would be very hesitant to give a PD-1 inhibitor, particularly a combination. So I think in CheckMate 012, which was initially exploring nivo/ipi within small cell lung cancer, that there actually were tumor-related deaths related to paraneoplastic syndromes, specifically limbic encephalitis. So I would be very hesitant in this patient to give immunotherapy, particularly combination immunotherapy. So obviously it’s easy in retrospect to be saying this, but I would have been focused more on chemotherapy. Highlights of ASCO 2021 — Corey J Langer, MD DR LOVE: So let’s flip over and talk about some papers from ASCO. And Corey has several papers that he reviewed. We encourage you to read what we call chalk talk slides. We asked them to make 1 slide, or a couple, on these papers. But we’re not going to go through everything on the slide. We’re just going to give them exactly 2 minutes, we even have a timer, to tell us the bottom line of these papers. And of course, as we’ve already said, Dr Wakelee presented really one of the most fascinating lung papers we’ve seen in a long time, adjuvant atezolizumab. Corey, what’s the bottom line in terms of what was seen here in this study, and do you think this is enough evidence to use this strategy in clinical practice? DR LANGER: The bottom line is this is a game changer. I think it’ll ultimately alter our therapeutic landscape, but in a subset of the entire population. Their hierarchal analysis started out with Stage II and IIIA, PD-L1-positive tumors, with a hazard ratio that was quite pronounced improvement in 2- and 3-year disease-free survival. Again, the OS data are very immature. The benefits do not seem to extend to those who have no PD-L1 expression. And buried in the presentation there was some interesting forest plots that showed N0 disease did not seem to benefit. If you look one of the sub-bullets the hazard ratio there is 0.88, for N2 0.66, for N1 0.59. So again, the benefit seemed to be patent in those with Stage II and IIIA. We have no separate analysis for the 1% to 49% group, 50% or higher PD-L1. And there about 25% who originally registered for this trial did not make it to randomization. We have a huge cadre of patients for whom we have zero information. Why did they fail to get to the randomization after completing chemoradiation? Finally, Justin alluded to this earlier, if a patient has an EGFR mutation in this setting preferentially use osimertinib after chemotherapy.
DR LOVE: So this is another paper we wanted your bottom line on, Corey, the CheckMate 816 trial, nivo plus platinum doublet versus chemo alone as neoadjuvant therapy. Again, bottom line, Corey, is this ready for primetime? DR LANGER: I don’t feel that this is quite ready for primetime. The data are tantalizing. We see a major improvement, significant improvement, in path CR rates, and major pathologic response, which is 90% or better, reduction in tumor volume. It does not quite match the data we saw in the precursor studies, the NADIM trial, which used this regimen, nivo plus platinum-based doublets, in Stage IIIA disease. But it’s still quite promising. The other big issue was concerns about surgery being compromised in those who were pretreated with the checkpoint inhibitor either alone or with chemo. And here there were absolutely no safety issues. There were no compromises in surgical outcomes. The video-assisted thorascopic surgery rate was actually higher in the nivo/chemo group. The lobectomy rate was higher. There were fewer pneumonectomies. R0 resection, which is clean margins, most proximal nodes being negative, again numerically higher for nivo/chemo. So the relevance is still unclear. We have not yet established neoadjuvant treatment, either alone or with a checkpoint inhibitor, as the standard in this setting. And I think we’ll ultimately need long-term disease-free and overall survival. DR LOVE: So another data set we wanted to ask you about from ASCO, Corey, was the 5-year update of the PACIFIC trial, the use of consolidation durvalumab after chemoradiation for locally advanced non-small cell lung cancer. Of course, this has really become standard. I’m curious what your thoughts were as we see the data now out to 5 years. It looks like things are holding up pretty well. Maybe this is going to be a prelude to what we’re going to see in the adjuvant setting with longer follow up, but it looks like these benefits are maintained. Any thoughts, Corey? DR LANGER: I agree, very gratifying. We see sustained survival advantage. I have to admit, I was a skeptic when this paper was initially presented. We only had PFS data. They were stunning on their own, with a hazard ratio that was particularly good in those who got on durva immediately after chemoradiation. But I was sold once the survival data came out. And here, at 5 years a third of the patients are progression free. We’ve not seen that previously with standard chemoradiation. We see nearly a 20-month improvement in the median survival and nearly 10% absolute improvement in 5-year survival. These data are without question unprecedented in the locally-advanced setting. Now this in patients who have made it through chemoradiation, who have no contraindication, at least to immunotherapy, this has become the standard. But there are a lot of caveats there. I dare say about 30% to 40% of the patients we start with chemoradiation will never make it through durva in this setting. DR LOVE: And again, another paper presented by Dr Reck is the follow up to the CheckMate 9LA study, Corey, a really interesting concept here of giving just 2 cycles of chemo along with ipi/nivo. Anything you want to say about what was presented? And more importantly, Corey, is this something that you think is a reasonable consideration outside a trial right now? DR LANGER: I definitely think this is a reasonable consideration. As I mentioned earlier, some of my colleagues in the Delaware Valley have started using this regimen for PD-L1 0 patients, where the benefits seem to be quite pronounced. You see in this table that I created that 2 cycles of chemo with sustained ipi/nivo led to a median survival of 17.7 months compared to 9.8 months with chemo alone. And for those with CNS disease, and it’s a substantial improvement in survival. The advantage here, as well, is that you have built-in second-line treatment. If ipi/nivo fails patients can then segue back to standard chemotherapy-based regimen. The toxicities are substantial and unpredictable. Patients out of the blue can have major problems, including pneumonitis, hepatitis, as well as the usual PD-1-based toxicities. And in truth we have no data to show that this regimen is superior to either KEYNOTE-189 or KEYNOTE-407, the histology-specific chemo regimens combined with pembro in the same setting. So those still are my default regimens, and I would have total equipoise comparing 9LA, 2 cycles of histology-specific chemotherapy with ipi/nivo, to a 189/407 regimen. Industry’s not going to do that trial. I think the cooperative groups really need to spearhead that. DR LOVE: We’re going to go on and see some more cases. Before we do, just to go back to Justin, any thoughts about the adjuvant atezo trial, Justin? Assuming this strategy’s approved, how do you see yourself integrating it into your practice? DR GAINOR: I completely agree with Corey about it seems like the node-positive patients were deriving more of a benefit. To me, it’s also interesting, the PD-L1 expression analysis. It really looked like it was the PD-L1 high, 50% and above, who were pulling up the rest of the PD-L1-positive subgroup. So the hazard ratio for PD-L1 50% and above is 0.43. It was 0.66 for the 1% and above. And I worry that we’re seeing a replay of KEYNOTE-042. If you recall, that was in the metastatic setting, where it was really the high expressors who were making that a positive study. So I really wanted to see, and was disappointed that I didn’t see, the breakdown for patients who were PD-L1 1% to 49%, because I think that would really put this study into context. So for high expressors, clearly I think this is going to be a standard therapy. I need to see that data for the 1% to 49%. Cases from the Community — Metastatic Non-Small Cell Lung Cancer DR LOVE: All right. Well let’s get back to some more cases. Now we’re going to focus a little bit on targeted therapy. We’re going to start out in a second with an interesting case with EGFR tumor mutation, but I just want to go and kind of tell you about the survey again that we did. This is a question we’ve been asking ever since ADAURA was presented, basically what are you going to do with a patient in the adjuvant setting. And what was really interesting is that when we started out last summer half the people who responded to this question were saying osimertinib without chemo. And we would show that to investigators, and they would go no, no, no, you’ve got to give chemo followed by osimertinib. Now, on the survey we did this past few days, it was 75% said chemo followed by osimertinib. Some people thought maybe last summer with COVID people were kind of getting chemo shy, and now they’re coming back. But in any event, obviously, as we said, osimertinib now has been really integrated into adjuvant setting. This is another question, and I was amazed that most people were familiar with amivantamab, a drug used in people with exon 20 insertions. People are split between whether it should be first line or second line. So let’s talk about some cases. This is a patient of Dr Pavel Levin, and pretty straightforward, presents with de novo metastatic disease. But we made it a little more complicated. In addition to having an L858R mutation the patient also had a MET exon 14 skipping mutation. Here’s Dr Levin. DR LEVIN: The question is how do you approach somebody like this. Do you start them on both inhibitor for EGFR and MET at the same time? So I ended up re-biopsying, getting a second biopsy, and that showed only 1 mutation, which was EGFR, and did not show a MET. But again, there are cases where we may not see all of the mutations present on the sample, and sometimes the liquid biopsy may be a little bit more comprehensive. So what do people do in those cases? DR LOVE: What did you do? DR LEVIN: I ended up starting with EGFR, just osimertinib by itself, kind of waiting to see. Usually, in my experience, the response is quite brisk. If I don’t see the response right away, then I will introduce MET inhibitor at the same time. DR LOVE: So we’re going to kind of blast through these cases. Corey, any thoughts? Of course, MET exon skipping is not unusual, as part of patients have already been on osimertinib when they progress, though sometimes we see that. But what do you think about this situation where it’s present right up front? DR LANGER: Very unusual. Osimertinib’s still the standard. Before the advent of capmatinib or tepotinib in second line I would have potentially added crizotinib. But now if that becomes a clear mechanism of resistance, and we have seen that, I’ve added capmatinib to osimertinib, realizing that osimertinib still has significant CNS penetrance and will help prevent progression of brain mets. So I have personal experience now with using both EGFR inhibitors and MET inhibitors. In this setting, as Justin will mention, amivantamab targets both EGFR and MET, may be an ideal drug, and it’s being tested now in combination with lazertinib, which is osi-like. So we’re going to have several options, and I think we’ll start thinking more in terms of chemo-free interval, time to initiation of chemotherapy, whether this is going to be second line or whether we’ll have a period where we give chemo and then segue to amivantamab and lazertinib at progression. DR LOVE: So Justin, one of the common questions we get from docs in practice is what do you do with the patient who responds to osimertinib and then progresses. And specifically, the question of should they have a repeat liquid biopsy, and how often can you find something else to target, and do you keep the osimertinib going, Justin. DR GAINOR: Yeah. A lot of questions there. So I think the first question I would ask is where are they progressing? Are they progressing in a single site? Or are they progressing in multi sites? So oligoprogression or not? Is it in the brain? So if patients are progressing in a single site of disease I’m a big proponent of using a local therapy and continuing your TKI. If it’s multifocal progression, then you want to start to think about switching therapies. In terms of FDA-approved options right now, that would be using a platinum doublet chemotherapy for patients with classical EGFR mutations. Do you continue the TKI or not? For me it all comes down to the brain. So patients with brain metastases, high risk for CNS metastases, those are the patients where I’m generally keeping the TKI on, acknowledging we don’t have prospective data for that strategy. The prospective data we do have is with the first-generation inhibitors, and didn’t show a benefit there. So for me it’s really about the brain. So patients with brain metastases I want to be keeping the TKI on there. And then to your point about repeat biopsies. I would say yes, I generally do. My practice is when I see the patient in clinic, scans are progressing, I’ll say let’s order a tissue biopsy, but as you’re walking out of clinic today we’re going to draw a liquid biopsy. It’s going to take me a week to get the tissue biopsy scheduled anyway, if the liquid biopsy comes back in the interim, shows something targetable, I can always then cancel the tissue biopsy. The things that are targetable, we’re looking for MET alterations, so we see MET amplification in up to 15% of patients progressing on osimertinib. That’s one of the big things. We can also see various fusions, ALK fusions, RET fusions, at the time of acquired resistance. Those would be the things that we’re looking for. And I would prioritize combos there. DR LOVE: So Corey, really osimertinib really was part of a new paradigm in oncology in terms of treating brain mets. And I think oncologists now routinely are using osimertinib in patients without CNS symptoms, particularly if they have bilateral and are going to require whole-brain radiation, and it seems like it works well in most patients. One of the questions we get is how applicable is this paradigm to other targetable situations? Do you do the same thing with your RET drugs, with your ALK drugs, where again, holding off on radiation therapy and using targeted treatment? Any thoughts about how wide this paradigm should be stretching right now, Corey? DR LANGER: It should stretch beyond EGFR. We certainly have very compelling data in the ALK realm for the second- and third-generation drugs, and certainly for alectinib and brigatinib, which have pretty much become our standards. Lorlatinib even more so, perhaps. We see similar data, particularly for entrectinib for ROS1, which has far better CNS penetrance than crizotinib. Other than that, those two drugs seem to be very similar in that realm. And we’re seeing data now unfold for both MET and for RET with 4 drugs recently approved in both those realms for CNS penetrance. I think the jury’s still out for sotorasib and adagrasib in KRAS G12C, although I wouldn’t be surprised if we see similar response rate. But we can put off whole-brain radiation or be very selective in terms of when we use CyberKnife® or stereotactic localized radiation. DR LOVE: So let’s move onto another case. This is a patient of Dr Nikesh Jasani, a young patient, 35 years old, a nonsmoker with metastatic disease, but with an ALK rearrangement/alteration. This patient also had a brain lesion, which was radiated before the patient got to Dr Jasani. He was telling me if he had seen the patient he would have held off and put the patient on alectinib. And as you can see, the patient was just started in January on alectinib, is having an excellent response. Here’s Dr Jasani’s questions. DR JASANI: Very pleasant 35-year-old female presented with cough, chest pain, and fatigue. She was found to have Stage IV non-small cell lung cancer with a dominant right hilar mass, multiple mediastinal nodes, bone metastases, asymptomatic solitary brain mass. We initiated alectinib in January of 2021. She has had an excellent radiographic and clinical response. Some questions I have is first-line therapy for ALK-positive non-small cell lung cancer. With the addition of these third-generation brigatinib and lorlatinib how are we choosing on which one we’re using optimally first line? In light of progression on the first-line ALK inhibitor what are the next-best steps in terms of repeat biopsy and assessment of resistance mutations? Also, if the faculty could touch on what is the management of CNS disease now in the presence of these new ALK inhibitors with significant brain penetrance? And to touch on some of the side effects of the newer agents such as lorlatinib and brigatinib. DR LOVE: So Corey, do you feel like you’re on rounds, and they’re throwing a million questions at you? Anyhow, I’ll add another one to it that quite a few people brought up to me, the patient who was started on crizotinib in the pre-alectinib days, do you think about switching them just to try to ward of metastatic disease, particularly brain mets. So first-line therapy, Corey, and would you switch somebody who’s been on crizotinib for a few years? DR LANGER: If they’ve done really well on crizotinib and we’ve been imaging their brain, and there’s no evidence of progression, I’d be a little bit hesitant. Alectinib has become our de facto standard. I would argue that brigatinib is probably equivalent, for that matter lorlatinib is just as reasonable a choice. Some of our colleagues on the West Coast, Ignacio Ou and others are preferentially using lorlatinib. But I’m concerned about the toxicity, specifically CNS toxicity. We also see rapid, major increases in cholesterol and triglycerides with lorlatinib. And from a safety standpoint alectinib really is probably amongst the safest TKIs I’ve used. When alectinib stops working, lorlatinib has a reasonable track record in that setting, with response rates of 30% to 40%, and additional CNS penetrance. And again, the final common pathway for these patients, ultimately for anybody with an oncogenic driver, when they do become TKI refractory, remains chemotherapy with or without an angiogenesis inhibitor. When the TKIs fail, I’ll generally use pem, carbo, and bev. DR LOVE: So we’re going to move onto another case, but I wanted to show you a question, again we put out in the survey about T-DXd, trastuzumab deruxtecan. You can imagine we’ve been talking a lot about it in breast cancer, GI cancers, gastric, colorectal cancer, but also this is an issue in patients with lung cancer. We asked you all what line therapy you would use T-DXd in in a lung cancer patient, and people are actually split. Some people even said first line, about the half the audience. The rest said second line. Again, it’s not approved, but where you would like to use it. So actually I’m going to ask another yes/no question to the audience. I’m just kind of curious, audience, have you ever used T-DXd for any tumor, breast, GI, lung? Have you used T-DXd? And of course for those people who have, you have to contend with the potential issue of ILD. And that leads into our next case. This is a patient of Dr Henna Malik, a 56-year-old man with adenocarcinoma of the lung and HER2 amplification as opposed to HER2 mutation. And actually it looks like half the audience has used T-DXd, I’m guessing probably in breast cancer, although it’s actually approved in gastric cancer as well. So Justin, listen to this case, and I’m curious what your thoughts are about T-DXd in HER2-positive lung cancer. Here’s Dr Malik. DR MALIK: He was actually a very healthy, young patient. He is 56 years old, Vietnamese male, nonsmoker. I started him on standard therapy with platinum, pemetrexed with pembrolizumab. And he progressed rather quickly, within 6 months. Recently, when I was reviewing this case, I did see the new clinical trial with 42 patients on T-DXd. It looks like they are responding, but this will be another option. DR LOVE: Have you actually used T-DXd in any patients? DR MALIK: I have a few patients with HER2-positive breast cancer, and they have had an excellent response, after 2 or 3 lines of therapy with metastatic brain lesions, and it’s tolerated very well. DR LOVE: So Justin, we’ll talk about the paradigm that’s evolved in lung cancer, that when you have targeted therapy that has a high response rate we’re using these agents over 50%, 60%, the RET drugs, for example. We’re not doing randomized trials anymore like we did with EGFR. It’s being brought in first line. What about T-DXd? The waterfall plot looks really good in lung cancer. It looks like it works better in HER2-mutant disease than HER2 amplified, which is what this patient had. Current and future role of T-DXd in lung cancer, Justin. DR GAINOR: Yeah. I’m glad you made that point. I think being very specific with our nomenclature, HER2 can be altered in several different ways. In lung cancer we see HER2 insertion mutations, exon 20. We find that in about 2% to 4% of patients. That’s where the data is the best for T-DXd. So in the DESTINY-Lung study we saw a response rate of slightly over 60%, with the median progression-free survival of 14 months. To me that’s very impressive data. In my head usually I have a threshold of response rate 60% and above with a PFS greater than a year, those are generally the agents where I’m thinking we should move those to the first-line setting. HER2 amplification, however, first I want to know what degree of amplification are we talking about? So actually getting a sense from the next-generation sequencing report or the FISH report kind of the degree of amplification. In the study of T-DXd they did look at HER2 expression, so not necessarily amplification. It was looked at and presented at World Lung, and there we saw lower response rates. So the response rates were 20% to 30%. I suspect that’s going to be a heterogeneous patient population. We going to want to get a better breakdown on how much was copy number gain. So I think right now that, to me, isn’t going to be enough to make it to first line in the HER2 overexpressors, but it may be viable in the later-line setting. DR LOVE: So we’re going to go on to another case, but Corey, a question in the chat room from Maura, who has a patient with prior pneumonectomy for adenocarcinoma of the lung who’s developed a contralateral nodule. And the question is if the liquid biopsy shows a targetable mutation, for example EGFR, do you actually need to get tissue or can you treat based on that? DR LANGER: It’s a little bit tough getting tissue in a patient who’s had a pneumonectomy. Certainly you run the risk of pneumothorax if you do a transthoracic CT-guided biopsy. You might be able to get it on bronch if it’s proximal enough. It’s critically important, of course, to look at the original tumor specimen and see if it has the same mutation. I would certainly act on it, at least consider acting on it. If it’s a solitary lesion, and it’s small enough, I would also strongly consider local therapy. Stereotactic radiation has a major role here, particularly if the lesion is spiculated, if it’s hot on PET, and it’s isolated. DR LOVE: That’s a great point. All right. One more case. This is an 82-year-old man who’s a patient of Dr Anish Meerasahib, and this patient has a high PD-L1 level. We were talking about that before, 75%, but also KRAS G12C mutation. This also introduces the whole topic of IOs in people with targetable lesions. We’ve seen a lot with EGFR. I’m not sure I’ve seen anything with KRAS G12C, but I’m really curious what the faculty thinks. Here’s Dr Meerasahib. DR MEERASAHIB: An 82-year-old retired family practitioner who’s a nonsmoker, new left upper lobe lung lesion, which is biopsied, and it confirmed it’s adenocarcinoma, PD-L1 75%. He started pembro in February. He’s done well with pembro. The question I had was about this KRAS G12C. Are we seeing very positive results in lung cancer? And is immunotherapy the right choice for him? Or would anyone consider adding chemo to pembro with a high PD-L1, low tumor burden? DR LOVE: So Justin, where are we today in terms of IOs in people with targetable lesions? Do we know anything about KRAS G12C? And what about the newly approved sotorasib? How are you integrating it into your practice? DR GAINOR: About 40% of all KRAS mutations in lung cancer are KRAS G12C. Importantly, the new agents such as sotorasib are only going to work in G12C, so you can’t use them for any other KRAS mutation. That’s a critical point. Second point, interestingly this case, a nonsmoker with G12C, is very unusual. G12C mutations are enriched among patients with tobacco exposure based upon the pattern of immunogenesis. So it’s quite unusual. So this oncogenic driver differs from all the others in that this is really heavily enriched among smokers. So there is more of a role for immunotherapy for KRAS G12C, particularly in a patient who has a high PD-L1 expression. And so I think I would still prioritize our standard first-line regimens for patients with KRAS G12C. And the G12C inhibitors right now, as monotherapy, are second-line agents, based upon the response rate of 37% in the CodeBreaK study. DR LOVE: So Cory, any experience with this agent? What do we know about tolerability issues? DR LANGER: We’ve had experience both in the Phase I and Phase II with sotorasib, AMG 510, and to be honest, it’s one of the best-tolerated small molecule oral agents that we have. Very minor side effects for the most part, mostly Grade 1 or 2. I agree with Justin. This is really, for now, second or third line. It does not meet his criteria, nor mine, for first line, which in my mind is the minimum PFS of a year or better, and response rate at least 50% ideally. And the PFS here I think was about 6.9 months. It was impressive, but it wasn’t overwhelming, and it’s now being compared to docetaxel as the second-line treatment in the G12C. There are studies looking at the other KRAS variants beyond G12C, so stay tuned. We’re going to have a huge portfolio, I believe, of agents ultimately available for what is arguably the largest mutation set. KRAS G12C is roughly equivalent to EGFR, and then you add all the others, as Justin pointed out, the 50% additional KRAS mutations. We’re talking about 25%, 30%, 35% or our non-small cell. Highlights of ASCO 2021 — Justin F Gainor, MD DR LOVE: So we’re going to finish out with a bunch of papers from ASCO Justin’s going to talk about. I’ve got a question in the chat room, though, that I think is very interesting from a Hashish. He’s got a patient who’s got an FGFR1 mutation, Justin. We’re going to be talking later on in bladder cancer about FGFR inhibition. Is that something to consider in lung cancer, Justin? DR GAINOR: The type of alteration matters. So FGFR really fusions are the most susceptible. FGFR point mutations generally are not as sensitive to FGFR inhibitors. DR LOVE: Interesting. Yeah, this is actually a mutation. So let’s talk about what happened at ASCO, particularly as it relates to targeted therapy. And Justin, you were talking about this study looking at amivantamab with Corey’s colleague, Dr Bauml, with lazertinib, which is you said similar osi. What was seen in this study, and what do you think it means, Justin? DR GAINOR: Yeah. So we’ve mentioned earlier in the discussion that amiv was approved for patients with EGFR exon 20. Here, this is looking at patients who have classical EGFR mutations, who have already received osimertinib but are chemo naïve. The combination of amiv plus lazertinib showed, I would say, a promising response rate in this setting, so response of 36%, a PFS shorter, 5 months. But what I think is particularly interesting in this data was when you start looking at some of the biomarker analyses because it’s showing hints that there are subgroups who may be particularly sensitive to this combination. So they broke it down a few different ways; one way they looked at patients who had EGFR- or MET-driven resistance based upon NGS. And among those patients we saw a response rate of 47%. But even more interesting, granted small numbers, they looked at just immunohistochemistry, and they had EGFR plus MET, they had a composite H-score biomarker, so 400 and above out of a max of 600. And they showed that 9 out of 10 patients actually responded in that subgroup. So I think it’s interesting. Clearly, we need more biomarker data here. Main side effects for clinicians to be aware of, particularly with the amivantamab, is with infusion reactions. These occur in most patients. They occur generally with the very first infusion. So it’s something that you and your infusion rooms really need to be aware of. So I think more to come with this combination. DR LOVE: So what about this new agent, patritumab deruxtecan, an antibody-drug conjugate? Maybe you can talk a little bit about what it is and what we know about it and what they reported here. DR GAINOR: Yeah. So we’re really seeing this emergence of antibody-drug conjugates in non-small cell lung cancer, and I think we talked about trastuzumab deruxtecan. Here we’re seeing a HER3 antibody-drug conjugate and also being explored in that classical EGFR mutation space, patients who had previously received a TKI and platinum-based chemotherapy here. So this is really an unmet need for us. And here we see very encouraging data, with a response rate of 39% in the overall patient population. Median duration of response was around 7 months. Interestingly, the biomarker analysis that they did in this study, they were looking at HER3 expression. They saw activity across a wide range of HER3 expression levels based upon immunohistochemistry. So I think we need to know more of who’s going to respond who’s not to this agent. But it’s still investigational. A randomized Phase II study’s now ongoing testing different dosing strategies. But I found this data quite encouraging. DR LOVE: So any tolerability issues? And any ILD as you see with T-DXd? DR GAINOR: Yeah, good question. I’m not aware. Corey may know better. I am not aware of high rates of ILD that were reported or that jumped out at me for this particular agent. DR LOVE: Corey, any comments on this agent and where you think it’s heading? Go ahead. DR LANGER: It looks quite impressive. The PFS is nearly double that seen with amivantamab and lazertinib, similar response rate. So as I said earlier, we’re going to have an array of options in this setting in EGFR-TKI refractory. Of note, when I had a patient who had developed resistance through MET 14 skipping mutation, was offered the trial with amivantamab. At that time lazertinib was not part of it. She had CNS mets, and she refused to go on the trial because she felt quite strongly and properly that the TKI was probably controlling the CNS mets. And so we ended up grafting capmatinib So it’s important that we have different lanes here in terms of disease type and the potential mechanisms of growth in those DR LOVE: So Justin, I want to ask you about another paper presented at ASCO looking at the issue of RET fusion and specifically this is follow up on the ARROW trial with pralsetinib. Any comments about what was reported here, what we know about this agent and others in RET-altered lung cancer, and how you approach first-line therapy in these patients? DR GAINOR: Certainly, as full disclosure, I’m the author of the corresponding manuscript. But with that, I think the main take-home point here is selective RET inhibitors are very active in RET fusion-positive lung cancer. Here we saw that the response rate in the treatment-naïve patient population was 74% to 88%, so a highly active agent. Just for rights in context for the pre-versus post-eligibility revision is that in the early iteration of this study, patients, to be treatment naïve and enter this study, they had to be not be candidates for platinum doublet chemotherapy. And so those patients tended to be older, have higher rates of brain metastases, things like that. The eligibility was subsequently revised once they started seeing activity with this agent, and you can see that the post-eligibility revision response rate was up to 88%. So this is in line. We now have 2 selective RET inhibitors, both pralsetinib and selpercatinib, that look extremely active for this disease. DR LOVE: So any comment, Corey, on management of RET-altered disease, effectiveness in brain mets, and choice of agent? DR LANGER: When it comes to choice I have total equipoise. I think the results are very similar, incredibly impressive response rates, as Justin’s pointed out. This becomes front-line treatment based on both the response and PFS data, and CNS penetrance. Though there is toxicity, though. It’s mostly Grade 1 or 2, but I’ve seen diarrhea and rash and some peripheral edema. But chemo is second line in this setting. DR LOVE: So Justin, one final question. We talked about ADAURA and the use of adjuvant targeted therapy, but we get lots of questions. We were talking about durvalumab in the locally-advanced, unresectable situation, and people are always saying what do we do with people with a targetable mutation? Do we apply the durvalumab model? Do we give targeted therapy after durvalumab? Do we do it instead of durvalumab? What do you do with a RET patient who has locally-advanced disease, Justin? Any thoughts? DR GAINOR: A very short answer. No. We were debating this for hours yesterday, so that’s why there is no clear answer, no clear consensus. In my practice, the best data we have is with EGFR, right? And in PACIFIC it really looked like EGFR patients didn’t derive benefit consistent with what we see in the metastatic setting. So in patients with locally-advanced disease I think it’s a long conversation. There are the purists who will say well we don’t have data, and so the default then is durva. And others will say well, we can’t ignore what we see in the metastatic setting, so we shouldn’t do it. For me, it’s a conversation with the patient, honestly. I’m more reluctant to use durva in patients with targetable oncogenic drivers. I fear if they do relapse the toxicity of then when you start the TKI. But it’s a hard question. We don’t have a clear answer. DR LOVE: So I’m actually going to close and ask Corey about it. But first, audience, I want to know, in general, if you’ve got a patient with locally advanced unresectable non-small cell, who’s got an EGFR tumor mutation, are you going to incorporate osimertinib into that patient’s treatment, whether or not you give durvalumab? Are you in some way going to give that patient osimertinib? Are you going to do what the investigators do, which is give durvalumab and wait? So would you include osimertinib as part of the therapy of these patients? And let’s see, Corey. It looks like about two thirds of the audience says yes. I’m not too surprised at that. We’ll let Corey and then Justin make final comments. Corey? DR LANGER: I’m not surprised either, though we have not a scintilla of data in this setting. It’s all by extrapolation from Stage IV disease, and it may be quite valid. But how long do you continue the agent? Do you do it for a year? Do you give it for 3 years as we’ve done with ADAURA? For that matter, do you give it continuously? The big concern I have with ADAURA is that the benefit will go away after the drug is stopped, that we’ll start seeing relapses. And that in turn may compromise survival advantages. So like Justin, shared decision-making. We have a very pointed conversation. It was only 5% of those accrued to PACIFIC that were EGFR mutant, and in fact in that group if you look at the forest plots for both PFS and OS there was no disadvantage. So I’ve both done it and not. Introduction DR LOVE: We’re now about to start our second module on GU cancers. We’re going to talk about prostate cancer, bladder cancer, and renal cell cancer. And we have a great faculty, Dr Arjun Balar from the New York Perlmutter Cancer Center and Dr Robert Dreicer from the University of Virginia. And we have a bunch of general medical oncologists who are going to be presenting cases, and we’re going to go through a number of papers from ASCO. And just to get warmed up, I want to ask both of you if you can pick a favorite paper you have from ASCO, starting with you, Rob. DR DREICER: So that would be the Fizazi paper, the PEACE-1 trial, even though the two plenary sessions were important, I think this is an important study that may alter practice over time as well. DR LOVE: And we’re going to talk about that. Can you just briefly refresh our memory about it? DR DREICER: So a randomized trial, but the part that was presented was the intensification of docetaxel and ADT by adding abiraterone, which showed a very significant improvement in radiographic progression-free survival. DR LOVE: Interesting. And Arjun, again, can you pick out your favorite paper? DR BALAR: I’ll kind of piggyback off of Rob, is that while there were obviously practice-changing data from the plenary sessions, the abstract that I was most excited about seeing was actually the long-term follow up from KEYNOTE-426, which was the long-term follow up from axitinib plus pembrolizumab versus sunitinib. And this established TKI plus PD-1 in the first-line setting, but the reason the long-term follow up was so critical is because we really need to understand in first line IO/IO therapy versus TKI plus PD-1. Long-term durable responses, do we really see that with TKI plus PD-1? And that makes us make really good value assessments in the first line. And that will allow us to make comparisons, and I think that really does affect practice. DR LOVE: And from our point of view, we’ll get to that later in terms of that, but what was your take in terms of the long-term impact indirectly compared to something like ipi/nivo? DR BALAR: Yeah. So unfortunately, what we see is that, especially with the PFS curves, that really rock-hard solid plateau that we see with ipi/nivo, with a 35% at 36 months, 42 months with ipi/nivo there that PFS curve doesn’t really budge. We don’t see that with axitinib plus pembro. It continues to drop steadily over time, and same thing with OS, and that tells us that pure immunotherapy-based approaches, when we can do that in the first line for patients who are eligible, I think that is, in my view, for patients a bit more valuable, or at least has some value differentially as compared to TKI plus PD-1. And then when you compare it also with long-term toxicity it really is differentiating. DR LOVE: So we’ll get to that when we talk about renal cell, but it’s just amazing how often similar issues come up in different cancers. Anyhow, here’s where we’re heading, and this is the way we’re going to approach all these modules. We’re going to do cases, then we’re going to talk about papers from ASCO, come back with more cases, these are all from the Texas Society of Clinical Oncology, and then we’ll come back with more papers. Cases from the Community — Prostate Cancer DR LOVE: So we’re going to start out with some cases, but first this is a question we asked to the audience, which is in general what systemic therapy do you add to androgen deprivation in a patient who presents with metastatic disease. And I’ll tell you, there’s at least 4 or 5 different answers. We’re going to get into that. But just the heterogeneity of responses that we see in the survey that we gave the audience, very interesting. This is that clinical scenario that we’re about to talk about. Dr Jasani has a 59-year-old man who presented with renal failure with metastatic disease and bulky retroperitoneal adenopathy. Here’s Dr Jasani with his questions about the case. DR JASANI: The questions I have for the faculty is what is the role for radiation in metastatic low-volume prostate cancer and to the primary prostate? Also, what is the ideal androgen receptor antagonist in the first line for a castrate-sensitive metastatic prostate cancer patient? And how do you decide between chemotherapy versus androgen deprivation therapy plus androgen receptor antagonist in high-volume disease? We went back and forth trying to figure out how to choose what is the best partner with ADT. Unfortunately, his insurance forced us into abiraterone. They declined apalutamide, which is what I initially had chosen. But how does the faculty determine which agent to use, or which class of agent, is another question that we have? DR LOVE: Any other questions? DR JASANI: The patient will have germline testing, but what is the role for BRCA-mutated, somatic or germline, in metastatic prostate cancer, as well as ATM and a whole host of other HRD mutations. We do understand that some of them are not as efficacious with PARP inhibitors. DR LOVE: So we’ll get into that also with the second case, Rob. I am curious, though, what kind of genomic assay you might send on a patient like this presenting with metastatic disease. And then his other questions about choice of partner. I thought it was very interesting that the insurance denied apalutamide. I don’t know how often you see that. But theoretically what is your optimal choice? DR DREICER: So your first question first. Patients present with metastatic disease, germline testing is routine, and I think it’s evidence supported, guideline supported. So that’s how I would start. The optimal choice of combination is obviously you have multiple choices, there are some aspects of the disease that if you present with low-volume disease docetaxel’s not indicated based on long-term follow up of CHAARTED, so you’re left with the other 3 agents. The data for all of them is useful. I tend to make decisions based on comorbidities. I tend to use more abiraterone than ARI use, but ARI use is perfectly appropriate, and there are certainly patients who are better served there. So no right answers there, but for docetaxel there is some data that tells us that only high-volume patients should be treated. The role of radiotherapy comes from STAMPEDE Arm G, where half the patients got ADT, radiation, and abiraterone, and although there’s not an overall survival benefit in that group there is a progression-free survival benefit. So there is certainly data to support that. DR LOVE: So Arjun, any comments on that, also the management of M0 disease with disease progression on ADT? Then you have darolutamide as a choice. So any thoughts about choice of partner in the endocrine-sensitive metastatic disease and also in the M0 space, Arjun? DR BALAR: Yeah. I’m glad you brought that up. In essence I agree 100% with what Rob said, and importantly docetaxel really for high-volume symptomatic disease, I think there’s value there. But the ideal androgen receptor blocker that’s next-generation or second-generation AR antagonist, darolutamide adds value because of its limited CNS penetration, whereas kind of enzalutamide with the secondary CNS effects, the risk of falls and so forth, we see less of that with darolutamide. And I’ve certainly had patients, even recently, where I would love to reach for darolutamide, so they’ve had contraindications to abiraterone because let’s say issues related to cardiac function or diabetes and so forth, but then they also are fall risks. So then I pressed to figure out what drug can I safely give them, and I push hard to try to get darolutamide even if they have M1 disease because right now the limited indication is for M0 mCRPC, right? So I certainly prefer darolutamide in those patients, and I would like to use darolutamide more often if I could. DR LOVE: So any comment, again, on tolerability issues with these various antiandrogens, Rob? And also the issue of rash with apalutamide, which you hear a fair amount about. DR DREICER: So as you well know, and our colleagues know, there are no comparative data. Each of the trials uses a placebo. When you look at each individual study the darolutamide trials seem to have less issues. Now assessment of toxicity was different in all the trials, so you really can’t do cross comparisons. I just look at the darolutamide trial and say in this study compared to the placebo patients had less CNS-type toxicities. The rash with apalutamide is real, and if you’ve got it you could argue do you mess with it or is there an advantage not to switch to enzalutamide if you decided an ARI is what you want. DR LOVE: Let’s listen to this case of Dr Henna Malik. This is a patient who actually had a BRCA2 somatic mutation, which is interesting, and metastatic disease. Here’s Dr Malik’s questions. DR MALIK: He progressed rather quickly through abiraterone over about a 6-month period because it was just an aggressive cancer. And at that time a lot of the treatments weren’t approved yet with the PARP inhibitors, so I went ahead and called one of the companies and tried to get compassionate use for olaparib. And he had an excellent response to treatment. He did extremely well for some time. His PSA decreased to less than 10. His bone disease improved. His adenopathy improved. He gained some weight. His pain was better. DR LOVE: Any tolerability problems? Cytopenias? GI problems? DR MALIK: He actually didn’t have many complaints. Cytopenias actually with olaparib was a lot better than the IV chemotherapy. Olaparib, he tolerated it very well. DR LOVE: So Rob, curious about your experience with PARP inhibitors in men with prostate cancer, particularly in terms of tolerability. Of course, oncologists have a lot of experience with PARP inhibitors in ovarian cancer, in younger women than you see with prostate cancer. What do you see tolerability wise? Do you see more cytopenias because there’s more bone involvement? What’s your clinical experience also in terms of efficacy? This patient seemed to do very well. Is that typical or atypical? DR DREICER: I think this particular patient is actually typical, and it actually represents part of the answer. We see a lot of patients receiving PARPs late in the disease course when they’re already pretty beat up, and it can cause significant anemia and other count issues, as well as GI toxicity. When you use it, in a sense, early, like this particular patient, they tend to tolerate it better. I only use it primarily in BRCA1 and BRCA2. I think there’s pretty compelling data that for the majority of the other DDR mutations for which olaparib was approved the utility of the drug is not great. DR LOVE: So Arjun, curious. This patient actually had a somatic BRCA. Do you approach them the same as somebody who has a germline mutation? And optimally, if you know right up front that the patient does have a BRCA alteration, when are you thinking about sequencing in a PARP inhibitor? DR BALAR: So if it’s a somatic BRCA2 mutation and it’s deleterious, yes, I would still treat them with a PARP inhibitor. Now Rob’s point is well taken. I think other alterations, I agree there’s less evidence to support the use. Now when I sequence it, and I think it’s similar to the way we think about docetaxel, sometimes the argument for docetaxel, getting it in earlier sometimes patients actually tolerate it better, same issue with PARP inhibitors. So I think it does make sense sometimes to get it in earlier if it makes clinical sense. Now that being said though, if a patient’s doing well, they don’t have high-volume or symptomatic disease, the notion of just getting it in for the sake of getting it in, that part I don’t necessarily agree with. To touch on the earlier point about differences between these PARP inhibitors, they really are different. I’ve had clinical experience on trials between talazoparib, rucaparib, olaparib, and these drugs are fundamentally different. And the safety profiles from lab abnormalities to also quality of life and the patients experience are fundamentally different. And so I think that will impact how these patients tolerate them, especially in the sequence of their treatment course as well. Highlights of ASCO 2021 — Robert Dreicer, MD, MS DR LOVE: So let’s talk about some of the papers that were presented at ASCO. And Rob, this is one of my favorites of the whole meeting, the VISION study of lutetium-177. We’ve been hearing about this agent for a while. This is a late-breaking abstract. What are your thoughts about this? Do you expect this to be part of clinical practice? And where do you see it integrating into the sequence of therapies? DR DREICER: So the first answer, yes. I expect approval, and it’ll be integrated. It’ll be interesting to see if the FDA requires positive PSMA PET/CT, and if so, they’ll have to change the indication for the current approvals for PSMA PET, but I suspect that’ll happen. Where it gets used is going to be a challenge, right, because this is a therapy that has to be administered by our nuclear medicine colleagues or in some settings by radiation oncology if they’re set up to do it. Which means for Arjun and me it’s not an issue. We work in integrated systems, and we work closely with our nuc med. But if you’re in a community practice, where you’re going to have to send this patient to a nuc med facility, but you’re still managing the patient, I think there’s going to need to be a little bit of integration and working out how to do all these things. But there’s no question it will be part of what we do going forward. DR LOVE: Do you see this potentially, Rob, as second-line therapy in metastatic disease after primary endocrine therapy? DR DREICER: So in my practice, if you ask me how I use radium, so if a patient has bone-only disease, they’ve progressed on initial ADT plus whatever, and they’re relatively asymptomatic, I’ll use radium. I’ll use PSMA lutetium in the same setting. DR LOVE: That’s going to be really interesting to see. So we already referred to the PEACE-1 study that Dr Fizazi, and you mentioned that was your favorite prostate paper. Can you comment a little bit more about what they saw there, Rob? DR DREICER: So this is a very interesting study, and they’re asking a bunch of different questions, some of which were not ready for primetime. It addresses the role of local radiotherapy in the setting of metastatic disease with or without abiraterone. The data that Dr Fizazi presented was the intensification of docetaxel. So folks got docetaxel with or without abi, and there was a more than 2-plus-year benefit of rPFS. That’s very striking. This was a large, well-done study. The survival data was immature at the time, but may be mature in a relatively short period of time. To me this is already significantly practice informing. Is it practice changing? Well, it’s on the cusp, and certainly if there’s a survival benefit that in a sense may further impact what docetaxel does. I think that’s really important data. DR LOVE: So Arjun, what about this issue of local radiation therapy in men with metastatic disease? Is that a strategy that you use, and in what situations? DR BALAR: So I think Rob had kind of mentioned this, is that this is from the STAMPEDE study Cohort G, and it looked at the role of localized therapy to the prostate, and it did improve survival. And in the PEACE-1 study they actually accounted for this, and that’s why it’s a 2 x 2 factorial design, but they actually looked for interaction. And interaction means that do you need 2 variables to kind of work together for a subsequent outcome to be beneficial. And there actually was no interaction. And so then they could pool those 2 groups together and then look at the independent effect of abiraterone in those groups. The standard of care arm was ADT with or without docetaxel with or without RT. So you could treat the prostate. You could add docetaxel. And those are 2 independent things. And then you really looked at the effect of abiraterone, right? And so in essence you could still treat the prostate if it makes clinical sense to do so. And I think in the US my sense is that we have actually probably limited uptake of treatment of the primary, primarily because if you look back at STAMPEDE the patients who did get treatment of the primary had limited disease outside of the prostate. It’s kind of similar to what we do with let’s say cytoreductive nephrectomy in kidney cancer. Really, its role is limited to where the primary tumor represents the bulk of the disease. And so I think in prostate cancer it’s kind of the same thing, and it requires a great deal of clinical judgment. I think the broader lesson from PEACE is to say that for patients, let’s say who are getting chemotherapy up front with ADT as per CHAARTED, as soon as they’re done with those 6 cycles you can quickly add on abiraterone. And I think many of my colleagues that see a bit more prostate cancer than I do were already doing that. And we can even throw that back to Rob, to what degree have you been doing it, because I think data from this trial suggests that the patients do benefit significantly from that kind of multimodality approach up front. DR LOVE: So I want to ask Rob about another paper, but real quick audience, have you used radiation therapy to the prostate in a man with metastatic disease? Not for symptoms, but in an attempt to improve long-term outcome. Have you used that strategy? And Rob, it looks like about a third of the audience has done that already. Maybe you can comment on that, as well as this next paper presented on the TITAN study, more follow up on apalutamide? DR DREICER: PEACE-1 was in de novo metastatic patients in case 1, so that’s not all comers. Radiotherapy, again, there are other trials, the HORRAD study and some others. Interesting enough, that’s local radiotherapy. Those are negative studies, but there are subset analyses that our radiation oncology colleagues are interpreting as suggesting benefit for low-volume patients. So I think it’s something that more data will help with. This study is just, again, long-term follow up of TITAN, and I think the take home for me was that the data that was shown originally with regards to apalutamide, the impact remains, long-term quality of life is maintained. So I think it’s useful to have long-term data. DR LOVE: I think I asked you before about the issue of rash with apalutamide, Rob. What’s your experience with that? What do you do to prevent and manage it? DR DREICER: Well, in all honestly, Neil, I don’t use a lot of enza or apa in that clinical setting. I tend to use abiraterone because perhaps it’s my practice setting. I see a lot of folks in their 80s and 90s. The cognitive impacts of those drugs are significant, and while abi is not without its challenges, I find it to be better tolerated. So I tend to avoid it, so I don’t have to manage it. DR LOVE: That’s interesting in terms of I’m sure a lot of these 80- and 90-year-olds have diabetes. Do you still give them abiraterone? DR DREICER: Yeah. I use 5 mg of prednisone for 98% of patients, and I must say that it’s the very rare patient where it really becomes an issue. DR LOVE: Agree or disagree, Arjun? And any experience with apalutamide rash? DR BALAR: So 100% agree with Rob. I’d say 95% of my practice is abiraterone with ADT. I think it’s much better tolerated. I do 5 mg once a day. And I actually rarely, if ever, use apalutamide for that reason. From a tolerance standpoint I think abiraterone is just much better tolerated. DR LOVE: Any preference for apalutamide versus enzalutamide, Arjun? DR BALAR: Probably if I had to choose between the two, I’d probably use enza, to be honest with you. But amongst all the AR antagonists, if I could get darolutamide for more of my patients I probably would do that. DR LOVE: So let’s go on to another paper, this is the KEYNOTE-199. This is an interesting study, Rob, of pembro plus enzalutamide. Any thoughts about that? DR DREICER: Bottom line is this work came out of folks at the Oregon Health Sciences, where they reported some anecdotal interesting stuff. Bottom line is when studied, and this is a Phase II arm, I must say I was underwhelmed. There’s really not a lot of activity here. And the updated analysis basically just shows when you follow the patients longer, they don’t do any better. There’s a Phase III ongoing, but to be honest with you, I’m relatively underwhelmed by this information. DR LOVE: So Arjun, breast and prostate cancer, I mean breast does have IOs approved in triple-negative metastatic disease, maybe it’s going to happen in localized disease, but certainly not the kind of impact we’ve seen in a bunch of other solid tumors. Any thoughts about the future not only of checkpoint but just immunotherapy, CAR T, bispecifics; any kind of immunotherapy in prostate cancer, Arjun? DR BALAR: So I’m forever the optimist, so I think eventually we will figure it out. You mentioned breast cancer and how we’ve been able to at least carve out a space for immunotherapy, and I think it goes back to how we’ve been able to kind of identify the molecular subsets in breast cancer better than in prostate cancer. I think that’s what it comes down to. So in breast cancer we know triple-negative breast, and we know it because we can reliably test for hormone receptor status and HER2 status, and we can say triple-negative breast is its own entity. In prostate cancer we have the Gleason grading and scoring system that falls along a continuum, and then there we have these really high Gleason score cancers. But then does that necessarily translate the same thing that we see in triple-negative breast? And are those real subsets the ones that respond to conventional checkpoint blockade? The answer is probably not. And then we have also these MSI-unstable tumors, that probably is 1% of tumors, but we already captured those in the current indication for pembrolizumab. So there is a subset of patients with prostate cancer that probably do respond to modern immunotherapy, but we can’t capture them in our current methodology for selecting them in clinical trials. Now moving forward, whether it’s some cellular-based therapy, bispecific antibodies, NK-cell engagers, or multiagent immunotherapy products, there are so many early-stage biotech companies that are investigating this because it is such a huge market that venture capitalists are dumping millions and millions of dollars into this, so we will figure this out. But that horizon is probably about 10 to 15 years away. DR LOVE: So Rob, you were referring to radium-223, and there was a paper at ASCO I was curious what your thoughts were, that looked at bone-protecting agents. That’s always been an issue earlier on with this. Maybe you can talk a little bit about how things settled out with that issue and what we know about this strategy here. DR DREICER: So this actually was useful to me because it pushed me to think about things a little differently. So the story started with radium-223 and abiraterone, more bone events, lots of fractures, study held, resumed with bone protective agents. A mirror study with enzalutamide was already going. They added bone protective agents. What this study showed was clearly people who get radium with one of these agents plus a bone protective agent do better. But what I found interesting was even the enza patients did better. Enza and abi have the ability to decrease symptomatic skeletal events by themselves, but this talked to me to say look, I am underusing bone protective agents in patients with active drugs that impact SSE. And it’s really informed my practice, and I’m thinking about this a little differently. So I think this was actually very useful clinical information. Cases from the Community — Renal Cell Carcinoma, Bladder Cancer DR LOVE: So we’re going to move on now and get back to some other cases, and also get into RCC, renal cell cancer. RCC is moving really fast, and we’re going to try to see if we can catch up on what’s going on. We asked the audience how they would manage a patient who’s 65 years old with a history of nephrectomy, presents 3 years later with asymptomatic bilateral lung mets. And Arjun, we saw a variety of responses, but the most common answer was ipi/nivo in this patient. What do you think about that answer? DR BALAR: I like that answer because I know that people will look at subgroups of favorable risk, and then they will say that look, the PFS curves are not all that different, and that the OS curves are not all that different, and these tumors have angiogenesis gene signatures, and I get all that. But that’s because remember these patients have a long natural history, and so you’re not seeing the difference in the benefit. But quality of life and safety and overall outcome of these patients are meaningfully different. And so I think you have an opportunity for an immune-based response that could actually lead to perhaps a durable CR, potentially off treatment. I think that’s a window of opportunity that you just can’t miss. And so for patients like this I generally counsel toward immune-based therapy, and ipi/nivo is a very, very reasonable choice here. DR LOVE: And of course, we’ll talk about the big adjuvant paper and what that might mean, but one of the things that has to be considered in general, which we maybe not want to think about because these drugs are so generally well tolerated, is the potential problem with autoimmune toxicity. And there are so many cases today we’re going to present where this comes in, including the next two renal cell cases. This is a 63-year-old man who’s a patient of Dr Ina Patel. This patient got ipi/nivo, which we were just talking about. Here’s what happened, and here’s what Dr Patel’s questions are. DR PATEL: Ipi/nivo was started for him, and he developed severe hepatitis. His AST went from 23 to over 1,000, and his ALT went from 20 to over 2,000. Steroids were initiated for this immunotherapy, and he still had to be advanced just from oral steroids into IV methylprednisolone. And then mycophenolate had to be started. This is a patient who actually was living in a very small town and had to be care flighted over to a major hospital. And this was only after 1 dose. Do you ever rechallenge with immunotherapy once there are adverse effects? He was followed with hepatology clinic, and they put him on mycophenolate and ursodiol, as well, and he was getting weekly liver function tests. And his LFTs were starting to slowly turn around. My question is what is your next line of treatment recommendation in a patient with metastatic renal cell carcinoma if they don’t tolerate immunotherapy? DR LOVE: And of course, Rob, we have the issue here that this patient got ipi and nivo. If they’d just gotten, for example, an IO/TKI whether we would have dealt with the same thing. What do you think about this case? What would you do? Would you consider single-agent IO ever in a patient who had this history? DR DREICER: So I do use ipi/nivo in basically all of my patients who are getting front-line therapy. This patient, again, and the case before, low-volume disease, late relapse, I might have watched the patient for a while just to see what the natural history is. So don’t forget that sometimes some of these people do very well. Back to the question. Since I do use ipi/nivo most of the time, this is at least Grade 3, maybe Grade 4 hepatitis, and the patient got reasonably sick, so I think in this juncture going forward there’s going to be an interim delay. I’d reimage the patient. If you see stable disease or better, I might consider just administering nivolumab going forward. With patients who don’t get quite as ill, yeah, I would resume ipi/nivo. DR LOVE: And again, that strategy of going back just to nivo and holding the ipi in people who have autoimmune problems, we have lots of cases where people do that. We’re going to talk about choice of first-line therapy, but this is another patient who got first-line therapy, got pembro/axitinib, so TKI/IO, but a similar problem. Here’s Dr Kodali. DR KODALI: She’s a 52-year-old woman and was found to have a large renal mass as the cause of hematuria. So she had to go through up-front nephrectomy because her hematuria was significant. And she did have lung metastases, as well as bone mets at presentation. I started her on axitinib and pembrolizumab as first-line combination. She’s now 3 months into treatment, and her recent restaging scan showed disease response in her lung nodules, as well as well as the bone lesions. But she’s developing LFT abnormalities. So I’m right now holding both her pembrolizumab and axitinib and waiting to see the trend of the LFTs. And what would be my options? And I have to kind of slowly introduce 1 drug at a time to see which 1 of the 2 are causing the LFT abnormalities. And we’re talking about ALT/AST in the 300 range. DR LOVE: Any questions for the faculty? DR KODALI: How often is LFT abnormalities? And can we rechallenge? And between the 2 drugs would we consider first the PD-L1 as the culprit or the TKI as the culprit? DR LOVE: So now we have a different doublet that we have to figure out here, Arjun, where they have a TKI and an IO. Now you have LFT abnormalities. How do you think about managing these? Do you reintroduce 1 at a time? And when you have LFT abnormalities do you assume it’s the IO? Do you look at when it developed? How do you sift through this one? DR BALAR: Yeah. So I’ll tell you, this is the single-most important challenge in TKI plus PD-1-based combinations. And while everyone says is axi/pembro better, cabo/nivo, lenva/pembro, and while you’re going through that mental exercise it’s probably much better just to know about the drugs and the pharmacology of the drugs, half-lives, that kind of stuff. So axitinib is 4 to 5 hours half-live. And that PD-1, even though you might hold that every-3-weeks dose today, that drug is hanging around for at least 3 to 4 months if the patient’s been on treatment for a reasonable period of time. And so for any suspected toxicity where you think it’s immune related versus from the TKI, with axitinib if you hold it generally within 2 to 3 days it should be gone. And so what I’ve done for quality of life-impacting toxicity such as diarrhea, reassess within 2 to 3 days. It should be gone if it’s from the TKI. If it persists or it accelerates you know it’s from the immunotherapy. Lab-based abnormalities, similar, right? So those LFTs, if they’re really from the axitinib and exclusively from the axitinib, check it within a week and make sure it really resolved more or less back to normal. And then there’s a lot of overlap where it requires a great deal of clinical judgment, and then the real test cases, then you start them on steroids. And ASTs and ALTs in the range of 300 is generally mild hepatitis, as long as the T bili and the alk phos are not up. This is not a clinical emergency, and so you can start them on steroids, if it’s still equivocal, then there’s your answer. And so this is one of the real big challenges. It’s really even tougher with cabozantinib because you hold drug, and that half-life is close to 55 hours. And so there you’re waiting for the toxicity to resolve over 2 weeks, and then lenva is in between. So it requires a great deal of clinical judgement and moreover just a lot of experience with the individual combination. And that’s when you develop real expertise. DR LOVE: So Rob, a couple people in the chat room have raised the issue of ipi/nivo and “favorable” risk, and I haven’t heard too many people say what you say. It’s kind of confusing, I find, even to figure out how to establish what favorable risk is, whether it’s clinical or you use one of the existing tables. How do you think about, in general, first-line therapy of renal cell, Rob? You also brought in the issue of observation without therapy. You have the issue of TKI plus IO versus ipi/nivo, and then as your colleague, Tom Powell says, the 3 identical twins, or even more if you want to include avelumab/pembro, and how do you choose among them. You have pembro/lenvatinib that’s not even approved, but people think maybe indirectly it even looks better. How are you sifting through all this, Rob? DR DREICER: So first of all, there is actually pretty good data. And again, I’m an old kidney cancer doctor. 5% to 10% of patients who present with low-volume mets, so somebody who’s 5 years out from nephrectomy, has low-volume mets, you biopsy, you prove it, that patient may just dink along for 6 months, a year, whatever, before therapy. So always think about that. Most of the time we’re not curing people, so I think there is that. The question about the regimens, I’m a big believer in treatment-free interval. Dr Balar talked about this earlier. The reality is that none of the TKI/IO regimens tell you when you can stop TKI. And anybody who treats kidney cancer, TKIs pile-drive human beings into the ground, and we all know it. So there’s no way that there’s a treatment-free interval, and the long-term follow up of the trial that Dr Balar referenced was also a little worrisome. IO/IO has a shoulder on the curve. You get out to 2 years with stable disease or better, we stop treatment. Many of those patients seem to do very well. I think we need to evolve to a place where we can treat the disease, get control, and look forward to a time where a patient can be followed without therapy. So that’s an underpinning of my approach. DR LOVE: So Arjun, one of things that I realize as I hear people talking about it is the importance of symptomatology. It almost reminds me, whether you’re going to add chemo to an IO in a high PD-L1 lung cancer patient, the issue of a patient who’s symptomatic. And it does seem like when we present symptomatic patients people lean more towards IO/TKI. Is that the way you approach it? DR BALAR: Yeah. That’s essentially it. I mean I think what’s embedded in the IMDC risks, but you can’t really pull it out, there’s performance status, time from nephrectomy and so forth, but what’s not in the IMDC risk criteria and was never pulled into clinical trials because it’s so subjective is the presence of symptoms, pace, and disease kinetics. That’s what I use much more often, which is do I need a response right away? Then I’m generally using a TKI plus PD-1. If I don’t, it’s ipi/nivo. That’s generally how I approach it. And exactly what Rob mentioned, toxicity in immunotherapy is binary. It either happens or it doesn’t, and when it happens, we can intervene quickly and resolve it very quickly. With TKI plus PD-1 everyone gets toxicity, it’s life altering. Within 3 to 4 months patients are asking for dose reductions, and it’s chronic 2-drug therapy. Whereas with ipi/nivo it’s 4 doses and the ipi’s done, and if they’ve gotten through that initial high-risk period the risk of high-grade toxicity to single-agent nivo by 6 months in is generally pretty low and very manageable. And so that’s that bigger picture that we need to think about, and the potential for stopping therapy is really nice at 1.5 to 2 years, especially if they’ve had a really nice PR or CR. So we think about that from the big picture standpoint as well. DR LOVE: Rob, any comments on choice of IO/TKI combination? I have heard people say maybe save the cabo. In this poll we asked people what their usual second-line therapy is. Overwhelmingly it’s cabo. I’ve heard people say save the cabo. Other people say give your best regimen up front, and they thought it was cabo/nivo. What are your thoughts, Rob? DR DREICER: Well, we have no comparative data, but I like what Dr Balar said about this. Dr Balar pointed out the half-life issue, use 1 regimen, know how to use the regimen, understand the toxicities. There’s no evidence that any of these regimens are better. I don’t believe it for a second. So therefore figure out what you’re comfortable with, and that’s what you should use. DR LOVE: So let’s go on now and talk about bladder cancer. We have some cool cases here. We asked this question in our premeeting survey in general, now we have sacituzumab, which one of these agents comes first, and two thirds of people said enfortumab. And we’ll kind of go into that a little bit. This is a 68-year-old man who’s a patient of Dr Zanetta Lamar, and here are her questions about this case. This is a patient who initially got gem/cis, had progressive disease, got ipi/nivo on a clinical trial, actually had a 4-year CR, metastatic urothelial cancer. But then progressed and is now on enfortumab. Here’s Dr Lamar. DR LAMAR: This is an interesting guy, treated on a clinical trial in 2015 at MD Anderson with nivolumab and ipilimumab and maintained a complete response for 4 years. He developed disease progression in his lymph nodes, and I started him on enfortumab vedotin. This patient’s performance status, despite all of his treatment, is very good. What would you consider if he progresses? DR LOVE: How long was he on the enfortumab? DR LAMAR: He had been on it for about 7 months. DR LOVE: And how did he do during that time? How did he feel? DR LAMAR: Overall, he actually did pretty well. He had some mild neuropathy. I had to do a dose reduction, but otherwise he did pretty well. DR LOVE: Any other questions about his case or about bladder cancer? DR LAMAR: So in this gentleman who had been on immunotherapy and progressed, if he had had an FGFR mutation would you prefer to use an FGFR inhibitor over a drug like enfortumab vedotin? DR LOVE: So Arjun, maybe you can talk a little bit about these 3 agents that are now available for metastatic disease, how they work, tolerability, and how you sequence them. DR BALAR: Sure. So I’ll try to give a very high-level summary, so EV, nectin 4, payload is monomethyl auristatin E, accelerated approval on the basis of a Phase II study that showed a 44% objective response rate, and then we just saw data from EV-301 in the third-line setting randomized against single-agent chemotherapy that showed a survival benefit, hazard ratio of 0.70 at the first interim analysis. So in my view, that’s the strongest level of evidence, and I’m not surprised that two thirds of your audience selected that as the appropriate choice. Now that doesn’t mean to say that in a patient with an FGFR alteration it’s not good to have choices. Now erdafitinib was approved on the basis of the BLC2001 study. The issue there is that the selected mutations, FGFR3 hotspot mutations, FGFR2 and 3 fusions, response rate is about 40%. These are not durable, but there are some safety issues with it. You need ophthalmologic exams. You have hair and skin problems, fatigue, hyperphosphatemia, GI toxicities, so from a quality of life standpoint has its own selective issues, and it’s not exactly as durable. But certainly it’s an active drug. It wouldn’t be my first choice clinically, I’ll be honest with you, but it’s certainly nice to have choices. Lastly, SG, an ADC that targets TROP2, its expression is a little bit more variable across solid tumors, and so I think it does have more broad applicability as compared to let’s say EV. Response rate was 27% on the basis of a single-arm study. Its accelerated approval just happened earlier this year. Durability, maybe not as much. We have no idea about survival. The TROPiCS study is currently ongoing, and so certainly it’s an option. The attractiveness also is that because it’s a different target and a different payload the safety profile is quite unique and does not really overlap at all with EV. Again, from efficacy and safety its issues are primarily myelosuppression and GI toxicity. I would say that it hits early, so whereas with EV the rashes can be an issue early on, but neuropathy over time is the dose-limiting issue. Generally, 4 to 5 months in neuropathy might be the reason you have to stop. Whereas with SG, whether it’s GI or myelosuppression, it happens early, within the first cycle or so. That’s the main difference. So I would probably say EV first, maybe erdafitinib I guess, and then SG. DR LOVE: So actually, I had the pleasure of doing a program the other day with Dr Arlene Radtke from MD Anderson. She’s done a lot of the work on erdafitinib, and she was actually bringing up using it second line before IOs. She thinks FGFR-mutation patients have cold tumors. I see, Arjun, you shaking your head. You don’t like that idea? DR BALAR: It’s not proven. DR LOVE: Yeah, well, it’s out there a little bit. Let me ask the audience, we’re talking about sacituzumab. Audience, I’m curious, have you seen a patient respond with breast cancer to sacituzumab? I don’t know how many people have actually used sacituzumab. It’s so hard to tell when new agents come out about their efficacy. 42% of the audience has had a patient respond in breast cancer to sacituzumab. So Rob, how are you thinking through sequencing these agents, assuming they’re eligible to get erdafitinib? What are you thinking about in terms of sacituzumab? It’s so hard to figure out where it fits. DR DREICER: Yeah. I agree with Arjun’s take on things. My enthusiasm for erdafitinib is pretty low in the big scheme of things. Look, it’s not unimportant, it’s the first truly molecularly targeted therapy, but we need to do better. And moving it earlier is an investigational construct. Let’s just leave it at that. I think for now sacituzumab, we have a little bit of data from the Phase II. There’s some efficacy in EV pretreated patients. We don’t really have data the other way around. Remember, in a year or two EV plus something might be a front-line drug, and the adjuvant use of drugs are going to change. There’s going to be a lot of movement in sequence because of new data that’s coming along, so in the meantime it’s nice to have an agent that seems to have activity and probably even in EV progressors. DR LOVE: Well the other thing, Arjun, I hear a lot of excitement about IO plus enfortumab, particularly pembro. Any thoughts about where that’s heading, Arjun? DR BALAR: So I think Rob just alluded to this, EV plus pembro, we have updated data at ASCO for EV-103, one of the primary cohorts, which looked at EV plus pembro in the first-line setting. 45 patients that were treated in a cis-ineligible group. 73% objective response rate, 91% with some decrease in tumors. The median duration of response is over 2 years, right? What we were hoping to see with chemo plus IO from IMvigor130 and KEYNOTE-361, and we didn’t see, is what we are now seeing with EV plus pembro. And so I think we expect, cautiously now, that the randomized trials that are happening now with EV-103 Cohort K and EV-302 that are enrolling patients and EV-103 Cohort K I think is going to finish soon, and we’re going to see data I think within the next year or two, hopefully within the next year, is going to really reshape first-line metastatic disease, where EV plus pembro is the standard of care across the board. And I think more patients are going to be able to safely receive that because the number one reason why patients are cis-ineligible is kidney function. Renal function is not a barrier to receive enfortumab. Neuropathy is. Now we have to deal with that separately. But renal function is not a safety issue with enfortumab. And now it’s also being tested in the perioperative setting in muscle-invasive disease before and after cystectomy, and I’m hoping we also start combining it with radiation and bladder preservation. That’s something that I’m really working on, and others as well. So I think this combination of EV plus immunotherapy is something that’s going to reshape how we treat early-stage disease potentially, as well as first-line metastatic disease. DR LOVE: Let’s do one more case. This is a 58-year-old man with metastatic disease. And Rob, I’m curious, you seem a little lukewarm on erdafitinib. This patient seemed like they did pretty well. Here’s Dr Prakash. How long ago did he start the erdafitinib? And how’s he doing? DR PRAKASH: He’s doing great. He’s been on it almost a year now. DR LOVE: Wow. DR PRAKASH: Yeah. So he’s tolerating it awesome. No problems whatsoever. DR LOVE: Did he have an objective response? DR PRAKASH: He did. He did. Had resolution of lung metastases. DR LOVE: What questions do you have? DR PRAKASH: Patients with metastatic bladder cancer who progress on first-line chemotherapy, what second-line therapy decision do you make? Do you check mutational analysis on everybody? And if you do find an FGFR mutation is erdafitinib the drug of choice second line? Or do you still consider immune therapy in that situation? In patients who do take erdafitinib, how strictly do you enforce ophthalmologic exams? And is there anything easy a clinician can do in the office to monitor the visual changes? In patients who receive erdafitinib second line, after progression on erdafitinib do you consider IO in that situation? Or do you think about enfortumab? DR LOVE: So Arjun, I think you already commented on the issue of the experimental nature of second-line therapy, but what about the ins and outs of using erdafitinib? These patients can have problems with their phosphorus. He mentioned the ophthalmic issue, central serous retinopathy, for example. Any comments on your experience with this agent? This patient seemed to do pretty well. DR BALAR: Yeah. And I’ll point out what was interesting, an FGFR1 mutation. I think the earlier trials of drugs like pemigatinib and others, where they were taking a broader look at FGFR signaling, and actually the scope may be much wider. It may not just be FGFR2 and 3. So I think we have more drugs that are being tested, so I’ll leave it at that, and there may be more than just 2 and 3. But to his point, it is tricky. I think all patients should get an OCT exam at baseline and monthly at least for the first 3 to 4 months. If you look at the data for safety in this specific issue the rates of Grade 1, 2, and 3 events really are at the highest within the first 3 to 4 months, and then they plateau, and you really don’t see them happen much afterwards. So that’s where you have to do it. If it’s challenging to get the patients in to see an ophthalmologist with experience with the drugs and so forth, kind of the quick and dirty thing to do in the clinic is an Amsler grid, and show that to the patient, have it done at baseline and do it monthly. And really what you’re assessing for is blurry vision. And again, as an oncologist if you’re old school and you want to do it, you can, and what you do is you dose hold, and then generally within 2 to 3 weeks you should see an improvement in their vision, and then you dose reduce. And usually with dose reduction these patients do okay. In a vast majority of cases this is a reversible toxicity. Highlights of ASCO 2021 — Arjun Balar, MD DR LOVE: So we’re going to conclude in a second with some more ASCO papers, but Rob I’d like you to respond to Albina in the chat room. We asked the question that I’ve been really curious about. We’re talking about HER2 now all the time in lung cancer, breast cancer, colon cancer, gastric cancer, but HER2 is not uncommon in bladder cancer. And Albina wants to know what about HER2-targeted therapy in bladder cancer. I’d like to know what kind of HER2 alterations occur, and I’m really interested about T-DXd, trastuzumab deruxtecan, whether you know anything about that in bladder cancer, Rob. DR DREICER: Well it’s a known target. It’s been a known target for a long time. Maha Hussein did a trial some time ago with HER2-targeted therapy. There are a number of molecules, including other small molecules, that are now actually in trials in this molecular subset. We need to see the data, right? I mean there’s no reason to believe that a subset of patients where this is a real driver of the disease it may be relevant. But it’s early, we need more information. But I think it’s possible that this will be another molecular target in the disease. DR LOVE: My favorite paper in GU from ASCO, which we’re going to get into next, adjuvant IO again, now in renal cell cancer. Dr Choueiri presented this study. Arjun, can you comment on what they say there and whether you think this is going to come into practice? DR BALAR: So my feeling is that it will, and my feeling is also that it should. And I know that there’s controversy about this because I follow Twitter, and I’m careful about this because I’m not the kidney cancer expert so to speak. I’m more of a bladder guy, but I treat a lot of people with kidney cancer, and I follow this field very closely. So the adjuvant study was an important trial, placebo-controlled, high-risk patients, including those with limited oligometastatic disease that was resected, although that was like 5% or 6% of the patients enrolled. So that was a very tiny subset. But you took intermediate-high-risk and truly high-risk patients, these are T3 high-grade, sarcomatoid features, clear cell tumors. And this was a well-conducted study, so pembro versus placebo. And you have a hazard ratio for disease-free survival of 0.68, a clear trend in overall survival. It’s not yet statistically significant, but this is where you talk about look at the curves. You don’t suffer from this concept of what’s called early informed censoring, which randomized trials with active drug versus observation suffer from, but you have a placebo-controlled study. And in my view, I think this really should impact standard of care. Why is it that there’s limited enthusiasm sometimes from the academic community? I think it’s that the adjuvant kidney cancer space has suffered from a lot of negative studies in the past, especially in the adjuvant TKI era, where it was negative study after negative study, like the ASSURE trial. And then lo and behold there’s one study with S-TRAC that turns out to be positive, the drug is approved, and no one uses it. And so then everyone says DFS is not a reasonable endpoint. And I understand, and that’s a very fair argument, but this is a different mechanism of action. Immune-based therapy, we can look at it through a different lens. And so we’ll see what the FDA decides. All that being said, though, eventually what I’d like to see is ipi/nivo in the adjuvant setting. I think that is going to be ultimately what patients will ultimately benefit the most from, but I think this is a step in the right direction. In my view, I think this is an approvable drug. DR LOVE: So ipi/nivo in the adjuvant setting. That’s an interesting thought. So Rob, when I think about people who kind of like to take things slow and not jump on things I think about you as one of those people. Do you like this? Ready to go? Or you want to hold off a while, Rob? DR DREICER: I think that data’s actually reasonably compelling. Again, I’ve taken care of kidney cancer a long time. The group of patients that were enrolled were very high-risk patients. It’s an incurable disease. I share Dr Balar’s relative enthusiasm. So if the FDA broadens the label I think for selective patients, certainly Stage IV NED, I will have the conversation. DR LOVE: Interesting, Stage IV NED. That’s interesting. So you commented before, Arjun, on the KEYNOTE-426 study, the follow up with pembro and axitinib. What about this paper? I thought it was really interesting, the idea of bladder sparing. A lot of patients are very reluctant or not even eligible for cystectomy. How about this trial looking at gem/cis plus nivolumab as part of a bladder-sparing approach? DR BALAR: Yeah. So we had 3 abstracts, all investigator-initiated trials, looking at the concept of bladder preservation in muscle-invasive disease. This was Dr Galsky’s Hoosier Cancer Research Network study. It was investigator initiated with an interesting concept. It was gem/cis plus nivo with this kind of selective bladder preservation on the basis of what we call clinical CRs. Now anybody who does a lot of bladder cancer will say clinical CR, what does that mean. You just don’t know what a real clinical CR is. So you get gem/cis plus nivo. You basically assess the bladder. Hopefully all the tumor’s gone. You do a good quality TUR, imaging, cytology, and if your best evidence shows that your tumor is gone, then you can offer the patients basically the option just to be followed. And then a good number of these patients remain in a CR, but several of them did have recurrences, and I think subsequently they did undergo a cystectomy, and a couple of them did still have muscle-invasive disease, including 1 patient who had node-positive disease. The problem here is that if you don’t definitively treat the bladder in one way or another, so if you decide not to remove the bladder, but you don’t have some other form of definitive local therapy, let’s say with chemoradiation, the surgical community is not going to be able to just really jump on this. So what you need is the additional layer of a biomarker to say that that clinical CR is also going to be a pathologic CR. You need to connect those two a little bit better than just with clinical assessment. So what’s missing there is a good quality biomarker. Now he’s done some good quality biomarker work to associate that clinical CR with let’s say ERCC2 mutations, high mutational burden, et cetera, and some of that work is ongoing. But I think that’s a key piece that’s missing here from just avoiding definitive local therapy to the bladder. So I think it’s avant-garde. I think it’s great. It’s a great trial, but I think we’re not yet ready for something like this. The urologic oncology community, the surgical community is not ready yet for this. DR LOVE: Do you use neoadjuvant systemic therapy, Arjun, followed by local therapy, radiation therapy, in older patients who are not eligible for cystectomy? DR BALAR: Yeah, absolutely. So in general when we talk about chemoradiation or bladder preservation historically it’s not included neoadjuvant cisplatin-based chemotherapy because we generally said that it goes before cystectomy. But when you think about it from a principle standpoint, perioperative they address systemic micrometastases. So if a patient can get neoadjuvant therapy and then definitive local therapy with chemoradiation you should do that, especially for patients who are declining cystectomy. So neoadjuvant cisplatin-based chemotherapy, and then chemoradiation to the bladder. But in general, you’re probably going to switch the concurrent chemoRT regimen there because if they’ve gotten 4 cycles of cisplatin that’s probably enough, so you might try 5-FU/mitomycin, for instance, with the radiation approach. DR LOVE: So one final question, Rob. It seems like so long, but I guess it’s only been about a year. Maybe it’s 2 years, I lose track of years, since pembrolizumab was approved in nonmuscle-invasive disease. Again, particularly in patients who are not eligible for cystectomy. And I want to get Arjun’s take on this too. This is really his work, but I’m just kind of curious how it’s played out in your own practice, Rob. What do you think about the strategy of IO in nonmuscle-invasive disease in patients who are resistant to BCG? DR DREICER: Well, clearly it’s an unmet need situation, and we’d all admit that the data that we have, although it’s interesting, is not explosive. I think there’s a whole host of IO intravesicle agents that are likely to come online in the US. To be honest with you, I think they’re going to replace systemic use just because of logistics. So I think a lot of the data that’s coming is intriguing. It may not be a relevant issue to worry about immune checkpoint as a single agent, although time will tell. DR LOVE: And final question to you, Arjun. Any thoughts, now we’re getting into the second year after these data? How’s it playing out in your practice? DR BALAR: So surgeons are a little reluctant. But when we have the conversations with patients about referring them for standard of care pembro patients are willing to receive it. We do it safely, every 3 weeks. We do a cysto at 3 months. If they’re in a response we continue. If they’re not we immediately counsel them about stopping treatment and say listen, cystectomy’s highly curative in this setting, and either we’re doing that or we’re doing something else. But I think we have to be safe about this. I agree with Rob that the data are there, they’re reasonable, but they’re not earthshattering, and we have a lot more work do to. Introduction DR LOVE: We’re going to move on now and talk about CLL and lymphomas, and also include our ASCO review, but slip in a couple of really interesting papers from the EHA, European Hematology Association, meeting. We have a great faculty for this discussion, Dr John Allan from the Weill Cornell Medical School and Dr Sonali Smith from the University of Chicago. We’re presenting cases from general medical oncologists in community-based practice from the Texas Society of Clinical Oncology. And we asked the faculty to put together what we call chalk talk slides, just one slide on the key papers that we’re going to talk about today. Check them out. Read through them. Here are the papers we’re going to be talking about from ASCO and EHA. And as we’ve been doing we’re going to go back and forth between cases and the papers. But just to kind of get started I’ve got to ask you about the EHA meeting. I’m going to start out with you, Sonali, because we had the big acalabrutinib versus ibrutinib paper presented at ASCO, but there was zanubrutinib presented compared to ibrutinib also at EHA. Sonali, what are you taking away from this? Zanubrutinib is not even approved right now in CLL, but where do you think things are heading in terms of choice of first-line BTK in CLL? DR SMITH: Yeah, so the one that was presented at EHA was in relapsed/refractory disease as well, and I think the main piece is that ibrutinib has been a phenomenal first in class, but the second-generation agents, whether it’s acalabrutinib or zanubrutinib, show noninferiority in terms of efficacy and a much better safety profile. So I think what was presented at EHA was very exciting, to see that you could have less cardiac toxicity and fewer Grade 1 and 2 adverse effects. DR LOVE: Although, John, one of the intriguing things about that, in contrast to the acala paper, is they reported some difference in efficacy. I know there’s some debate about the trial and how it was done, how they read out responses. We know they can be second duration better tolerated. Do you think any of them are going to turn out to more efficacious or do you think that maybe that’s just a function of better tolerability being on therapy longer? DR ALLAN: Right, yeah. So I think in the ALPINE study the primary endpoint was response rate, which in CLL is somewhat debatable on how important and relevant it necessarily is into a long-term outcome on a continual therapy. But even with that said, at the interim analysis, even though the progression-free survival wasn’t a predesigned endpoint to be looking at that point, there was some trend and efficacy benefit in PFS for zanubrutinib as well. So I think it’s important that when you look at these two studies, ELEVATE and ALPINE, you have to recognize that they are in very different patient populations. The ELEVATE study was in 17p/11q-deleted relapsed/refractory CLL, which is very high risk, obviously. 50% of those patients had (del)17p disruption. The ALPINE study was all comers. So I think there is this thought that if you can stay on drug maybe there would be a PFS benefit by having a less toxic drug. We do see discontinuations lower in each of these studies in the newer-generation arms. And obviously they have really high-risk disease that benefit may get lost because even if you can stay on drug they’re still going to be at risk for progression on that agent. And maybe that’s why we see kind of a noninferiority there, and maybe a trend or a potential benefit in PFS in the ALPINE study, where it’s kind of lower-risk patients to where if you can stay on drug, you do get there. With that said, these BTK inhibitors are different across the class. And there may be some efficacy there in terms of inhibiting BTK turnover, et cetera, and that possibly could be translating into some of these endpoints we’re seeing. But I think it’s still very early and we really need these long-term data to understand if there is a best in class or a best agent of the 3. DR LOVE: Well, I mean just about these two trials there’s also going to be a lot of discussion over this next year about how they were done. We were working with Dr John Gribben the other day, who is the head of EHA. He was talking about the way they classified responses. I think they called response with leukocytosis, they approached the way it was approached in the past. So we’ll see as these trials are dissected what it really means and what happens in terms of particularly first-line therapy of CLL. And that gets into where we’re heading because we’re about to go through some cases. Cases from the Community — CLL and Follicular Lymphoma DR LOVE: And we’re going to start out with a case of CLL. This is a 60-year-old patient. Before we get to that, we asked the audience how in general, what’s your first-line therapy in a 65-year-old patient, IGVH unmutated disease, (del)17p, TP53 negative, which of course needs to be ruled out. And Sonali, we saw, at least in the audience, really a split between venetoclax/obinutuzumab and BTK, the audience primarily choosing acalabrutinib. How do you think through a scenario like this, Sonali? DR SMITH: Yeah, I think this is where the discussion with the patient is really important about limited-duration therapy versus indefinite therapy and having that discussion about both short-and long-term toxicity. The other piece that I think comes in is comfort and familiarity with using venetoclax. The initial trials and data were notable for some of the tumor lysis syndrome and hyperkalemia. And of course with the current stepped-up dosing we don’t see that for the majority of patients. But I think there’s probably still some residual discomfort with just jumping to that right away. DR LOVE: Yeah, and I think also people were sensitized this past year to keep people out of the clinic, out of the hospital with COVID, and maybe venetoclax got dropped off a little bit. I’m curious, again, before we kind of get into the case, John, are there any situations where you think there’s an advantage to either BTK or venetoclax/obin in CLL, at least in terms of first-line therapy in terms of efficacy? DR ALLAN: Yeah. I mean I think we don’t really have head-to-head data to really guide any of that decision-making or identification of a perfect patient for one specific approach. With the CLL14 data we are starting to see some curves separating. High-risk 17p-deleted patients seem to have an inferior PFS, though it’s still pretty good, and they’re off of drug for 3 years before they’re starting to hit their median PFS around this 4-year mark, or close to it. And alternatively, the IGHV-unmutated group is starting to separate itself, where they’re meeting a PFS right around 5 years, again, 4 years off of drug. So that’s really, really good. And is that not good enough to say that we shouldn’t offer a fixed duration for these patients? I’m not so sure we’re there yet. We really need to understand retreatment. I think a lot of the data suggesting that underlying mutations and some of these things that we considered high risk aren’t really necessarily high risk in terms of inferior outcomes, like NOTCH and SF3B1 and some of these kinds of substudies that have been performed never really identifying them having too much relevance. So I think I agree with Dr Smith about it’s a discussion. It’s still about tailoring the treatment to the patient and their wishes. And obviously in these high-risk patients maybe there could be some benefit of continual therapy, but that doesn’t mean that a BTK inhibitor versus a BCL2 inhibitor approach is better. We just don’t know that. And there are studies, CLL17, coming out, et cetera, that could show this data that we need to know to understand this question. DR LOVE: So let’s just dip our finger into it with one case. Again, we could talk about it for a long time. This is a younger patient, 60 years old, presented with symptomatic disease, particularly adenopathy. Here’s Dr Jasani commenting on the case and asking a few questions. DR JASANI: A gentleman with bulky lymphadenopathy who wanted actually a time-restricted treatment, not something indefinitely. And I actually gave him the venetoclax and obinutuzumab-based regimen. He got 6 months of obinutuzumab, 1 year of venetoclax, done quite well, and actually we were able to manage everything outpatient. What does the faculty think, especially with the newer data on acalabrutinib over ibrutinib? How are you incorporating the venetoclax regimen with obinutuzumab? And how do you exactly monitor these patients for TLS in the outpatient setting in the community? DR LOVE: Any questions about the use of MRD in CLL? DR JASANI: Yeah. How are they actually using MRD status? What are they doing? Are they using NGS or next-generation flow? And how does that affect your clinical decision-making? In a person, hypothetically, on a long-term BTK inhibitor, what does an MRD-negative status mean? Do you stop therapy based on it? DR LOVE: So John, so many questions that come up with CLL. Maybe we can just start out with MRD. We know in the venetoclax/obinutuzumab study they measured MRD at the end of the year, but they still stopped therapy. Do you think there’s a role for MRD measurement right now outside a trial in patients with CLL, John? DR ALLAN: Yeah. I mean I think there is a role. I don’t know if there’s a role necessarily at this point in time to make treatment decisions based on an MRD status. As you stated, these studies stopped treatment regardless of an MRD status. And really the tool is useful at this point in time as kind of a prognostic indicator of someone who’s going to do well. With that said, we do have these problems when you do check it. Okay, if you’re MRD positive what do you do with that? We know that they are likely going to progress sooner than someone who’s MRD negative, but right now it’s not necessarily recommended to use that data to extend treatment or not. So I think there’s a lot of, not controversy, but a lot of opinions out there, and arguments to be made on either side of the argument, and the coin, whether to continue treatment and kind of see if the response deepens. There is some limited data to suggest that responses may deepen over time with continual therapy versus just stopping, and kind of lift that resistant pressure, potentially, so upon a relapse 3, 4 years later that you can still use that agent, et cetera. So I think in terms of MRD it’s very helpful. I do check it a lot for my patients. They’re interested in it as they start to learn about these regimens. But I’m really using it more of a tool to educate them at the end of the treatment so they can make informed decisions about potential continuation of an agent, if they’re tolerating it well, versus just stopping outright, and they may know what that might look like into the future. When we get to combination treatment, I do think there are some new studies being done. CAPTIVATE is one, where they are incorporating MRD decision-making into the study. So I think these studies are being done, we just don’t quite have the long-time follow up now to understand if that will impact a decision tree. DR LOVE: So a quick question to the audience. Audience, have you sent an MRD assay in a patient with CLL outside a clinical trial in your practice? Interestingly, only 15% of the audience has sent a MRD assay in a patient with CLL. So Sonali, two people in a row asked the same question, which is do you treat people who are asymptomatic who have high risk, (del)17p, and would you, if you could, use the combination of BTK and venetoclax outside a trial? DR SMITH: Yeah. So the high-risk question is a really important one because it’s a source of great stress for both the patient and the physician. But to date there is no data that treating somebody before they need treatment is going to benefit them. But this is being asked prospectively in an intergroup study that is SWOG-led looking at essentially combination therapy with a BCL2 inhibitor, venetoclax, and ibrutinib and obinutuzumab, so a triplet approach for patients with the highest-risk disease if they’ve been diagnosed within a year. And so I think we’ll have some preliminary data over the next several years, but today the recommendation is not to proceed with therapy for somebody, even if they have high-risk features. DR LOVE: Venetoclax and BTK. We saw the GLOW study at the EHA meeting comparing it, I think it was to chlorambucil and anti-CD20. Of course, it killed it, so to speak, much better, but is it enough to get you to want to actually use it right now, or do you want to see more data, Sonali? DR SMITH: Yeah. I would like to see more data, but I’ll tell you that I think people are already using that combination, and the EHA presentation, I think, is going to support what some people are already doing if they can get insurance approval for it. DR LOVE: All right. Let’s move on and talk a little bit about follicular lymphoma. We asked this question to the audience, third-line therapy, third line and beyond’s getting more and more interesting, so we said what’s your third-line therapy in follicular lymphoma after BR and R-squared, the usual first- and second-line therapy. And we said the patient has an EZH2 mutation, and actually the most common answer was tazemetostat. We have a case that really brings up another issue, which is first-line therapy. And this is Dr Amanda Blackmon who has a 50-year-old man with newly diagnosed follicular lymphoma, presented in 2018. Here’s the case and the question. 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 R-squared 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 population 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 R-squared versus R-chemotherapy. Does the extent of this patient’s disease have any influence on which regimen you would choose? DR LOVE: So John, up-front therapy of FL in patients who require it. It seems like every investigator I ask says BR first, R-squared second, but I did a program with Dr Nathan Fowler from MD Anderson, who of course did the RELEVANCE trial, and he says, “Oh yeah, at MD Anderson we use R-squared up front.” How do you think through that decision, John? DR ALLAN: Yeah. So I’ve been using a lot more R-squared in the front-line setting myself. I see a lot of CLL patients, and I’m kind of coming from this paradigm of trying to go chemo-free. And I have seen a lot of great outcomes, kind of similar as Dr Blackmon, her case that she presented, and also I see a lot of the data lining up with what’s been published from the RELEVANCE study. So I think it’s still this question of what does the patient want. The RELEVANCE study does have a longer treatment period. There is a lot of maintenance rituximab there, as well as a longer period of the lenalidomide being used versus just 6 months of BR. So there are some issues there. There are financial issues there, toxicity difference, though I can find the lenalidomide the very well tolerated. So I agree. I’ve been moving more and more towards front-line R-squared, and I think we will continue to potentially see that trend as people adopt it or try it and have success with it. DR LOVE: Although Sonali, when I was talking to Dr Fowler, they use R-squared for 6 months. Most people the objection they have is in the trial they used it so long. He uses it for 6 months. Anyhow, to be continued. The debate’s been going on ever since the data came out. Sonali, how are you approaching third-line therapy? That’s to me what’s kind of getting complicated. You have tazemetostat. A lot of people want to use it if they’re EZH2 mutated. But you see responses in people who aren’t mutated. How do you decide about third-line therapy? DR SMITH: Yeah. I think the issue with follicular lymphoma is that not all third-line patients are similar, and there is this concept of kinetic failure. So the patients who have had early progression of disease and then get second-line therapy and relapse very quickly, I think those are the patients where I’ll start to think about more aggressive approaches, such as CAR T, as opposed to a single agent oral approach. And then you have the other patients who have a very long duration of response in between therapies, and they need palliation, and that’s where I think tazemetostat really has a role. We could also start to think about the PI3-kinase inhibitors, and now we have one that’s better tolerated, I think, and easier to give as an oral agent, so we have quite a few. But it comes down to really a discussion about who needs a monotherapy oral agent versus something more aggressive. DR LOVE: And of course you’re talking about umbralisib and a fourth PI3-kinase inhibitor. That’s oncology, right? In oncology 2020, four PI3-kinase inhibitors in follicular lymphoma. People wonder why it’s difficult to be a general medical oncologist. Highlights of ASCO and EHA 2021 — John N Allan, MD DR LOVE: Anyhow, let’s talk about some papers. And we talked about this study which was presented by Dr Byrd. John, what was your main takeaway, and I’m particularly curious about what your thoughts were about the differential issues in terms of tolerability and toxicity with ibrutinib versus acalabrutinib. DR ALLAN: Yeah, so this study, as a just quick summary, looked at acalabrutinib head-to-head versus ibrutinib in relapsed/refractory CLL with high-risk disease, (del)17p and 11q. It was not a blinded study, so that’s also important to keep in mind. It was open label. But ultimately, I think it’s kind of proven the point that we’ve heard about for years, that the second- and third-generation BTK inhibitors are better in terms of toxicity. And so it kind of proved that point. I think a lot of people may have seen some of these differences, but were maybe more surprised that it wasn’t wider in terms of AFib rates between the two agents. Where in some of these earlier Phase II studies that had similar amount of follow up the AFib rates were possibly lower, in the 5% to 6% range, where we’re seeing it in acala at 9.6 I think it was, versus 16.7. So it was a little closer than I think many people thought might have happened. But ultimately, there’s other endpoints that were seen, hypertension, et cetera, and these are pesky kind of adverse events that you need to monitor and deal with. And anything that can have less toxicity and a similar outcome is obviously a very important step forward for our patients. And I think they’re going to be attracted to it. Physicians will be attracted to it. And I do think we can kind of extrapolate these findings, even though this was in relapsed/refractory high-risk disease, for the most part I expect no difference of whether you’re using it in a front-line setting or not, and we continue to see low rates of AFib, et cetera. So I think it’s relevant. I do think it proved a point, finally, that the second-generation BTK inhibitors are better tolerated, and I think it will potentially increase kind of a switch to them more so in these front-line settings, as well as in relapsed setting. DR LOVE: That’s interesting that we’re hearing from docs in practice and investigators that they thought there was a difference just based on their clinical experience. Sonali, what about arthralgias and myalgias? Not as concerning as atrial fibrillation, but sometimes a reason that people have to have dose reductions or even stop therapy. Based on the data and also your clinical experience, do you think those are also less with the second-generation agents? DR SMITH: Yeah. I mean anecdotally I do think that they are less, and that’s what some of the studies would show as well. In the ELEVATE trial they showed some of the other toxicities, just looking at all grades, and there is a more favorable safety profile for all-grade toxicity for a lot of these quality of life types of symptoms. I think with ibrutinib one of the challenges is that the FDA-approved dose is probably at the higher end of what might be effective. And so we’ve seen this before in some of the real-world data, publications up to 40%, 50% of people, maybe even more, who are on the FDA-approved dose of ibrutinib will need a dose reduction, dose delay, or treatment holiday because of these arthralgias and other low-grade but still very impactful adverse events. DR LOVE: So we talked about the ALPINE study of zanubrutinib, and we’ll see where that heads as we learn more about this study. This is the other paper that we were talking about looking at the combination of ibrutinib/venetoclax, but as a fixed-duration approach, John. Any comments about this, the CAPTIVATE study? DR ALLAN: Yeah, so I think GLOW may be the counterpart to CAPTIVATE, this looked at 3 cycles of ibrutinib followed by 12 cycles of ibrutinib/venetoclax, and then every patient stopped. Unlike in the previous reports of the CAPTIVATE study, it was an MRD-guided response adaption treatment paradigm. But what this found, and what’s important to remember about CAPTIVATE, it’s young patients. Median age was like 60, I think, comparatively to GLOW, which was 72, somewhere around there. And I think we showed a lot of safety in this data. 92% of patients completed the treatments. There was no tumor lysis. That’s the nice thing about this. It’s an all-oral therapy. The debulking strategy, I think, is a little bit easier to deal with, honestly, than obinutuzumab induction with venetoclax/obinutuzumab. And no lysis was noted, high rates of MRD, and the PFS is super promising. It’s very early, only at 24 months since starting treatment, which is only what, 10 or 15 months off of therapy ultimately. But it’s promising, and I do think this will be a very relevant option for many patients to utilize, mostly because it’s an all-oral approach with a nice ability to tumor debulk and not really worry so much about a lot of monitoring or a lot of office visits, et cetera, as you start the therapy. DR LOVE: And of course, here’s the GLOW study that we’ve been talking about. I’ve heard people say that they think maybe this is going to lead to approval, which would be really interesting if this is an option. Interesting too, what you were saying, is it going to be easier to give ibrutinib and venetoclax than obinutuzumab and venetoclax? So I guess we’re just going to see where that heads. I’ll be interested to see what Sonali thinks about these next two papers on CAR T. Can you talk a little bit about the SCHOLAR-5 study that Dr Gribben reported at EHA, John? DR ALLAN: Yeah. So this study was looking at SCHOLAR-5, which is a retrospective cohort. Ultimately the point of this study was to kind of weigh the inclusion criteria, kind of balance the two studies the best that they could, and compare outcomes of CAR T-cell versus what do we normally do in third-line settings, which included PI3-kinase, et cetera. And kind of went to this question that we had just previously using tazemetostat, and where does CAR T-cell come into play there. Ultimately what they found is that the CAR T cells had improved response rates, progression-free survival, and overall survival from the ZUMA-5 study compared to this SCHOLAR-5 retrospective propensity-weighted evaluation of third-line targeted agents in FL. And so I think the point of the study was to show CAR T cell’s very effective and probably more effective than kind of the single-agent PI3-kinase approaches or the tazemetostat approaches that we currently have in this setting. But again, as Dr Smith previously stated, it’s about the patient that’s in front of you. It’s not a one size fit all. They had no discussion about toxicity in that abstract, and so CAR T-cell still has some of those issues, where some of these targeted agents, especially the later-generation PI3-kinase inhibitors, and even the EZH2, have very favorable toxicity profiles. So it’s not necessarily a game-changing thing, but it is pretty impressive to see the outcome data with CAR T-cell in that third-line FL setting. DR LOVE: And this is another paper that John reviewed looking at tisa-cel. But I’m curious, Sonali, kind of taking a step back, how you see, at least right now, the efficacy of CAR T therapy in general in FL compared to, for example, diffuse large B-cell? Do we see a shoulder on the curve? DR SMITH: Yeah. My approach for CAR T in follicular lymphoma, or at least my thoughts about it, has evolved pretty significantly over the last 6 to 8 months. When I first saw the CAR T-cell data in follicular lymphoma, ZUMA-5 being the first one, I thought well, this is promising, follow up is short, but how many patients are really going to be eligible for this, and which patients. And now as more data goes by, and now we have the ELARA trial, we have the ZUMA-5, we have this comparison that I think is instructive, it’s clear. There’s a portion of follicular lymphoma patients who are not well served by just the continuous low-level intensity therapy, and that this is where we have to start to really work as a community to identify which patients should go to CAR T. I’m certainly feeling much more optimistic. The one concern that still is there, because you asked about the comparison to diffuse large B-cell lymphoma, is that there isn’t quite the plateau on the curve that we see with DLBCL, that after 3 months or 6 months there are limited relapses. In follicular lymphoma we do need more follow up, and I’d love to see a little bit more of a plateau. Cases from the Community — Mantle Cell Lymphoma, Hodgkin Lymphoma, Diffuse Large B-Cell Lymphoma DR LOVE: So I’m going to talk now a little bit about mantle cell lymphoma and get into some cases. And so one thing we asked the audience this week was what they’re usual second-line therapy is in an older patient with mantle cell, and a vast majority of the audience said BTK inhibitor. But it was interesting that I think only 15% said zanubrutinib, the majority said acalabrutinib. We have a case that we’re going to talk about in a second, but just kind of curious, John, what’s you’re second-line therapy after BR, whether or not you give R maintenance or not? Most people do. BTK? And if so, which one? DR ALLAN: Yeah, so I obviously and using BTK inhibitors in that setting kind of on label for sure. And I think from all the data that is being generated of the second-generation inhibitors. I’m kind of moving to them pretty quickly and building my experience there. Obviously, no head-to-head data specifically against ibrutinib with these other later-generation ones specifically in mantle cell lymphoma, but we do now have three studies basically, of head-to-head data, two of them with zanubrutinib against ibrutinib, one in Waldenstrӧm’s, now one in CLL, and then we have the ELEVATE study in CLL. And I think both are great options. I think I have found good luck with zanubrutinib, and I am using it a little bit more often than with acalabrutinib. It’s hard to say if you can really assess any true difference in efficacy from any of these agents, obviously, at this point in time, specifically in mantle cell lymphoma. Obviously, there is suggestion. Maybe zanu may have some activity in the Waldenstrӧm’s study and the CLL study, but I think it’s easy to use. I have not seen too many toxicity issues, but my experience is growing. It’s really early, obviously, and I don’t have that much long follow up, but obviously any of these second-generation ones I do think most people are quick to jump into. DR LOVE: So Sonali, the way we do our guidelines or consensus is we just ask a whole bunch of people what they do, and if they all do the same thing we call it a consensus. And it’s also interesting to ask the people over the years, as we do, and see how things change. And we just did a survey of investigators. And one of the things that was really interesting that we hadn’t seen in the past, it sounds like people are thinking about BTK up front in mantle cell, particularly in older, frail patients. Sonali, have you ever done that? DR SMITH: Yeah. I have not personally used a BTK inhibitor as monotherapy up front for an older person with mantle cell lymphoma, but there are data being generated right now, first of all in younger people through the intergroup study, where BR is the backbone, then there’s with or without ara-C and with or without a BTK inhibitor, which in this case is acalabrutinib. For the older patients, the nonchemotherapy approaches — I mean chemo/BR is still active for the older patient even if you have to do a dose reduction. And then out of the non-chemo approaches, R-squared I was part of that trial that was run out of Cornell, the Jia Ruan study, and really found that to be very easily tolerated. And at ASCO this year we saw from Tycel Phillips that there is a venetoclax/R-squared Phase II trial that may be useful down the road. But to answer your question, I have not used a BTK monotherapy as first-line therapy in anyone just yet for mantle cell. DR LOVE: So let’s move on now and talk about a case. This is a patient of Dr Prakash, a 66-year-old man with mantle cell. Interestingly, presented with a splenic rupture associated with a car accident, was also found to be pancytopenic, had lymphocytosis, a leukemia type of picture. Here are Dr Prakash’s questions. DR PRAKASH: I saw him a couple months ago. He came into the hospital, no prior medical care pretty much, came in with a fall and a partial splenic rupture, pancytopenia. Bone marrow biopsy showed mantle cell lymphoma/leukemia. DR LOVE: So what are the questions you would like to hear them discuss about this case? DR PRAKASH: In a patient who presents with mantle cell lymphoma/leukemia, significant symptoms, do you treat with ibrutinib up front, or do you do bendamustine/ rituximab chemotherapy initially? Which BTK inhibitor do you prefer? Is it ibrutinib, zanubrutinib, or acalabrutinib? In refractory mantle cell lymphoma, do you think about transplant at all; autologous versus allogeneic? And what’s the role of CAR T therapy in that situation? DR LOVE: So we talked about some of the issues in terms of BTK choice, John, but what about CAR T? When do you think about it? It’s now approved in mantle cell. I hear a lot of interesting cases of people doing really well. How is it approved to be used, and where do you think ideally it’s going to fit in? DR ALLAN: Yeah. I mean I think I have sent some of my mantle cell lymphoma patients for CAR T-cell. I do think it’s an active agent. I do think mantle cell lymphomas may be a little bit different in terms of potential toxicities that you may see. There’s other extranodal involvement, bowel involvement, things like that that we need to be wary of when we’re using CAR T-cell. And so I think it’s got a great role. A lot of the data in relapsed mantle cell lymphoma, especially after progression on BTK inhibitors, shows outcomes are pretty poor. And I do think even though we’ve got other targeted agents that can be kind of used off label, venetoclax and other PI3-kinase inhibitors, and R-squared, and proteasome inhibitors, et cetera, I think CAR T-cell still offers the benefit of the real deep activity and potential durability of that activity. So I do think it’s a very important option for our patients, especially in this type of patients who’s younger, in their mid 60s. And I do think it’s a great option for a patient in that setting, especially if they’ve progressed on ibrutinib. But I typically am still using it post a BTK inhibitor, and kind of maxing out that less toxic approach because there is really good data, and that’s kind of where it’s kind of relegated to at this point in time. DR LOVE: Any comments about CAR T? And also this issue of the leukemic type of mantle cell where you see high white counts, sometimes people even think it’s CLL initially. Do you approach those patients any differently? And what’s your experience with CAR T? Does it fall more into an FL type thing or more like diffuse large B-cell? CAR T therapy in mantle cell in terms of efficacy, any other comments about mantle cell? And what about venetoclax, John? Is that something you use in mantle cell? DR ALLAN: Yeah, absolutely. I mean I think it’s got great activity there, for the most part. I do believe the durability still could be an issue, potentially. We don’t have a lot of long-term follow up. Maybe it’s better in combination with ibrutinib. Some of those studies are kind of being done. We see this synergy across histologies, and so it makes sense to kind of potentially add it onto a BTK inhibitor in those patients that are progressing. We don’t really typically see a lot of BTK mutations in mantle cell lymphoma. There’s other resistant mechanisms that are occurring. And so I think it’s a great option for sure, especially in our older patients that may not tolerate CAR T-cell so well. If you’re starting to get into your later 70s or even early 80s, things like that, a targeted approach with venetoclax can absolutely help our patients out, get them in a remission, get them feeling better, and get some durability of that efficacy. So it has a role. There’s a lot of important studies that are kind of being done, and obviously we just kind of need to wait and see and potentially start to see some durability. And then maybe there’s a question of does CAR T-cell come into play before you kind of go to some venetoclax-based kind of combination or not. But right now, promising activity. It’s very encouraging, and it’s a discussion to have with patients about these two very different approaches potentially. DR LOVE: John, what about prevention of TLS with venetoclax in mantle cell? I’ve heard it said that it’s not much of an issue, but what about in patients like this who have this leukemic mantle cell? Do you follow the package insert, if it’s over 25,000 they’re high risk? DR ALLAN: Yeah. I typically do, and looking for bulky disease, et cetera. There’s some differences. Obviously, there’s this leukemic non-nodal form, and it can behave very indolently like CLL sometimes, and can be confusing at initial diagnosis. And that’s a little bit of a different kind of disease. But then you also have these blastoid kind of variants that have very proliferative disease, and patients who’ve been relapsed/refractory in multiple lines that you see, those patients are obviously much higher risk. They have a very high proliferative fraction. They’re circulating. And we’ve admitted patients when the white count was very high. We try to debulk a little bit, sometimes with anti-CD20 you can do that. But many times they need therapy pretty quick, and you need to get the drug onboard, and you don’t have so much time to do that. So I kind of follow the package insert because there are no real great guidelines specifically in mantle cell lymphoma. So I follow that package insert based on the TLS guidelines there when I use it. DR LOVE: So we’re going to move on now and talk about a couple cases of Hodgkin lymphoma. And of course one of the big questions there is first-line therapy. We saw the ECHELON-1 data presented. It seems like a long time ago, but I guess a few years ago. When we presented this patient with high-risk disease the vast majority of the audience said BV+AVD. But we want to tease out a little bit about how you approach first-line therapy nowadays after we’ve seen the data. We’ve seen some more follow up data. We saw some at ASH. Dr Nguyen has a 26-year-old patient, and here’s the case. 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) + 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 + AVD, and she actually entered a complete remission. And interestingly, her pituitary mass turned out to be a prolactinoma. So my questions for the faculty here is would the faculty consider using BV+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 see or 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 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 very healthy, so her pregnancy is moving along well. DR LOVE: So Sonali, again, revisiting this question we’ve had out there since ECHELON on choice of first-line therapy. Usually when we ask docs in practice, as well as investigators, if it’s high risk people usually think about BV+AVD, but then you get into a debate with standard-risk patients. How are you thinking it through, the choice of first-line therapy? And what’s your experience in terms of how people tolerate, for example, BV+AVD? DR SMITH: Yeah, so I think the BV+AVD approach is very, very active, both because of the progression-free survival, but also particularly in the high-risk patients. And in terms of the doctor’s questions about fertility and some of the longer-term complications, to my knowledge there’s no specific data for BV+AVD, but the ABVD data is very reassuring about infertility and other long-term toxicity. When it comes to front line right now, though, I am putting everybody on S1826, which is a randomized prospective trial looking at nivolumab/AVD versus BV+AVD. And the advantages to that trial is that there is no PET-adapted approach after the first 2 cycles, which although PET adaption has been fruitful in many settings, there’s also some potential challenges with interpreting a PET scan after 2 cycles, including false positives, the incongruent results sometimes when a mass shrinks but it’s still PET positive, and then also the quality of the PET. So the trial is really my first choice right now. DR LOVE: So come on, Sonali, we’ve got to do off trial too. What do you do if they can’t go on a trial? You can’t escape that way. DR SMITH: Yeah, no. You’re right. Although I will say that this is an NCTN trial. Everybody in the country should have it close by, if not onsite. DR LOVE: It’s a great trial for sure, awesome trial. DR SMITH: Yeah, easy. But off of a study I would do BV+AVD, particularly for this young patient with very high-risk disease. I think, some of the older patients, BV can be toxic because of the peripheral neuropathy. There’s also pancreatitis that has been seen that can be severe. And if they have low-risk disease I would think about the RATHL approach, but for most people I use BV + AVD. DR LOVE: So John, again, curious about your thoughts of first-line therapy, and also what do you do with people who relapse after BV + AVD, go to transplant, and theoretically would be eligible for BV consolidation? DR ALLAN: Yeah. I mean I think that’s an interesting case posed there. Especially in a young woman, I think BV+AVD is a great option because you kind of follow the RATHL study, and in this case where they didn’t do fertility preservation, and you think about going to escalated BEACOPP, you really can get yourself into a challenge of potential infertility at that point in time. Whereas with ABVD if you’re able to be in the 85% that are PET negative you’re going to be fine and not have an issue, but you just won’t know that going in. So that’s one advantage in someone who doesn’t have fertility preservation, to think about BV+AVD. I think the PFS data’s there. It’s not a super earthshattering, wide difference. The study had some issues in terms of the composite endpoint, et cetera, that’s there. But ultimately, obviously, it’s a PFS benefit. It seems to benefit younger patients with higher-risk disease in general. The nice thing, as Dr Smith brought up, is that there is no PET adaption, which you get rid of those issues with interpreting a PET scan. You can continue on the therapy and finish it out without necessarily having to make this complicated decision sometimes about what to do. Regarding your second question about kind of using BV in the front-line setting and then maybe not having it as salvage, there is recent data now with pembrolizumab versus brentuximab showing a PFS benefit favoring pembrolizumab, so it does appear potentially the better salvage agent anyway. And so I think there’s one of these scenarios where there’s a lot of activity with these PD-1 drugs, so I’m not necessarily so worried about using BV front line because I do know we’ve got one salvage chemotherapy as well, we’ve got clinical trials, but we also have pembrolizumab/nivolumab/PD-1-directed therapy as a potential option in that second-line setting to kind of get into a deep remission prior to transplant or in a patient that is transplant ineligible. DR LOVE: Also, I will mention I believe that at ASH with the 5-year update on the ECHELON-1 study they did report pregnancies, a number of successful pregnancies in patients who got BV+AVD, like this patient. Of course, this patient was also getting treated for a prolactinoma. Who knows how that affected it. Anyhow, let’s move on and talk about diffuse large B-cell lymphoma. We asked this question, and I’m thinking, Sonali, the answer to this question maybe’s going to change pretty soon, which is what’s your usual therapy or first relapse in diffuse large B-cell. The audience says chemo and transplant, which has been the standard up to now, but I’ve heard there’s a press release out there, Sonali. We have a bunch of trials out there comparing CAR T to transplant in first relapse. I think there’s one, I forget the name if it, that now has a press release that’s positive. Sonali, are we moving towards CAR T at first relapse for diffuse large B-cell? DR SMITH: Yeah. I do think that CAR T’s going to get moved up for a select patient population. That question was a little bit challenging because I wasn’t sure if it meant that the patient had progressed on R-CHOP and therefore had primary refractory disease or progressed right after that. And I think there’s a little bit of a difference because somebody who has primary refractory disease or relapses let’s say within a month or two, currently the standard of care is to go ahead with salvage chemotherapy, but the likelihood of them entering a complete response is very low. In the other hand, if somebody has a relapse that’s at least a year later I do think it’s still reasonable to try the salvage chemotherapy and get them to autotransplant. And there is CIBMTR data that if they’re in a complete remission by PET scan that there are still people who will benefit. However, the BELINDA study and other trials that have been ongoing randomizing early relapsing and refractory patients to CAR T versus autotransplant look really exciting. And intuitively it makes sense that somebody who’s progressed very quickly after R-CHOP is probably chemoresistant and using a nonchemotherapy-dependent approach is probably going to be more fruitful. I think there’s still a lot of questions about timing, toxicity, patient selection, and durable remissions, not to mention cost, but I do think that CAR T’s going to get moved up for a number of people. DR LOVE: So let’s go on to our last case here. This is a patient of Dr Meerasahib, an 84-year-old woman with diffuse large B-cell, EBV-positive diffuse large B-cell, gets treated initially with mini-R-CHOP, has relapsed disease, and now getting polatuzumab, rituximab and bendamustine. Here are the doctor’s questions about this case. DR MEERASAHIB: I started her on second-line polatuzumab vedotin, rituximab and bendamustine, and she had 2 cycles already, and she has done really, really well, hardly any side effects. The question is how do we treat EBV-positive diffuse large B-cell lymphoma? Do we treat that different, because given the aggressiveness of the course, is there any different line of treatment for that? And how to we approach that if it is in the elderly population? This is an aggressive disease, and there is a good chance that she will progress at some point, and what will be our next approach? Should we be thinking about R-squared, CAR T? What would be the panel’s suggestion for that? With the new data of tafasitamab and lenalidomide, instead of the R-squared will the panel use that in a second-line or even a third-line setting, or rather stick with pola/benda/rituximab, and go to tafasitamab/lenalidomide as a third line, or even R-squared? DR LOVE: Or lonca-T, as I’ve learned a new, short name. I couldn’t pronounce loncastuximab or whatever it is, but I like lonca-T. So first of all, Sonali, how do you think through in general second-line therapy in an 84-year-old with diffuse large B-cell nowadays? DR SMITH: Yeah, I think that the physician that we just heard from really had all the right options listed. I mean we now have tafasitamab/lenalidomide, we have pola/BR, we have selinexor, and we have lonca-T all FDA approved specifically for this setting. And I think picking between all of them, there’s really no clear guidance on which one to pick, although I will say with the pola/BR the bendamustine can be toxic, and so we often have to reduce the dose, and that selinexor has probably been moved more to a palliative setting when it’s used as a monotherapy. But the real question for an 84-year-old is her fitness. If she has really fit, there is no upper age limit, per se, for some of the cellular therapy approaches, as long as she has all of the social support and the interest in going through something like CAR T. Some of the trials did include older patients. And not that I’m advocating that for all patients, but I wouldn’t take it off the table for her. And then the other question that he had was about R-squared, and that is definitely something I’ve used in the relapsed setting for older or more frail patients, but it’s primarily restricted to patients who have a non-germinal center phenotype, tend to be CD10 negative, or perhaps have double expression by protein of MYC and BCL-2. But picking between all of those is a little bit challenging. One last thing I guess I’ll just say about the options that are out there is that tafasitamab/lenalidomide has a very long duration of response for people who are in second line. So maybe this is true for most therapies, that the earlier you use it the better, but the durability for second line is actually very interesting. DR LOVE: What about tafasitamab before CAR T or after CAR T? They’re both CD19. It reminds me of some of the debate that goes on in myeloma about belantamab mafodotin before or after CAR T. Again, the same target. What do we know about that in diffuse large B-cell, Sonali? DR SMITH: Yeah, so there is data that people have received anti-CD19 therapies either before or after anti-CD19-directed CAR T-cell therapies, and the impact is lower than I would have expected. I would have thought that if you use something against CD19 you’re going to down regulate the antigen, and then the CAR T may not work as well. But at least the small amount of data that’s out there suggests that this may not always be the case. And then in terms of post CAR T using an anti-CD19–directed therapy, there are mechanisms of resistance outside of downregulation of CD19, so I think it’s still reasonable to consider, although the post-CAR T setting is just such a dismal place to be in general that I don’t think people have a whole lot of options. DR LOVE: John, any comments about your experience with CAR T? And also this interesting question Sonali brings up about using it in octogenarians. Kind of how do you think through eligibility? What are some of the specific things you think/worry about with CAR T in older people, John? DR ALLAN: Yeah. I have an interesting perspective. So I don’t actually do the CAR T procedure, our bone marrow transplant colleagues kind of take our patients through that in our group, and so I’m kind of a gatekeeper of many patients to them. I always ask the patients if they’re interested in it. I want them to get information about it, and I want them to be informed at a level that I can’t necessarily do that for them in terms of all the logistics, et cetera. And so I do definitely refer almost all patients, regardless of age, to our colleagues to help make that decision. With that said, I like things that are off the shelf because I can keep treating my patient, especially if they’re transplant ineligible or they are CAR T-cell ineligible and older, I’m trying to kind of palliate that disease in these relapse setting in DLBCL. With that said, some of my experience of our older patients, I do think it’s not a preclusion to someone, but if you start to get into the 80s and higher I do think there are some potential risks there, and it has to be well thought out, and obviously a very fit 80-year-old. But again, I also agree that all patients should probably have the option and discuss it and hear about it, pros and cons, et cetera. With that said, and I think with bispecifics kind of coming around that might be able to move into that space, for me I would be able to deliver that easily and possibly get the same type of effect. So it’s going to be a very crowded space over the next few years as bispecifics come into play, and how do we sequence those with CAR T-cell, et cetera. But ultimately I can say that all patients should probably hear about the option, especially younger patients that are going to be fit and have no issues with it because I do think if you’re in that second-, third-, fourth-line setting and you haven’t had CAR T-cell, and you’ve got DLBCL, a lot of these agents that we talk about, it’s more palliative in nature. It’s about stability of disease, getting some type of response, and maintaining whatever that response is without potential thinking about cures or really deep CRs, et cetera. DR LOVE: Sonali, I’m just kind of curious. I’m starting to hear more about outpatient CAR T. I hear people saying the reimbursement issue for inpatient is a real problem. Do you see CAR T moving into the outpatient in the near future? DR SMITH: Yeah, I do. And at ASH last year we saw the OUTREACH study, and there’s a couple of other studies that have looked at real-world experiences. You have to be careful because even though they’re real world and outpatient they are still specialized centers that have 24/7 access to medical care and emergency support services available. So I don’t think this is going to be something that can be done in isolation in a solo practice or something. But I do think that there will be extension of CAR T services and opportunities throughout the country in nonacademic medical centers as we learn more about the safety and how to prevent the toxicity. And you’re right about the reimbursement. The reimbursement is going to probably shift to lower costs of care at sites that are outside of the major academic medical centers, and that may pressure the use of this. Highlights of ASCO and EHA 2021 — Sonali M Smith, MD DR LOVE: So let’s talk about some of the papers that you wrote summaries of, beginning with this ECOG-ACRIN study. A lot of times these big Phase III studies, by the time they mature we’ve kind of moved on. I’m not sure if that applies to this study or not. What was the bottom line here, Sonali? DR SMITH: Yeah. So this was a prospective trial of BR with or without bortezomib as part of induction and then followed by rituximab with or with or without lenalidomide. And we heard about the first portion, the induction, and the bottom line is that bortezomib did not improve any of the outcomes that they looked at and did add some toxicity. So we still don’t know yet about the maintenance component, but yeah. DR LOVE: So I think we mentioned this before, the venetoclax/R-squared combination. Sounds really kind of interesting in mantle cell. Sonali, what did they report here? DR SMITH: Yeah. So this is what we talked about, venetoclax plus lenalidomide and rituximab in treatment-naïve mantle cell lymphoma. And it really seems surprisingly well tolerated. I mean no unexpected toxicity. There were cytopenias, as you might expect. And the CR rate by 1 year was 100%. This is still a pilot trial, and these were younger patients. The median age was 65. They capped it at 70. And there were some deaths, although some were related to lymphoma. So I think this is something just to keep your eye on, and hopefully will be looked at in a comparative setting going forward. DR LOVE: So let’s talk about a couple papers looking at Hodgkin lymphoma. What about this CALGB study that Dr LaCasce reported, Sonali? DR SMITH: Yeah, so I think this is a practice-changing trial. PET-adapted therapy in Hodgkin’s has had an important role despite some of the pros and cons that we’ve already talked about. But this was one of the first prospective multicenter trials done in North America that is specific to bulky disease. And bulky disease here was defined as 10 cm. All patients got 4 cycles of ABVD and then had a PET scan, and if they had Deauville 1, 2, or 3, which was about 80% of the patients, they went on to just have more chemotherapy with no radiation. And their outcomes are really outstanding, with a PFS of 83% and overall survival of 99% at 3 years, which is when most of the relapses would have occurred. So I think the majority of patients with bulky classical Hodgkin lymphoma can avoid radiation therapy, and I think that really is practice changing. DR LOVE: So one more thing I want to ask you about is this press release that just came out actually just a few days ago, the TRANSFORM trial, a Phase III study, I guess comparing CAR T therapy, lisocabtagene as second-line treatment with relapsed disease compared to autologous transplant that apparently is positive. Is that a big surprise to you, Sonali? And do you see CAR T moving up? DR SMITH: Yeah, no. I was really excited to see this press release, and it goes back to what we were talking about, which is when to use chemo plus transplant for relapsed diffuse large B-cell lymphoma. And I think both the TRANSFORM study, as well as the BELINDA trial will give us some of this information. But I see it moving up, particularly for those patients who relapse early and have chemoresistant disease. DR LOVE: So one more thing I want to just bring out there. John, you mentioned selinexor, which is now approved in diffuse large B-cell. Of course, we have a lot of experience with that in myeloma. It was really interesting, in myeloma too, in the beginning, people really had a lot of problems with it, and then as they use it more and change the schedule, now it seems like it’s much better tolerated. John, what do we know about selinexor in diffuse large B-cell, and do you use it? And if so, when? DR ALLAN: Yeah, with selinexor, it is interesting molecule in terms of its mechanism of action is one of these selective uptake nuclear export inhibitors, in terms of affecting MYC and other transcription factors, et cetera. So it can really potentially impact some of these high-risk DLBCLs and high-risk lymphomas that activate these certain pathways. With that said, as you stated, there are some toxicity issues with the drug, even as kind of monotherapy. We see a lot of cytopenias, thrombocytopenia, asthenia, and you need to modify the dosing a little bit and manage that. And especially in these heavily pretreated DLBCL patients that have had maybe a lot of chemo, they don’t have a lot of marrow reserve, and it can be a difficult agent to potentially stay on. And I think, obviously, trying to get it in combination with chemotherapy or moving it up in combinations is important to think about. I guess right now I’m using it really kind of on label, and it’s kind of one of these drugs that I’m using kind of to palliate the disease as we’ve gone through some of these other agents, the CD19-directed agents, et cetera. That’s where I’m really thinking about this drug, though you can get some responses. The overall response rate’s relatively low in general, but again, very highly-refractory patient population. I think these combinations with chemo are interesting. We’ve participated in a study here in salvage chemotherapy with RICE, and while there is some great outcome data that can be seen, there are some toxicity issues with cytopenias, prolonged cytopenias. And so I think we’ll have to be careful as we move it forward to not potential inhibit our ability to give R-CHOP or whatever it is that’s currently the curative approach, and not impair that ability to administer full doses of these agents, because we don’t want to kind of impair that. But obviously that’s why we’re doing these studies, to understand it, and I think there’s some potential there, for sure, with modifying the drug, understanding it better, how to decrease those toxicities. Introduction DR LOVE: We’re now going to talk about GI cancers as part of this ASCO review and case presentations here today. We have Dr Tom Abrams from Harvard Medical School and Dana-Farber Cancer Institute, and Dr Randy Hecht from UCLA GI Oncology Program. We have general medical oncologists from the Texas Clinical Society of Oncology presenting cases today, and our faculty has put together these chalk talks about some of the key presentations at the ASCO meeting. And we’re going to talk about a bunch of papers in colon and gastric cancers, as well as HCC and pancreatic cancer. We’re going to go back and forth between cases and papers, but I just want to take a breath and take a step back and start out with you, Randy, and ask you when you think back to the ASCO meeting any one paper in particular that sticks out in your mind that you found interesting, provocative, and relevant? DR HECHT: Probably Ian Chau’s paper, which I think is also practice changing, nivolumab in squamous cell carcinoma of the esophagus. Even though we had actually two trials, there was also a Chinese trial — people forget how common squamous cell carcinoma of the esophagus, even though we don’t see it as much as around the world. So I think that was one of the things that was particularly interesting. A lot of the others were kind of updates and kind of broadening things and spreading them out, but that was one of the more interesting ones. DR LOVE: Tom, any favorites from your point of view? DR ABRAMS: Yeah, there were really no obvious practice-changing data that were presented in the GI world, in the hepatobiliary world, but there was Makawita paper, that we will discuss, is pretty interesting in that it really establishes IDH1 and IDH2 as real drivers of biliary tract cancer. And I think that’s very provocative, and I think it provides the confirmation that precision medicine is moving in the right direction. DR LOVE: Yeah. We’ve been calling cholangiocarcinoma the new non-small cell lung cancer because there’s a lot of targetable potential lesions. Audience. Yes or no, have you used an IDH inhibitor; have you used an FGFR inhibitor in cholangiocarcinoma? Have you done that? I’m just kind of curious whether the audience has tried that strategy. And actually, it looks like about a quarter of the audience has already done that in this pretty uncommon tumor. Cases from the Community — Colorectal Cancer, Gastric/Gastroesophageal Junction Cancer DR LOVE: Anyhow, we’re going to start out talking about colorectal cancer and gastric cancer. We’ve got some cases to begin with. And the first case is in MSI-high cancer, and we did a survey of the audience prior to this meeting this week. We got about a hundred responses. We asked this question to the audience: what’s your usual first-line therapy? And the audience says pembrolizumab. But we gave this survey to you all, as well, and you guys say ipi/nivo. Randy? Really? DR HECHT: Yeah. First of all, one of the papers we’re going to discuss, which is KEYNOTE-177, has more complete data. And I know we’re not supposed to do cross-trial comparison, but one of the things that you said was in a younger patient, so if you’re a younger and healthier person. If you look in CheckMate 142, there was a combination, the response rate was significantly higher. And I think that the other key thing for ipi/nivo is that it’s important how you dose the ipi. This is not your grandfather’s ipi. And I think if you dose it, for example, the way that Ian Chau did or that they did in some of the more recent trials, it is a much better-tolerated drug. So that’s where I would go, particularly in someone who I thought could tolerate the effects. DR LOVE: Interesting. Well, here’s our first case. This is a young patient with MSI-high metastatic disease, but interestingly this patient also has a somatic BRCA1 mutation. Really curious to hear what you have to say about that. Here’s Dr Jasani talking about this 40-year-old man. I’m really curious too about younger people with colorectal cancer, 40 years old, we have lots of cases like this. Here’s Dr Jasani. DR JASANI: What is the ideal up-front treatment in these MSI-high colon cancers? Is it dual checkpoint inhibitors with nivolumab with ipilimumab? What is the timing to rechallenge with colitis based on the grade of the colitis with the checkpoint inhibitor? And some of the data to touch on for remissions and long-term cures in patients who have Stage IV disease on immune therapy. And lastly, a little bit of insight into this phenomena we see with immune response in checkpoint inhibitors, with persistent masses, and many times these are acellular or fibrotic scars when you go and actually rebiopsy them. DR LOVE: I guess another thing here is this patient had a BRCA1. DR JASANI: Yes. This was in the NGS. It’s a somatic. He did get germline testing that did not show a germline BRCA. Is there a role for PARP inhibition in a somatic BRCA-mutated colon cancer? DR LOVE: And Tom, I’m going to add what do you do with people who are MSI high and also BRAF mutant. But going back to this case, this patient actually got ipi/nivo, which is what Tom you also said that that’s your favored. But this patient developed Grade 3 colitis, as you just heard, and was put back just on the nivo, colitis came back again, stopped all therapy. The patient’s actually doing really well. So Tom, why do you prefer ipi/nivo? Do you rechallenge when you see colitis? DR ABRAMS: Well, I preferred it based on the exact same reasons that Dr Hecht just outlined, the high response rate, it’s a younger patient, you want to be as aggressive as possible. And with the modern way of dosing the ipi it does seem to be much more tolerable. Obviously, this patient got Grade 3 colitis, and then even after rechallenging with just nivolumab it persisted. But it’s proof of how well this regimen works is in that you’re now a year out from their last challenge with any therapy, and they are still disease free. So there’s a chance that this is actually a patient who’s been cured. And I think I wouldn’t, at this point, rechallenge them with anything until you actually know for sure that they’ve recurred. To my mind, this patient has a very reasonable chance of being disease free for years into the future. DR LOVE: So any thoughts, Randy, about PARP inhibitors in patients with BRCA mutations that have cancers? Lung cancer, et cetera? I don’t know if there’s much literature or data out there. Have you ever used a PARP in a patient with colon cancer, Randy? DR HECHT: I personally have not. Dr Abrams got the easier question on that one. And I actually went back and looked. And so most of the trials that we think about, of course, are germline, but there is a data set for somatic mutations in other diseases. And I’m not aware, other than the occasional anecdote. So I do think that would be a possibility. But I’m hoping, like Dr Abrams said, if you look at people who do well for a while, those curves to flat for both PFS and OS. And maybe the fact that he had such a bad toxicity in a way is it’s got to taste bad to be good sort of thing, is that there’s some data that they may do better. So my hope is that you never get to it, but I would certainly keep that in my back pocket. And I would not ReDOS this patient any time soon. DR LOVE: We’ve had a couple cases already in other modules with people with issues with ipi/nivo. Tom, any comments on this phenomena of the younger patients with colorectal cancer? We’ve heard things about the microbiome, but nothing that really makes a whole lot of sense to me. Any thoughts about why we’re seeing this, Tom? DR ABRAMS: Just the fact that more and more patients under 50 are being diagnosed with the disease? I don’t think anyone knows the answer to this question. There’s a lot of theories. It’s almost certainly some environmental factor, diet, environment, because this has been such a quick evolution in incidents. But I don’t think there’s been any clear explanation for the obvious rise in incidents. DR LOVE: So we’re going to go on and talk about another case. This is a patient of Dr Anish Meerasahib. Again, young patient, 53 years old, KRAS-mutant metastatic disease, gets various therapies, typical therapies, FOLFOX/bev, and now is getting regorafenib. Actually, he wanted to use a PI3-kinase inhibitor plus immunotherapy but was not able to do that. In any event, this patient got regorafenib, and here’s Dr Meerasahib’s questions. What dose of regorafenib has been she been on? DR MEERASAHIB: We started 40 and went up to 80, and she went up to 120, couldn’t tolerate 120. She dropped it back to 80. Now she’s on 80. At that time, I was not really sure what to use, and then I used regorafenib because I thought we can still use the VEGF blockade to some extent, and with the multitargeted approach it felt better than TAS. What does the panel feel about it? When TAS-102 is used, does it make sense, since the VEGF blockade is no longer there, should we add bev in addition to TAS-102? In terms of dosing of regorafenib, what’s the ideal dose of regorafenib in the palliative metastatic setting? Do you all start at 80, or do you start from 40 to 80 and 120? DR LOVE: So Tom, age-old question it seems like, but we have seen some new data. I’m curious about whether or not you’ve used TAS-102 plus bev. And his thought about the importance of keeping VEGF blockade, is there a typical scenario where you’re more interested in VEGF continuation? Maybe patients who’ve had prolonged responses previously. And of course, the age-old question about dosing of regorafenib, Tom. DR ABRAMS: Yeah, so I think when you’re choosing between regorafenib and TAS-102 or TAS-102 plus bev you’re obviously in a situation where you’ve gone through the effective regimens, and you’re now down to regimens that have minimal efficacy. And so you’re always trying to balance side effects versus some degree of efficacy. And I think that TAS-102 plus bev is probably more effective than TAS-102 monotherapy, but it’s still not a tremendously effective regimen. Whereas regorafenib, for some patients, can be reasonably effective, then you’re dealing with toxicity. So I take it on a patient-by-patient basis, and I think there’s no right answer there. When I start regorafenib, however, I always start at 80 and really use the ReDOS scheduling, which is a week at 80, if they tolerate it go up to 120, if they tolerate it go up to 160. No one ever really tolerates 160, so you’re generally going down to 120 or staying there. Maybe 80 is your maximal dose, and that’s fine. I don’t think there’s anything wrong with that at all. Whatever they tolerate is what they tolerate. DR LOVE: So let’s go into our next case. I always like cases that start out 92-year-old. This is a patient with metastatic disease who had a BRAF V600E mutation who got various therapies, but what was interesting to me is that last September the patient was put on encorafenib/cetuximab and is still on it and doing pretty well other than some probably unrelated, age-related blepharitis. Here’s Dr Levin. DR LEVIN: We started him on encorafenib and cetuximab, and he has responded well. The lung nodules that he had almost completely disappeared, and his tumor marker has improved as well. Now 92, and his goal was to finish writing his book. So he’s writing his biography, and he just told me about 2 months ago that he finally finished it. DR LOVE: How did he do in terms of his skin with the encorafenib and cetuximab? DR LEVIN: So he actually did really well. He wasn’t having significant skin issues. We did start him on tetracyclines to kind of prevent the rash. Eventually he will progress, so at the time of progression what do we go to? Do we completely stop BRAF inhibition now that he has BRAF mutation? And do we switch him to just another line? DR LOVE: So Randy, can you comment on your experience with management of BRAF-mutant colon cancer, particularly with this regimen? It’s kind of interesting to see this patient did so well tolerability wise with two agents that can be associated with particularly skin toxicity. What’s your experience with this approach, Randy, and at what point do you use it? DR HECHT: No, we definitely use it. It has activity, the BEACON trial. The only problem is, and this person has done well, is that if you look it’s a little disappointing in that the duration of response is not as long as we would like. And I think what you had asked is actually exactly the right question because I think this is going to come up, unfortunately, relatively soon, in that. So my experience has been it’s something that you can get people through. You mentioned blepharitis. I think we always work really closely with our ophthalmologists. I think that’s important. The other thing I think that’s interesting, this guy had several different cancers. I would have genetics, even though with a BRAF mutation, those are almost always sporadic, but other NGS to make certain that he doesn’t have some other targetable lesion. You probably already did this, and I just have the information that you’ve already said. Now the question I think that has also been brought up is do you switch? Do you continue BRAF inhibitors? I couldn’t find any data on that. There’s a little bit of data in the melanoma literature, but I don’t think it’s really strong. And melanoma we know is not colon cancer when it comes to BRAF. You need, for example, the anti-EGFR because of the feedback loops. So when he progresses, unless he dies of something else, he’s 92, I would go onto something like regorafenib or TAS-102, probably with bevacizumab. DR LOVE: So let’s move on and talk about what is, I think, one of the most confusing areas where we get the most questions, which is the use of checkpoint inhibitors in gastroesophageal cancer. So hopefully you two can help straighten this out in a few minutes. We’ll start out with a case. This is a 59-year-old woman with signet cell carcinoma who actually got neoadjuvant therapy with FOLFOX, who currently was getting it at the time I talked to Dr Kodali. Here are her questions about this case. DR KODALI: I have a 59-year-old who presented with epigastric pain and GERD symptoms, and endoscopy showed just diffuse ulceration, and it was biopsied. It turned out to be signet cell diffuse gastric cancer. She was initiated on preoperative FOLFOX chemotherapy regimen, and she’s now had 3 cycles of FOLFOX, tolerating well, and going on to hopefully get to surgery. The question I have for the investigators is what are our options for preoperative chemo versus chemo/XRT? And what’s the options for adjuvant PD-L1 therapy? And anything added in the neoadjuvant setting for PD-L1 in a high-risk scenario? In the front-line setting, with respect to the CPS score, nivolumab is approved. So I’m not sure in the adjuvant setting how they’re using the CPS score for the PD-L1 therapy. DR LOVE: So Tom, let’s talk about localized gastroesophageal cancer, both adenocarcinoma, squamous cell carcinoma, CPS low or elevated. How do you approach, first of all, preoperative therapy, and then postoperative therapy, particularly if there’s residual disease? DR ABRAMS: Right. So I mean I think everyone’s confused about this topic. I think part of the problem is that some of the studies really look at gastric cancer and GE junction, others are looking at esophageal and GE junction, and they are different but the same, and we tend to try to mix them up as best as we can for each patient. For locally advanced disease, and this is gastric cancer, typically patients are going to receive some degree of perioperative chemotherapy, either FLOT or FOLFOX, this patient is on FOLFOX, then they go to surgery, and they get more chemotherapy afterward. That’s not a situation where we would then consider adjuvant nivolumab typically. That’s more reserved for the esophageal cancers, or the GE junctions, who receive preoperative chemoradiotherapy, have residual disease, and then go on to receive nivolumab. And that’s a setting in which we always knew that patients didn’t get a lot of chemotherapy. They probably need to get some more. There’s high rates of recurrence. And this provides a new standard of care for patients irrespective of CPS score. For this patient, I would say they would probably go on to get surgery and then more chemo, and then you would enter a protocol of active surveillance. And then if they were to recur, then you might consider a checkpoint inhibitor along with chemotherapy based on recent data. DR LOVE: So we’ll go through some of that. Randy, what about the metastatic situation? The first-line metastatic situation. How do you think through whether to add an IO? And how does the CPS score tie into that? DR HECHT: So this has been really confusing, like you said, up front. And they’re confusing for a number of ways. What Tom had just said about whether you’re lumpers or splitters with esophageal versus gastric. We know that squamous cell is a different disease and probably more sensitive. The other thing is that I think, as this patient’s physician Dr Kodali pointed out, about CPS score and PD-L1. And in fact, if you look at the trials they’re not all done the same, and they’re not all done with the same antibody. So the more recent data, as Tom was alluding to, which actually was just published by Yelena Janjigian, in front line makes it easy because it says that at least the FDA approval is in all comers in front line. So that actually makes it easy. I don’t have to worry about the CPS score. I don’t have to worry about the PD-L1 staining. Also, I see many patients who have been biopsied in the community. I have no idea how good or bad their staining is. It gets sent to someplace. I have no idea. So that makes it easy. Now if you asked me, and I think this is one of your questions later on, what is the benefit of IO in someone who has a very low PD-L1 expression? However you want to do it. Almost all of us have gone back to CPS. And I would say it’s probably small, but I can’t say that it’s non-zero. In that group the hazard ratio was about 0.92. So I feel that this is now the standard of care. It’s made it easy. All these patients, like this patient, who have distal gastric cancer and has a high chance of recurrence, and probably you’ll be treating this patient with an IO agent such as nivolumab in combination with chemotherapy. DR LOVE: So let’s talk about HER2-positive disease. We asked the audience this question, which is what’s your usual second-line therapy? We said in a patient who got FOLFOX/trastuzumab, but I guess in the future people are going to be getting FOLFOX/trastuzumab/pembrolizumab. We said the patient in this situation had a low CPS. I don’t know if that even changes the way you approach it. But we got a variety of answers. The most common one was ramucirumab/paclitaxel. We did have some people saying continue trastuzumab and switch chemotherapy. But I’m just kind of curious because, Tom, both of you said T-DXd, trastuzumab deruxtecan. Would you like to comment? DR ABRAMS: Sure. I think based on the study that was presented at ASCO GI it clearly becomes the new standard of care. The drug itself has toxicity. There’s a significant amount of interstitial lung disease that can happen, and some of it can be severe. And so you have to monitor these patients. But it is an effective drug for your HER2-amplified patients, and it really is a new standard of care in my estimation. DR LOVE: So let’s bring in a case. There’s a specific question related to this case that I think is really interesting. A 48-year-old patient with HER2-positive GE junction adenocarcinoma. The patient ended up getting surgery, had a node that was suspicious afterwards, but on trastuzumab when a solitary brain met was discovered, Randy. So this met was removed. There was no other mets. The patient got radiation therapy. And actually, Dr Martins continued the trastuzumab, which kind of comes out of a breast cancer paradigm that we’ve had for a while, which is if the patients not progressing systemically, they develop isolated brain met, keep the same therapy going. I don’t know if that applies to GI or gastroesophageal cancer. But here’s Dr Martins. DR MARTINS: We settled on FOLFOX as his neoadjuvant regimen, and obviously HER2 positive, so we were able to give him neoadjuvant trastuzumab. And his insurance didn’t really bat an eye at that. You just never know what you’re going to get with them. So he had a beautiful response by PET scan. His recurrence was in the brain. He had a solitary brain met. And he’s single. He lives with his mom, nice guy. And actually, we had a heart-to-heart that day when he had the brain met, and he said, “Dr Martins, I don’t know if I want to do this anymore. I don’t want to live like this.” And I said, “But you know, a solitary brain met is not an un-survivable thing. You could possibly go back to normal.” So long story short, I was able to persuade him. We agreed that he would live through this recurrence and then decide what to do. He had surgery followed by radiation to the cavity. One question for the experts is do they agree with my decision to continue the trastuzumab after the brain met. Would they have done something different? And my perpetual question, the role for immune therapy in his case. And obviously there are a bunch of new HER2-active drugs. How many of them have crossed over to esophageal cancer? And what can I use in him next? Because I’m worried he is going to progress, and I think I’ll be able to persuade him to do more treatment as long as his quality of life is good. DR LOVE: So Randy, first of all, right now with this resected brain met would you keep the trastuzumab going, or stop therapy, or switch to something else? DR HECHT: Well, they obviously take good care of their patients in Texas because this patient has done extraordinarily well. And the brain met was over a year ago. So if it ain’t broke don’t fix it. But for trastuzumab in failures, at least in general in upper GI cancers, there’s some Japanese data that probably continuing trastuzumab beyond progression isn’t so good. Now back to Dr Martins’ original question. This is kind of a sanctuary site. GE junction/esophageal cancers, of all the GI cancers, are the ones most likely to have brain metastases that we see. But I would continue. Maybe there’s something different now. You’ve radiated, you’ve cut, and you’ve changed the blood-brain barrier. As to his question about other drugs, there’s really virtually no data. As many times in HER2-positive disease we follow in the footsteps of our breast cancer brethren. And only now are drugs like tucatinib really being looked at that has a lot of activity in brain metastases. And so I feel that if he progressed that’s probably where I would go. As for continuing with T-DXd, or fam-trastuzumab deruxtecan, there’s very little data, I think, in any malignancy for brain metastases. So I would keep going. If he progresses, as I think has been pointed out, most of the time now we’re doing IO up front. But there’s definitely a role for IO, I think, in second and third line. How this fits in in this complicated patient is kind of art, whether there really is synergy between trastuzumab and a PD-1. But I think that you’ve done really well. This patient is a star. And I would keep doing exactly what you’re doing. DR LOVE: So Tom, we’re going to go through the data that was presented on chemo/trastuzumab plus IO, but do you look at CPS level at all when you have HER2-positive gastroesophageal cancer in trying to decide whether to bring in an IO?
DR ABRAMS: Well. Fortunately or unfortunately, this hasn’t actually come up for me clinically to this point yet, and I haven’t used a checkpoint inhibitor with trastuzumab yet. Even though it is FDA approved, I’m not certain that that would be exactly what I would choose right now, especially irrespective of CPS. I think if the CPS were quite high, I’d be more inclined to do it. But that’s not come up yet, for me at least. Highlights of ASCO 2021 — J Randolph Hecht, MD DR LOVE: So let’s talk about some of the papers, including the paper that I just mentioned, and we can maybe dig a little bit more into this. So Randy, first of all there was an update of the KEYNOTE-177 trial, pembro, in MSI-high disease. Can you comment on what they saw there? I guess they were looking for survival and didn’t find it. DR HECHT: Yes. But the problem with all of these is crossover. And so I think there are a couple really interesting things about crossover. So one, 60% of people crossed over. And in fact, if you look at the survival, the p-value is pretty good, showing that probably earlier PD-1, pembro, is better than later. So that’s one thing that you pull out. The other thing that’s really depressing and concerning is that 40% of the people didn’t crossover, We think of patients in first line, and we think about them in second line, but not every person who’s in first line is in second line. And so that’s another reason to try to treat people up front. There may also be some falloff. And so I think you may have to look at your patient. So if you have someone who has a relatively poor performance status, has a large disease burden, if you look at the curves, particularly for PFS, there is this kind of early falloff, and these patients may not have made it, particularly if they didn’t get a good response from IO. So I think that the question is going to come up. There are trials that are underway looking at combinations. There are also nivo/ipi trials, as well, coming up, like for example, the questions that you asked. So I think that for a patient who has a reasonable disease burden who only wants a single agent, I think that this update actually just cements what we had already thought about its role in this subgroup of patients. DR LOVE: So we were talking about HER2-positive disease and T-DXd. I was kind of surprised that it wasn’t approved in colon cancer. It was approved in gastroesophageal cancer. But we did see more data from the DESTINY-CRC trial at ASCO, Randy. What were your thoughts about it? DR HECHT: I think it’s important to look at NGS really for all these patients. I think anyone in a GI cancer really deserves NGS, and this is a minority of people. I think the data looks better than other combinations, like with lapatinib or with pertuzumab. I think one of the things that was a little bit disappointing was that I was hoping that this was really going to pick up those patients who had lower levels of HER2 expression. And if you look, it’s great if you’re IHC 3+ because that’s what you would expect, almost, with an ADC. That’s the target. But even if you were ISH positive and IHC 2+, that the response rate really wasn’t that great. It was less than 10%. And in those patients who were ISH negative and C2 hybridization negative basically I don’t think it really helped at all. The other thing I think that’s important for this is that some of these patients had prior trastuzumab up front, and it shows that, as has been seen before, that you can give it in patients who may have already had prior trastuzumab. I think, as Dr Abrams pointed out, 4% of these people died, I think it was 3 patients died from interstitial lung disease. So this is something that you have to really pay attention to. And we really hate to kill patients. The cancer’s doing enough stuff already. And I think that probably our breast cancer colleagues are more familiar with this. But this is not something you fire and forget. DR LOVE: Yeah, and we hear a lot about people watching patients very carefully, educating them to report any respiratory symptoms, looking carefully at restaging scans to check that out and hopefully pick this up earlier. We were talking before about TAS-102 plus bev, and we actually saw a paper on that, Randy, at ASCO, the TRUSTY study. Any comments? DR HECHT: Well, we can do that in like one sentence. Irinotecan still matters, okay? And irinotecan is okay in second line because one of the things I specifically put in my report is that sometimes hazard ratio is reported in different ways in different countries. So TAS-102 did worse, okay. So I’m not saying this doesn’t have activity in third line or in salvage or even in fourth line, but even though irinotecan in these arms, particularly FOLFIRI, which is available in the US, some of those patients had S1, and irinotecan has under 10% response rate. But this is one more thing saying it’s better than this. So I think that this is all you have to think about for this trial. DR LOVE: And I think that’s kind of the way it’s always been sequenced, and I guess it’s not going to change. DR HECHT: Exactly. DR LOVE: What about this FIGHT study? We were talking about FGFR alterations. And we saw this, I think initially at the ASCO GI meeting, bemarituzumab, or bema. Can you comment on that given combined with FOLFOX first line? DR HECHT: Yeah. Actually, my colleague here, Zev Wainberg, presented that at ASCO, and then Dan Catenacci has presented more updated data. This is really interesting data because if you notice that we’ve been talking about 3% or 5% or 2%. And so we still don’t necessarily understand the biology. But this is different than in cholangiocarcinoma because these are tumors that overexpress, and depending on what your cut points are, up to 30% of upper GI adenocarcinoma. So this is more than HER2, either overexpressed by staining FGFR2b or had detectable ctDNA. And I think actually the median’s actually understated. If you look at the curves, now this is a Phase II, and it’s going into Phase III, is that there’s even more of a tail of a curve than I would expect if this is really a signal transduction inhibitor. The other thing is that if you’ve got a lot of expression, you do really well. And if you’re in this really small group that has expression and positive ctDNA we don’t see hazard ratios, and I know the numbers are really small, but like hazard ratio for PFS of 0.15. I mean these patients did incredibly well. I think the other thing that’s really important about this versus the small molecule inhibitors that Dr Abrams was talking about is that I think this is better tolerated. So you don’t get some of the toxicities, particularly like hyperphosphatemia and others. Now you do get corneal toxicity, and they were very careful at looking at this because this has been picked up in early trials. But it seems to be really manageable. And in fact I’ve had these discussions with Zev, who has more experience because he was helping run the trial, and it seems that other than stomatitis and this manageable corneal toxicity it’s pretty well tolerated. So I think as you said, it’s becoming lung cancer. DR LOVE: Yeah. So Tom, any comments about bema, so to speak? What fraction of patients have the alteration, incidentally? DR ABRAMS: So it’s overexpression. And as Randy said, it’s up to 30%, so it’s a very high number, more than you’d expect. But we don’t often look for this. So I think it’s going to become something we should be looking for based on these data. This is a drug that’s effective. This is a patient population that heretofore wasn’t really singled out, wasn’t carved out, and we should probably be looking at this more closely. DR LOVE: So here’s the paper we’ve been talking about that led to the FDA approval even before ASCO, pembro plus trastuzumab with chemotherapy; Dr Janjigian from Memorial. Anything you want to say about the data, Randy? DR HECHT: Yeah. I mean Yelena Janjigian had an earlier, smaller trial with a really high response rate. So this is just preliminary data with response rates. And so first of all it’s nice to see in a randomized setting that the response rates, while a little bit lower, are still significantly higher than what you saw without having pembro. So these patients all had trastuzumab, and then they added pembro to it. The other thing that I thought was really important was that there wasn’t an increase in adverse events. But I think that this in some ways already is, but around the world if it’s really positive, will be the new standard of care. The only other thing it makes me think about is that we had talked about, for example nivo/ipi, and that is there a role in selective patients, perhaps in the future, about chemotherapy-free regimens if these are really, truly synergistic. This paper won’t answer that, but I look forward to this, and I really think this will be a positive trial. DR LOVE: So one more thing. When we were talking, Tom, in our lung cancer session about KRAS G12C mutations and AMG 510, sotorasib, we’ve seen data on this in colon cancer. What do we know about it? And do you think there’s a future for this agent in colon cancer, Tom? DR ABRAMS: We don’t have good options for the KRAS-mutated population. G12C is not the most common molecular abnormality we see in KRAS, but it’s certainly out there in colorectal cancer. And this may be something to think about. This is a very early study. I think we’re still learning about this, but the fact that there were some PRs and certainly some stable diseases with some shrinkage, that’s very encouraging, and certainly something we’re going to be following closely as time goes on. DR LOVE: Randy, did you have something you want to say? DR HECHT: There are also ongoing trials. There’s adagrasib in their trials. I think in this 3% of patients combining with chemotherapy may be actually where we’re going to go by moving these drugs further up, the trial that we’re helping develop moving these things further up the chain to first line and second line. Cases from the Community — Hepatocellular Carcinoma, Cholangiocarcinoma DR LOVE: Let’s talk a little bit about HCC, a pretty big shift that’s going on now the last year or two in terms of first-line therapy for HCC in terms of atezolizumab and bevacizumab. We were curious, and we asked the audience this past week what their usual second-line therapy is in a patient who gets atezo/bev first line for HCC, and by far and away the most common answer was cabozantinib. Randy, is that the way you approach patients who progress? Or how do you think through patients? DR HECHT: I’m fortunate, I’m actually going to defer to Dr Abrams. I have Rich Finn in my group, of course Rich did the atezo/bev and several other trials. So I actually do not see these, but I do try to keep up with it. And cabo sounds like a very reasonable option. Though I think as you know, there’s really not a lot of data in this setting. DR LOVE: Absolutely, because everything shifted when atezo/bev came in first line. So Tom, at this point is atezo/bev considered, in general, standard of care first line? And what do you do second line? DR ABRAMS: Yeah, it certainly is. I mean and I think the update that Rich Finn just did at ASCO GI really hits home. It’s a highly effective regimen. Afterward, I think it resets. And so I would use lenvatinib because it’s a very reasonable first-line agent. And while cabo, I think, is totally fine, and actually cabo does have, in the study that led to the approval with cabo, there was a segment of population that had received IO prior to cabo. So it’s very reasonable. But I think lenvatinib is well tolerated. It has a fairly high degree of efficacy relative to other TKIs. And so that’s probably what I would use for most patients. I think what’s an interesting thought is can you go from IO to IO. And that’s really an area of exploration. So far we don’t really know the answer to that question, but I think it’s very interesting to think that perhaps after atezo/bev one could go to nivo/ipi. And that may actually be something that could be effective, as well, especially since a lot of the problem with atezolizumab is due to the development of neutralizing antibodies. So if the drug is really not effective because of these neutralizing antibodies it’s not really refractoriness to a checkpoint inhibitor per se. And so I think that this is an area, there are studies that are being done, being devised, looking at checkpoint inhibitors after failure of atezo/bev. DR LOVE: So I’m kind of curious, Tom. In the past a lot of oncologists have come up to me and said by the time we get these patients with HCC they’ve gotten so much liver-directed therapy I can’t even give them systemic therapy. In the past we never really saw much in the way of responses, to sorafenib for example. Now we’re seeing objective responses to this combination. I’m curious whether or not in general you’re using maybe less or later liver-directed therapy now and going with systemic treatment. Or is the paradigm pretty much the same? DR ABRAMS: I think the paradigm has changed. For patients who are eligible for liver-directed therapy I think it’s a very valuable thing to do. But we’re not going to do like the several treatments with liver-directed therapy so that you just totally blowout their liver, and then by the time they have no liver function left, then they send them your way, and they say give them drugs. That’s not what happens anymore. Everyone is basically in agreement that these regimens now have real efficacy, so after one treatment with Y-90, then they’re sent to you. And by that point that’s good. They’re stabilized. They’ve had some treatment, and you can get them on a systemic regimen such as atezo/bev, and hopefully that will have some effect. So I do think the paradigm is changing. We’re using liver-directed therapy in conjunction in close proximity to systemic therapy as opposed to just exhausting the liver-directed therapies before sending them to a medical oncologist. DR LOVE: So a couple interesting questions in the chat room, Tom, from Demetrius. What do you do with a patient who has hep C that needs to be treated, but also HCC that needs to be treated? Can you do that at the same time? Or you do one first? Meyer wants to know, do you see the same responses with NASH-related HCC as you do with viral with atezo/bev? DR ABRAMS: So the second question has been looked at, and it looks as though there really aren’t any differences in response to atezo/bev relative to the cause of the cirrhosis. So that’s a simple question. There really isn’t one. And a lot of the other drugs that have been looked at, where it’s the same thing, they’ve maybe seen some improvements in hep C-related HCC to some of the TKIs, but that really was never very convincing data. DR LOVE: Do you treat the hepatitis C first, the HCC, or vice versa? DR ABRAMS: I think you can just treat it simultaneously. I don’t think there’s any real issue there. It’s such a highly effective regimen, and it’s fairly short lived. So I think if you really feel the need to treat both, then treat both. DR LOVE: So Tom, I’ve got a really good question for you. Actually, Dr Levin has a really good question, which is would you use an IO in a patient who’s had a liver transplant? Here’s Dr Levin. DR LEVIN: My question to them would be how often do they actually have successes with post-transplant patients using immunotherapy? Is liver an exception, or would they consider post-kidney transplant, what other organs have they tried? The transplant team, when I was discussing it with them — and it was kind of very different, actually, from what our tumor board, so we have a little tumor board where we would discuss it with medical oncologists, and I would say 90% of the oncologists present in the room said they probably would not try immunotherapy in this case. But at that point I felt that I have exhausted all our options, and I didn’t really see much of an outcome. I had extensive discussion with the patient. And the transplant team actually was more willing to try. She had a good response, with some improvement in quality of life, because at the time of presentation she was short of breath, and then her shortness of breath improved. Her liver enzymes have stayed normal the whole time. I didn’t have to hold immunotherapy. I didn’t have to reduce anything. We just continued. She was seen by transplant team every 3 to 4 weeks just to make sure that everything stays pristine, and then ended up developing disease progression at about 4 months out. DR LOVE: And her transplanted liver was fine? DR LEVIN: Right. The liver was fine. DR LOVE: Wow. Wow. So Tom, I think I saw you shaking your head no before when I asked the question. DR ABRAMS: Oh, man. No, no, no, no. Not at all. I mean look, I think the thinking on this has evolved. A couple years ago when I did an HCC educational symposium the thought was you never give an IO after transplantation, and there are these published case reports and small studies showing an unacceptable rate of organ loss. So obviously patients are going to just die if that happens. But there is data out of Asia that maybe this could be done. And certainly IO has been given in patients with kidney transplants and patients with heart transplants, patients with lung transplants even, safely. So if you develop an algorithm where you are increasing the immune suppression to an extent where you can give an IO and have less of a chance of losing the organ, that actually can work, and you’re seeing that in case reports. And certainly Dr Levin did this and did it well. And unfortunately, the patient didn’t have a terrific response, it wasn’t one of these magical long durations of response, but it worked for a time. And I think if you have the infrastructure, and you have a transplant team that’s willing to really closely monitor your patients, and this is really critical, adjust the immune suppression upwards, then I think you can do it. Not every patient’s going to be eligible for this. Not every medical center’s going to be equipped to do this. But I think it’s something that can be done, and we’re learning more about how to do it. It’s a really fascinating thing to think about. And I applaud Dr Levin for giving it a try. I think it’s wonderful. DR LOVE: So Jian in the chat room says that they have a patient who also had a liver transplant from an identical twin, I don’t know if that makes a difference, got nivolumab, did fine, no liver dysfunction. Mohamed has a question I’ve heard a lot, Tom, what about people who are not Child-Pugh A, specifically Child-Pugh B, and atezo/bev? DR ABRAMS: Well, the study was with Child A. I think we understand that that’s a select percentage of the HCC population. You’re going to have a lot of Child Bs. It’s a very well-tolerated regimen. I don’t think it’s unreasonable to think about it in your well-compensated Child Bs. Child-Pugh score is a dynamic score. It can change with the slightest bilirubin change, the slightest albumin change, so I wouldn’t necessarily say absolutely no for the Child Bs. You just have to be very careful in those patients. DR LOVE: Randy we’ve talked a lot today, and we’re going to be talking later on in both our GYN session and breast sessions, about PARP inhibitors. We talked a little bit about it in our GU session with prostate cancer. Any update on where we are in PARP inhibitors for pancreatic cancer, Randy? And what’s your experience in that regard? DR HECHT: So yeah, I think you’re referring, of course, to the POLO trial, which was in germline BRCA-mutant patients with pancreatic cancer. And just to remind people that per NCCN Guidelines all patients who have pancreatic adenocarcinoma should have germline testing. And we do see these patients, perhaps it’s living in Los Angeles, but we certainly see a lot of these patients. I think one of the really important things also to remember, and this goes back to Eileen O’Reilly’s trial, which was actually a negative trial, but these patients do really well with platinums, particularly gem/cis, so not just FOLFIRINOX where they do well. And in fact in the POLO trial they had all gotten platinums, a lot of them got FOLFIRINOX, but the gem/cis, which is incredibly well tolerated, and we see very long responses to this. And so the POLO trial was a bit gamed, I have to be honest. And for full disclosure I was worked on the mock ODAC, but it was versus nothing. So it was a maintenance trial versus holding chemotherapy. And there was improvement. What I would say is that I think that PARP inhibition, at least so far, has been disappointing in pancreatic cancer. I think that we know that ovarian does really well, and they do incredibly well either with or without germline BRCA. Triple-negative breast cancer, it does okay, but not as well as I would have hoped in many respects. And pancreatic cancer, like always, pancreatic cancer really brings up behind, where I think the benefits, while not zero, are small, and I really wish that it was more. I’m being honest. I don’t know really what the role after POLO is. Highlights of ASCO 2021 — Thomas A Abrams, MD DR LOVE: So Tom, we asked you to review a few papers from ASCO. We were talking about IDH inhibitors in cholangiocarcinoma, and we saw this data presented at ASCO on IDH1 and IDH2 intrahepatic cholangio. Any comments? DR ABRAMS: Yeah. I mean I think this is a really powerful study looking at the immune profiling data and genomic data for intrahepatic cholangiocarcinomas. So what they found was that in patients with intrahepatic cholangiocarcinomas with IDH1 or IDH2 mutations, these mutations were mutually exclusive, so you didn’t have both, and all of the IDH1 mutations occurred at the same locus, the R132 locus, and the IDH2s were overwhelmingly at the R172, and then a few, 6%, at that R140. So these were highly conserved mutational hotspots. And these patients also had fewer co-occurring targetable genomic alterations than patients who had IDH wild-type disease. They had much fewer FGFR2 rearrangements, much fewer ERBB2 and BRAF mutations. I think that’s really very, very powerful data showing that these mutations are critical driver mutations to carcinogenesis and should have effect when targeted. These tumors were also less immunogenically associated with response to immune checkpoint inhibition. They were less MSI high. They had lower TMBs. And they were lower frequency of PD-L1 positivity. So IDH1 and IDH2 seem to be very, very, very important to carcinogenesis in intrahepatic cholangiocarcinoma. DR LOVE: So is this the therapy you’d want to give first line, Tom? And any tolerability issues? I assume you don’t see differentiation syndrome, which you do see when you use these agents in AML. DR ABRAMS: You do not see differentiation syndrome. I think it speaks to the fact that these are not as responsive to treatments as leukemias are. But I think they achieve mostly stable disease after failure of gem/cis, and they’re very well tolerated, extremely well tolerated. So I would think that it is a natural to try to bring it into the first line, combining it with chemotherapy, and seeing what kind of responses and what kind of durations of responses you would get out of that. Because these are extremely well-tolerated regimens as single agents. DR LOVE: So I’m going to ask you to talk about one more paper, but Randy, another question from the chat room looks interesting, 69-year-old patient with metastatic pancreatic, gets nab/gem, progresses, but has a BRAF V600E mutation. Do we know anything about BRAF therapy in pancreatic cancer, Randy? DR HECHT: Not that common. Because we know, for example, that at least 90% of patients with pancreatic cancer have KRAS mutations. Unfortunately, very few of them are G12C, so unlike lung cancer where it’s really common, we’ve been discussing whether it’s even worth trying to put these trials together because it’s like in colon cancer, which is 3%. BRAF, I’m not aware of a lot of data. In cholangiocarcinoma Zev presented some data with BRAF inhibition, and there was significant benefit. Tom, are you familiar with the trial? I’m not with specifically in pancreatic, but I think it would be worth looking at. I would consider trying at some point in time anti-BRAF-directed therapy. DR ABRAMS: So yeah, in extrahepatic cholangiocarcinoma there’s not an insignificant number of BRAF-mutated cancers, and they are responsive to BRAF inhibition. BRAF is almost always a very important mutation in carcinogenesis. I think in pancreatic cancer you don’t have a lot of great options. It is rare, but it certainly is worth, I think, treating a patient off label if you really have exhausted other options. DR HECHT: I agree. I agree. But there’s so many things like how sick is the patient, do they need a response, I think they’re more likely to get it with chemotherapy. But I would keep it on the table. DR ABRAMS: Is it a V600E mutation or is it another kind of type 2 or type 3? I think that’s important. But assuming it’s a V600E mutation I would definitely give it a try. DR HECHT: I agree. DR LOVE: So does giving it a try mean the colon approach to BRAF with EGFR antibody or the lung/melanoma approach to dabrafenib/trametinib, Tom? DR ABRAMS: That’s a good question. DR HECHT: I would do like they did in the AURORA trial, which was for cholangio. I mean they’re really extrapolating, and I think that was single agent, if I remember correctly. DR ABRAMS: Yes. DR HECHT: With that. And I think it’d be really hard to get cetuximab or panitumumab in pancreatic cancer. DR ABRAMS: I agree. DR LOVE: Dan in the chat room says ROAR was for BRAF and that he has two patients who were treated with dab/tram. Interesting. DR HECHT: Yeah. The question is do you get the feedback loop like you get in colon. DR LOVE: Right. DR HECHT: And I’m not certain that you do. Introduction DR LOVE: We’re going to talk about gynecologic cancers, and particularly what’s happened recently. We have a great faculty, Dr Deb Armstrong from Johns Hopkins, and Dr Krish Tewari from the University of California at Irvine. We’re going to have cases presented from general medical oncologists in community-based practice, mostly from the Texas Society of Clinical Oncology, who’s partnering with us on this symposium today. And of course, we have what we call chalk talk slides where in one slide we try to ask you to summarize the key points of the major papers, particularly from the ASCO meeting. Here are some of the papers we’re going to be talking about as we move forward. We’re going to start out with some cases, and we’re actually going to start out with ovarian cancer. I just want to take a deep breath and talk a little bit generally about ovarian cancer because so much has happened in the past couple years. I just want to start out and ask you, Deb, when you see a patient with ovarian cancer, typically they’re going to present with Stage III disease, being considered for debulking surgery and all the other things we’re doing to talk about. I’m curious how you think through genomic evaluation of the newly diagnosed ovarian cancer patient. What is what you consider right now your standard minimal genomic workup, regardless of family history? DR ARMSTRONG: So it’s really important to have this information by the time an individual completes initial chemotherapy. It’s even better to have it early on. So what we want is germline genetic testing and specifically, most importantly, for the BRCA genes. If you look at all ovarian cancer patients about 20% of them will have a germline mutation. 15% of them will have BRCA1 or 2, but there’s another 4% to 5% that will have one of another germline mutation that we think has led to their diagnosis. Another 5% to 10% will have somatic BRCA mutation, so it’s actually important to do the next-generation sequencing. And then we get into a little softer area about is it important to do homologous recombination testing because that identifies patients who get a greater benefit from PARP inhibitors. So you can kind of do things sequentially. Unfortunately, just NGS for somatic BRCA1 and 2 is probably not enough because the data is that you can miss about 5% of the germline BRCA mutations by just doing next-gen sequencing. So you probably have to at least do both of those, and then whether or not to do HRD is a little bit individualized because there’s some benefit even for people who are homologous recombination proficient. DR LOVE: Another important question in the newly diagnosed patient, Krish, is the question of neoadjuvant therapy or not. I’m curious how you think through that decision nowadays. DR TEWARI: Yeah. I use a lot of neoadjuvant chemotherapy mainly because when I’m considering surgery we really just have one chance to get all the disease removed. So if they’ve got widespread peritoneal carcinomatosis, disease at the porta hepatis, extra-abdominal disease, if they’re malnourished, if their performance status is not very good due to medical comorbidities, I tend to use neoadjuvant chemotherapy. And the patients, for the most part, especially the ones with the most common type of cancer, the high-grade serous cancers, they respond really well to neoadjuvant. And then it makes for a less morbid operation as part of an interval debulking procedure. I’d say only about a quarter of my patients do I operate on them without having first given chemotherapy to. And those are patients that I need to know for sure that I can remove it all. Cases from the Community — Ovarian Cancer DR LOVE: First let’s ask the audience a couple questions before we kind of get into the case. So audience, I want to know, you’ve got a patient who’s got a BRCA germline mutation, and she’s got Stage III ovarian cancer, Stage IIIC as is often the case. She goes right to surgery, has optimal debulking surgery. I’d like to know what you’re going to be thinking about. Well actually we asked this question, and I’m going to ask the audience in a second yes or no about another question. So we asked the audience in general what do you think about in this situation, and everybody says PARP inhibitor, Deb. But there’s a little bit of a split. Most people say olaparib, but others say niraparib. Are either one of these reasonable approaches? And also, Deb, for how long? DR ARMSTRONG: Well, so the duration question, to me, is easy. I use what was used in the trial. So the olaparib SOLO-1 trial, which was specifically in BRCA mutation carriers, used the olaparib for 2 years and stopped. And the curves do not come back together, so I think that’s fine. The niraparib trials have used 3 years. Interestingly, you can use niraparib in this situation if you want to. I think the second malignancies thing is certainly less concerning in front-line maintenance, but I think the longer you use the PARP inhibitor the more one, I think, has to worry about that. So I think that’s the easy question. Olaparib’s been around the longest period of time, and we’ve had approval for that in the BRCA-mutated ovarian cancers, so most of us have used that for a longer prior of time. But occasionally there’s patients who may only want to take a medication once a day, so niraparib is a very reasonable option. I think the harder one is the bevacizumab issue. DR LOVE: Well that actually comes up in the case that we’re about to discuss. So this is a 65-year-old lady who actually was BRCA wild type, both germline and somatic, but was HRD positive. She actually presented with ascites and had omental caking, ascites, mesenteric lymphadenopathy. Well here’s Dr Prakash talking about the case and the questions that he has about it. DR PRAKASH: She was interesting, BRCA negative, but had HRD positivity. DR LOVE: How was she after she finished the chemo? DR PRAKASH: She was great. Some peripheral neuropathy, but that was about it. DR LOVE: So you put her on olaparib. Did you think about continuing the bev? DR PRAKASH: I did, but she really didn’t want to do anymore intravenous therapy. But since she received bev up front I think I would have continued bev and added olaparib. DR LOVE: Any questions for your colleagues? DR PRAKASH: What is the role of PARP inhibitor in a woman who does not have a BRCA mutation but does have HRD on somatic testing? In women with ovarian cancer who are on long-term PARP inhibitor therapy, how much do you worry about development of MDS in these patients? How long would you continue a woman on olaparib as maintenance therapy? Would it be 1 year, 2 years, or longer? Since niraparib is approved for women in maintenance therapy regardless of HRD testing or positivity, would you even test women for HRD? And if they are BRCA and HRD negative, would you still give them PARP inhibitor? DR LOVE: So Krish, I should have mentioned this patient, because of the fact she had ascites and so much disease, got neoadjuvant therapy, and that included bevacizumab. And he actually wanted to continue the bevacizumab, but as you heard the patient didn’t want intravenous therapy. So there’s so many things to talk about in this case. First of all, Krish, let’s talk about the HRD status in this patient. Can you talk about what we know about the benefits of PARP inhibitors in people who don’t have BRCA mutations, and particularly no other mutations, PALB2, et cetera, but then they have an HRD assay that’s positive? What do we know about those patients, and how do you manage those patients, Krish? DR TEWARI: Yeah. I do things similar to our physician that just presented that case. But with a patient with HRD I would really encourage the patient to continue with bevacizumab and then add olaparib as he suggested he would have done had she not wanted more intravenous therapy. I think the PAOLA-1 data is very important in this regard and the follow up to PAOLA-1, some additional analyses that were presented at SGO actually demonstrated that if you do next-gen on these patients you’re going to miss quite a few patients that may be HRD positive. So I like to do HRD testing if their germline and somatic BRCA is negative. DR LOVE: So Deb, of course another question that he brought up that a lot of people bring up is the issue of MDS. We know that these agents do have effects in the bone marrow. In the relapse setting heavily pretreated patients, in the SOLO-2 trial of olaparib, we saw a fair amount of MDS, but we saw MDS in people who didn’t get olaparib because they were heavily pretreated with chemotherapy. Right now, particularly in the up-front maintenance setting, What’s your approach in terms of that, Deb? DR ARMSTRONG: You can justify maintenance PARP inhibitor in just about everybody, even the patients who are HR proficient. Based on the PRIMA study there’s still a benefit in that group of patients. So I think you get more information about the magnitude of the benefit if you do the HRD testing, and so some people want to know that. Sometimes people say I’m going to go on it no matter what. I think the good news in the front-line PARP inhibitor maintenance is that the incidence of secondary hematologic malignancies remains pretty low. And even the update from SOLO-1 from SGO the incidents of patients, that’s BRCA mutation carriers, and in those patients with longer-term follow up is only 1.2% in the PARP inhibitor arm. It’s 0% in the control arm, so this is probably related to that. But that’s unlike in the maintenance setting in the second line platinum-sensitive patients, where as you noted from SOLO-2 it’s up as high as 8%. And even in the NOVA study in recurrent platinum sensitive it’s 3.5%, but it’s 6.6% in those patients in NOVA who had a germline BRCA mutation. So our BRCA mutation carriers might be a little bit more susceptible. Some of these patients will have had chemotherapy for breast cancer, so maybe that contributes to their risk. But I think it’s reassuring that in the front-line setting the incidence is pretty darn low. DR LOVE: So in a second we’re going to hear another case where the issue of toxicity and tolerability of PARP inhibitors comes in. But we were talking about niraparib, Krish, and one of the things that was seen early on is it looked like we saw more thrombocytopenia than we’re seeing with other agents. And then the cooperative groups came up with the “weights and plates” approach in terms of dosing of niraparib. Can you talk right now about how you think through dosing of niraparib and how you vary that based on the platelet count and the weight, Krish? DR TEWARI: Yeah. I think that’s a really great observation. With the weights and plates, or what we call the RADAR analysis, we knew that patients that started out with a platelet count under 100k or under 77 kilos, those patients would be at significant risk for developing niraparib-induced thrombocytopenia, which can be very severe. And so what was nice about the PRIMA study, and the RADAR analysis came out of the NOVA study, but the PRIMA study, they were actually able to change the dose on the label to 200 mg, where originally the starting dose was 300. So I think as clinicians we have a choice. We can either just start patients on maintenance niraparib at 200, or we can use weights and plates, and if the patients do not hit either of those benchmarks, a weight under 77 kilos or a low platelet count, start with 300, and they should do well. We’ve seen a lot less severe thrombocytopenia since the dose was changed. DR LOVE: So we’re going to go onto another case now. This is a 77-year-old woman, a patient of Dr Sulfi Ibrahim, with a germline BRCA mutation. And as is really standard of care to get a PARP inhibitor for these germline, even somatic BRCA I would say, this patient got it, but as you’re going to hear the patient ran into a problem with her counts. Here’s Dr Ibrahim. DR IBRAHIM: Because I knew she had a germline BRCA mutation I recently started her on olaparib. A very motivated lady, eager to complete the 2 years of olaparib. However, her treatment course has been complicated by significant anemia. So about a month after starting olaparib I got a CBC, which showed a hemoglobin of 5. To my surprise, actually, she did not complain much about it. Upon questioning she said she had dyspnea and fatigue, but she actually did not complain about it. I transfused her blood, and I dosed reduced the olaparib to 300 mg in the morning and 150 mg in the evening. Two weeks afterwards I got a repeat CBC, which again shows a hemoglobin of 7. And I transfused her again. My question would be how best to manage this lady who is extremely motivated to stay on the olaparib and complete the 2 years of adjuvant therapy, but obviously does have significant anemia with the olaparib. Should I dose reduce her further? Or would anybody advocate the use of erythropoietin-stimulating agents to manage her anemia and keep her on a higher dose of olaparib? DR LOVE: So Deb, also your experience in general with cytopenias with these agents, not just olaparib, but niraparib, and what would you do in a situation — I know this is very unusual, but what would you do in a situation like this? DR ARMSTRONG: Well it’s true that all of the PARP inhibitors are associated with some anemia. And although the rate of overall anemia is highest with the olaparib, the rate of severe anemia is pretty similar, or a little bit higher, with rucaparib and niraparib. So I don’t think switching the PARP inhibitor makes a lot of sense. I think obviously any patient, especially if this is an acute anemia, obviously you need to rule out hemolysis or blood loss. We know that some cancer cells have erythropoietin receptors, and you can actually stimulate cancer. We know in cervical cancer, we did a study, and the patients who got erythropoietin during chemoRT actually did worse. So we try to stay away from red cell growth factors in our patients with solid tumors. I can’t remember the last time I’ve used it. I think like either a pause in dosing or a dose reduction, as he did, is the right thing to do. And especially in someone who’s strongly motivated. I think even going down to a low dose and then working your way back up. If it’s close to when she’s finished chemotherapy there’s probably still some bone marrow effects from the chemotherapy. And my experience has been that if you drop the dose you can sometimes go back up with the dose the further away they get from chemotherapy. So I think modifying the dose, I might have gone to 150 or 200 BID, and then worked my way back up. But I think what he did was absolutely reasonable. And again, but I think also just making sure there’s no other reason. Again, the incidence of MDS/AML is pretty low. This sounds like it happened pretty quickly when she started on treatment. But I have a very low bar to get my hematology colleagues involved and do a bone marrow workup if we feel like we need to, so… DR LOVE: That’s a good point though, that these people just finished chemotherapy, and maybe their marrow’s not quite in the best shape. I’m kind of curious, Krish, also about nonhematologic issues with PARP inhibitors, particularly GI effects, what you see. Do you give patients pre-emptive medication? What do you see in terms of quality of life issues with PARP inhibitors? DR TEWARI: Yeah. I think the GI issues fall into 3 categories, and I talk to patients about this pretty extensively when I’m counseling them to get on PARP inhibitor, regardless of which PARP inhibitor I’m using. One thing I talk about is acid reflux. So I have all of my patients on an H2 blocker, just from the start. There’s also a little bit of nausea associated with the PARP inhibitors, nothing severe, so I always make sure they have some antiemetics prescription filled. They can carry it in their purse, use it as needed. And then also a little bit of diarrhea. We’ve seen that as well. And that’s easily managed with antidiarrheal agents, and I make sure they have an active prescription for that. But I don’t have them take antinausea medication or antidiarrheal medication pre-emptively, but I do have them on H2 blockers. The GI is the main thing. Fatigue, even fatigue outside of anemia, can be a problem with PARP inhibitors. But most patients are pretty motivated. They’ve been waiting for some type of oral therapy for years. Oral therapy that doesn’t cause them to lose their hair. And so for the most part quality of life has been stable I would say. Highlights of ASCO 2021 — Deborah K Armstrong, MD DR LOVE: Let’s talk about some of the papers that have come out recently, particularly at ASCO. And Deb, we gave you several to review, and of course IOs keep trying to push their way into ovary and so far haven’t quite been able to make it. This is an interesting study, the so-called GINECO trial looking at neoadjuvant chemo plus IO, a strategy that we’ve already talked about a number of times in solid tumors. What did they see in this study? What do you think it meant? DR ARMSTRONG: Yeah. Well so first of all, they could give it without a lot of undue or unexpected side effects or toxicities. This was a small, randomized Phase II study, and they unfortunately didn’t see that the addition of pembro to neoadjuvant chemotherapy with or without bev improves the complete resection rate or progression-free survival. Now they said that when they were designing those statistics, they actually had assumed a lower rate for the control arm, but the control arm did better. But I think that’s why we do randomized trials, because you need to compare the populations. There are much larger randomized Phase III trials going on, and I think Amit Oza did a talk a year or so ago and estimated there’s around 5 to 6,000 newly diagnosed ovarian cancer patients undergoing trials with an IO in the up-front setting. So we’re going to get the answer to this soon, whether larger trials might show a benefit. Ovarian cancer doesn’t seem to be one of those hot cancers. Certainly the markers that we look for response to immunotherapy, high tumor mutation burden, microsatellite instability, high-level PD-L1, CPS high. We don’t see that a lot in ovarian cancer, and it’s not surprising that we’ve not seen really high response rates to immunotherapy in general. I would like to just point out that in almost all the trials that we’ve done with immunotherapy to date, if you look at forest plots, the clear cell carcinomas always are just a little bit over the edge favoring the immunotherapy. And there’s actually some reason to think that ARID1A mutations are pretty common, and they may actually induce the microsatellite instability. So the clear cells, it may be the exception in ovarian cancer. In advanced disease it’s a small fraction, but it’s a group that doesn’t do well with chemo. So I always keep that in the back of my mind for the clear cell patients. DR LOVE: Krish, any thoughts about the future of IOs in ovarian cancer? I think I saw a small cohort of lenvatinib/pembrolizumab that looked a little bit encouraging. Antiangiogenics plus IOs is a strategy that’s been looked at in a lot of cancers, renal cell, HCC, we were talking about it before. Anything you have any hope or interest in in terms of immunotherapy with ovarian cancer, Krish? DR TEWARI: Yeah. I agree with Deb that it does not appear that ovarian cancer generally is a very hot or immunogenic tumor. But I am hoping that the combination of antiangiogenics will help, especially VEGF inhibition because in addition to promoting tumor angiogenesis VEGF is very immunosuppressive in the tumor microenvironment, and it’s possible that with dual inhibition, both VEGF and PD-L1, or PD-1, we may have a breakthrough. And so I’m very optimistic. I get it. We’ve had at least 3 very large trials that have been negative for IO in ovary, which is disappointing, including a trial that did have bevacizumab in it. But I’m still optimistic. We just haven’t figured it out yet. DR LOVE: Yeah. Oncologists are always inveterate optimists. So speaking of immunotherapy, we did see a paper at ASCO, Deb, of vigil immunotherapy, maintenance vigil immunotherapy. What is this strategy, and what did we learn about it at ASCO? DR ARMSTRONG: Yeah. So kind of going back to the autologous tumor vaccines, it’s got an unpronounceable name, gem something or other, so they shortened it to gem in the title. But it’s again that whole concept of an autologous tumor cell vaccine and using this as maintenance after initial chemotherapy in patients who had responded. When they looked at the overall population, they didn’t see an improvement in progression-free survival. But interestingly, we’ve been talking about the PARP inhibitors and how beneficial they are in the BRCA mutation carriers or the HR deficient, but they actually specifically looked at the HR proficient group, which is about half of our initially diagnosed ovarian cancer patients. And they actually did see improvements in progression-free and overall survival in that HR proficient group. And so that’s a group where, again, the PARP inhibitor maintenance may have a little bit of benefit, but it doesn’t have a lot. And so I think if this kind of data holds up this would be a potential use in that group of patients who don’t get as much benefit from PARP inhibitors. DR LOVE: So Deb, what about mirvetuximab, the antibody-drug conjugate? When I was hearing about it a year or two ago, I was all excited about it, then I go kind disappointed at it. Where are we today? Again, Dr O’Malley presented more data on this at the ASCO meeting. DR ARMSTRONG: Yeah. So this is follow up from the mirv study. This is an antibody-drug conjugate that uses folate receptor alpha as the target. And folate receptor alpha, there’s not a standard assay for that, but it looks like it’s overexpressed in 90%-plus of high-grade serous ovarian cancer. So a very interesting target, and not overexpressed in a lot of normal tissue, so probably not having a lot of offsite toxicity. So this was a study looking at mirv in combination with bevacizumab in patients with either platinum-sensitive or platinum-resistant ovarian cancer with high tumor folate receptor alpha expression. And they categorized them as to moderately or very high expression. One of the things that we didn’t get from this is how many of the screened patients fit in that category. So that would be good to know since we don’t have a standard assay. There were very significant overall response rates and duration of response in both of those groups, but they had a 59% overall response rate in the platinum-resistant patients, and that’s really unprecedented. I mean I can’t think of any treatment we have that’s shown a response rate that high. So I honestly think, again, if these data hold up this could potentially be a really interesting combination in that group of patients. Again, I think we need to know like what percentage of the patients met their criteria for expression. There also were about 40% of patients who had previously received bev, and whether or not those differences in the response you see, whether or not patients had received bev. DR LOVE: So Krish, we were talking earlier that there are now 2 antibody-drug conjugates approved in bladder cancer. Do you think we’re going to see antibody-drug conjugate coming into gynecologic cancer, we’ll talk later on about tisotumab vedotin, but in terms of ovarian cancer, either mirvetuximab or any other antibody-drug conjugate, Krish? DR TEWARI: Yeah. I was actually very excited about this abstract that you just discussed with Deb. The question I have is was the objective response blinded. I mean was it a blinded review, or was it investigator assessed? Because I think that response was just so dramatic that it’d be really important. If it was investigator assessed they could always get it rereviewed by a blinded independent radiology committee. And I think if that holds up, we may see an antibody-drug conjugate. I like to call them suicide bombers or Trojan horses. I’d like to see that in ovary. DR LOVE: Yeah, two antibody-drug conjugates approved in HER2-positive breast cancer also, as well, and another one coming along. So Deb, another paper we want to ask you about Shannon Westin reported. It relates to a resistance to PARP inhibitors. And maybe you can talk a little bit about what we know about the mechanisms of resistance, whether or not you see benefit to a second PARP inhibitor after a first one, and this strategy looking at adavosertib in these patients. DR ARMSTRONG: Yeah. So especially now where probably at least 50% or not more of our newly-diagnosed patients are going to be getting PARP inhibitors this is a huge issue, and I do grant reviews for research, and this is like number one priority on all of these ovarian cancers, like what do we do with PARP inhibitor resistance. You can get these reversion mutations where there’s basically a second mutation that basically restores the reading frame and now, even though you had a germline mutation, the BRCA is functional. And we probably can’t overcome that type of PARP inhibitor resistance. But other mechanisms of resistance, the goal of studies like Shannon’s is to try to see if combining things that alter the DNA damage milieu and increase sensitivity to PARP inhibitors. And adavosertib is WEE1 inhibitor. So this is a huge area of research, huge area of clinical need. This was a really heavily pretreated group. These are all patients who’d had PARP inhibitor. I will say 90% of them had some benefit from PARP inhibitor, so these aren’t people who got treated and really never had a benefit from it. Interestingly, the adavosertib actually had a reasonable response rate of 23% by itself, while the combination was 29%. But there was a longer duration of response and better PFS in the combination arm. One of the things that was most interesting to me was that the adavo in the combination arms had about a 20% response rate in patients with BRCA mutations. But in the non-BRCA mutated the response rates were 31% and 39% respectively. So maybe this is doing something in these patients who didn’t have germline mutations in improving sensitivity. DR LOVE: I know Shannon is doing a neoadjuvant study of PARP that I haven’t seen any results on. But there was a paper in BRCA patients using talazoparib in breast cancer that saw a path CR rate in the neoadjuvant setting of almost 50%. And I’m curious what your thoughts are, of course we don’t know what we’re going to see in ovarian cancer, whether you see PARP inhibitors potentially coming into the neoadjuvant setting, Deb. DR ARMSTRONG: Well it’s interesting because we have a proposal for one of these studies that we’re sending around our group, and it’s a little bit of a tug of war about people who are feeling maybe we should not be using this alone in patients who haven’t had chemotherapy before or not. In breast the neoadjuvant approach with the pathologic complete response is a very clear regulatory pathway. I think it’s been done much more easily. I think in ovary it has that potential, but I think people are still anxious and nervous about that. But I think if you have a patient, and you know that they have a BRCA mutation, we know that de novo response rates, even in patients with recurrent disease, are very high. So I think it’s a very rational approach. But a lot of people, I think, are going to be saying our standard of care is our standard of care for a reason, and we need to be giving these people chemotherapy. So I would be comfortable with it, but I think other people might not be. Cases from the Community — Endometrial and Cervical Cancers DR LOVE: Let’s talk a little bit about endometrial cancer. And this is a question we asked the audience in a survey that we did, which is in general what do you think about in a patient who has MS-stable endometrial cancer. Most people said lenvatinib/pembrolizumab when we asked them what is considered standard. We asked them about MSI-high disease. Most people said pembrolizumab. I’m curious, Krish, we were talking about MSI-high colon cancer, and both of the faculty said in younger patients they would use ipi/nivo. I’m curious in MSI-high endometrial cancer how you would generally approach first-line therapy. Do you go with pembrolizumab, Krish? Or are you tempted to use ipi/nivo? DR TEWARI: I’ve been using pembrolizumab. I’ve not had a lot of experience personally with ipi/nivo, and the small experience I did have, the ipi is sometimes difficult to get patients through. But I think the combination makes a lot of rational sense because the ipi, the anti-CTLA-4, helps encourage trafficking of the CD8-positive T lymphocytes, which is a substrate for anti-PD-1 therapy. So I think the strategy scientifically looks good, and there’s clinical evidence, like you said, in colorectal cancer, and even some other cancers, that the combination is good. But in my practice, I’ve been sticking with pembrolizumab for the patients with the high tumor mutational burden or microsatellite instability high. DR LOVE: So we’re going to on to a case of MSI endometrial cancer, and this patient of Dr Henna Malik actually got it second line after chemotherapy, and actually responded but had a lot of intra-abdominal problems, maybe related to response, actually had a rectourethral fistula, then ended up getting put back on pembrolizumab, but globally has actually responded and done well with pembrolizumab. Here’s Dr Malik’s questions. DR MALIK: She’s on pembrolizumab 200 mg every 3 weeks, and her last scan did show a response from the 11 cm tumor to it’s now 4 cm, in the pelvic area. DR LOVE: And has she had any tolerability issues with the pembrolizumab? Any autoimmune problems? DR MALIK: She did have some diarrhea. It was Grade 2. We used some loperamide and atropine and diphenoxylate that tend to help, but I don’t know how much of that was also related to some of the other factors that were affecting those areas. I have had conversations about this patient, about hospice even before starting pembrolizumab because she was looking quite frail. But the reason I bring up this case is because do we need to use pembrolizumab in the up-front setting for certain mutations or tumor types. She had a p53 mutation, very aggressive cancer. DR LOVE: So Krish, we were talking before about the fact that now in colorectal cancer MSI high we have a randomized study that shows that immunotherapy’s better than chemotherapy. Are we going to need to do the same study in endometrial cancer? Is it your take that maybe these patients would be better off getting it first line? DR TEWARI: Yeah. I think that’s really reasonable. I mean before we get to that we’re going to have to see what the GY018 trial from the NRG shows, because that’s using chemo with or without pembrolizumab in patients with newly-diagnosed advanced disease with measurable disease or recurrent with measurable disease. But I think that from there we’re always a little bit behind the colorectal folks, but I think we do need to do that trial because I’d be comfortable treating a patient with pembrolizumab up front because if they progress, I can always use the carboplatin/paclitaxel subsequently. But I’d like to do it as part of a trial. DR LOVE: So Deb, another question that comes up a lot in these patients is duration of therapy. A lot of patients get out on a plane, they’re doing really well, they’re tolerating therapy. This comes up all cancers where IOs are used, how long do you use it for. How do you think that through with MSI-high endometrial cancer, Deb? DR ARMSTRONG: Yeah. I think it’s interesting because the young lady who did the original study of MSI-high colon versus MSI-high other cancers, we had 10 endometrial cancer patients on that study. And that was the groundwork for a lot of this. And we have one patient from that study who’s still on pembro. And every time we talk, is it time to stop? It’s been like 7 years now. So she’s doing well. She’s not having toxicities, so we’ve continued. Is it a chance that she’s cured? Absolutely. I think that she’s gone 7 years and no disease progression, absolutely a chance that she’s cured. But who knows? I think as long as the patients are tolerating the therapy, we would generally continue it. But the duration of therapy is a huge question, and I think especially for people who are having some toxicities. You can’t go on forever for a lot of these patients. DR LOVE: Krish, did you have a question? DR TEWARI: Yeah. I just wanted to just make a point about the duration of therapy. The patient that was just presented by our guest presenter, I had an exact same patient. I was discussing hospice with her. She was 79 years old. She was very, very frail, and then surprisingly we just got pembro approved, and after 2 treatments her quality of life improved, and I’ve had her on it now for 3 years. And this person was going to the ER, 5 visits in one month. Her son, he told me he thought it was the end. This was 3 years ago. And so when pembro works, sometimes it really works. And so I’m not turning it off because when I scan her I can still see the cancer, but it’s just very small. It’s just smoldering, and she’s got a great life right now. I just wanted to add that. DR LOVE: No. And I’ve heard plenty of cases like that. It’s really amazing to hear these stories. I’ve heard people come out of hospice. They got IOs, went into hospice, and came out of hospice. We have another case of endometrial cancer. This is MS stable. Actually, this patient got pembro/lenvatinib, and they ended up discontinuing the lenvatinib. Maybe they could have worked a little bit more with it. I want to hear from you how you deal with these issues. We’ve had so many cases presented this past year of people who got lenvatinib/pembro. There’s so many questions out there about dosing, about how to handle tolerability. But let’s hear what Dr Patel says about this 64-year-old woman. DR PATEL: — carboplatin/paclitaxel, didn’t tolerate it too well because of neuropathy. And then we were changing over to immunotherapy. They did a subsequent scan that showed a great response to immunotherapy. But at the same rate her blood pressure was very much elevated, as is the issue with lenvatinib, and it had to be discontinued. I would love to hear the recommendations for community oncologists on how they can dose-reduce lenvatinib in the setting of conjunction use with pembrolizumab. And in these scenarios, because we’re seeing such a good response with immunotherapy, how long do you actually continue that immunotherapy for these patients? DR LOVE: So Krish, I’ve heard all kinds of approaches. Theoretically the dose of lenvatinib is supposed to be 20 mg. I hear people starting at 10, people at 14, 18. How do you think through dosing of lenvatinib? And how do you figure out whether it’s the lenvatinib or pembro, if you have a problem like diarrhea, which one’s causing it? DR TEWARI: Yeah. That’s a great question. So with the dosing, I start at 20. I have colleagues and partners that start at 14, talk about dose escalating, but I start at 20, and then if I do a dose reduction, I’ll go down to 14 as my first dose reduction. And I would have to say, quite honestly, most of my patients end up at 14, some are even at 10, because the hypertension can be an issue, diarrhea as well. And in terms of how do I figure out which of the two drugs is causing the diarrhea, if the diarrhea is severe, and I’ve had a couple cases of that, I’ll have patients hold the lenvatinib. And if it improves significantly, I think I’ll chalk it up to lenvatinib and then dose reduce them when we resume things. Nice thing with the oral daily therapy is you do have the option to titrate around and play with the schedule a little bit. DR LOVE: So Deb, I’m curious about your experience and how you approach giving pembro/lenvatinib. Also your experience with hypertension, how you deal with that. DR ARMSTRONG: Yeah. So I’m a little more cowardly than Krish is, and I usually, in somebody who’s very fit and healthy, I will start at 14. In somebody who’s a little more frail I usually start at 10 and then work my way up. Most of these patients will have a pharmacy plan where you have to go through a specialty pharmacy, and it takes a few days before they get the medication. So I actually have them get a blood pressure cuff. I have them send in their blood pressure readings for twice a day because I really want them to be monitoring their blood pressure pretty carefully. I almost never start at 20 because most of my patients can’t tolerate 20. And I think patients do better when you start with a tolerable dose and work your way up rather than start with the full dose and have toxicities. For me it works better, but I’m just maybe a little more cowardly than Krish is. So I think you have a window of time for most of these patients. You can’t write a prescription and they get it 2 hours later. So you have a little time to get them working on monitoring their blood pressure. DR LOVE: What do you see in terms of response, Deb, both in the trials, as well as your own experience? It sounds like a lot of people have objective responses. About what fraction respond objectively, and how long do the responses last typically?
DR ARMSTRONG: Yeah. So Vicky Makker’s original Phase II study had a response rate of I think 38% or 39%. It’s interesting, the patient that was presented today she said has a p53 mutation, and that might be a high-grade serous endometrial cancer. And interestingly in the initial Phase II trial I think 38% of the patients had high-grade serous endometrial cancer, and that’s a tough one to treat. That one we don’t have a lot of treatment for. So it’s kind of been my go-to second line for the high-grade serous endometrial cancers and our regular endometrial cancers. It’s been my go-to second line. So I have used it a lot. The responses can be quite long lasting. Interestingly, I just inherited a patient probably about 3 or 4 months ago. She had lived in Florida. Her husband died, so she moved up to the Baltimore area to live with her kids. She’s 88 years old. She actually had MSI-high disease, but went on pembro and progressed. And her doc down there actually added in lenvatinib, which I would not have done. Yet that’s been a year and a half ago. But she’s on 10 mg every other day. So I’m not rocking the boat. I’m not moving away from that, but it hadn’t really occurred to me to add it into somebody who you might have predicted would have responded to pembro but didn’t. But that’s food for thought for me. So certainly very low dose. I mean I’ve never used 10 every other day. She’s 88, but she’s tolerating it well. DR LOVE: Wow. What an amazing story. I was just going to ask you what you do with a patient, not everybody does respond to IOs with MSI. And it kind of makes sense to at least try adding in lenvatinib. And in your case it sounded like it worked. Let’s talk a little bit about cervical cancer. The thing I’m most looking forward to hear is Krish to talk about this data he just presented on cemiplimab. But anyhow, let’s start out with a case, then we’ll see what Krish thinks about his data. So a 39-year-old lady of Dr Patel has a PD-L1-positive tumor. And this is an example of somebody who did well on IOs with metastatic cervical cancer. Here’s Dr Patel. DR PATEL: She had done chemotherapy for over a year, and now she was progressing, multifocal nodal mets, and a pelvic tumor. She was PD-L1 positive. This, of note, is right in the thick of COVID as well. And so pembrolizumab was offered to her. She actually did 10 cycles of pembrolizumab, tolerated it very well, and responded well to therapy. She started to gain weight. She herself reported this improved quality of life within the past last 6 months. So she’s actually doing well. I think what’s great is you have this patient who did chemotherapy for a year, started to have a poor quality of life and progression of disease, and we switched over to immunotherapy with great response. But then now how long do you continue this immunotherapy? Because on PET scan you’re not really seeing a large burden of disease. And if there is progression, at this point she’s already had immunotherapy, and she’s already done quite a bit of chemotherapy, what would be the next line of therapy? DR LOVE: Any other questions? DR PATEL: If they don’t have PD-1 positivity would you use immunotherapy? And do you have a preference for which one? DR LOVE: So let’s talk a little bit about the issue of immunotherapy with cervical cancer. And I think a lot of people, Krish, expected to see a lot of activity, it’s a viral-related disease, and yet the first report I think that most of us saw, I think it was like a hundred-patient 1-arm study of pembro that actually got it approved. I think the response rate was around 15% or even less. And I think there was a widespread impression that IOs really don’t work too well. To me, I haven’t heard a case of somebody doing as well as this patient. And I think people are a little bit lukewarm about it. It’s approved only in PD-L1-positive disease. And people are asking ourselves I think a lot of questions about why wasn’t it higher, and then boom all of a sudden you come in with this cemiplimab study. So can you kind of describe what the study is, what you saw, and what you think it means, Krish? DR TEWARI: Yeah. Thank you. So you’re right, pembrolizumab got accelerated approval in the second line for PD-L1-positive patients based on a 14% objective response rate. So the cemiplimab study was a Phase III randomized trial in that same population of patients, meaning they were in need of second-line therapy. They had to have progressed on platinum-containing therapy used to treat recurrence or metastatic disease. And in the cemiplimab study we showed a significantly improved OS irrespectively of PD-L1 expression at enrollment, meaning we enrolled patients, both PD-L1-positive patients and PD-L1-negative patients. We’re still looking at that data specifically to see what the response rates are in each group. But there was an OS advantage in the squamous cell population, the overall population, and although the adenocarcinomas were not part of the statistical hierarchy, there does appear to be an OS advantage even in the adenocarcinomas. So as a second-line agent cemiplimab versus single-agent physician’s choice chemotherapy did improve survival. And this, as you noted, was presented at the ESMO virtual plenary and the KEYNOTE-826 was announced that it had met its dual endpoints of OS and PFS for pembro with chemo in the front-line setting. So very excited about all of this work that’s going into cervix. And I think that you’re right, we were a little lukewarm about pembro’s 14% objective response rate earlier. It did get approval, but I think things are much more promising now, with two big Phase III randomized trials reporting. DR LOVE: So chemo plus pembro up front, a strategy that’s out there for a bunch of cancers, including lung cancer. I think there’s, is it the BEAT study, that was actually looking at that also. DR TEWARI: Yes. I’m sorry. The BEAT study also includes bevacizumab. DR LOVE: Bevacizumab as well. So Deb, I’m just kind of curious, when you saw these new data what your thoughts were about it. To me it kind of changed my perception about the value of immunotherapy in cervical cancer. Any thoughts? DR ARMSTRONG: Well first of all, the fact that a drug could get approved with a 14% response rate just tells you that we don’t have a lot for our patients after front-line therapy. I will tell you, my high horse about all of this is that we have very good data that patients who get wide-field radiation, and that includes patients who get chemoradiation for cervical cancer, are lymphopenic at least a year later and probably will have lifetime lymphopenia. And I think that the response rates to immune checkpoint inhibitors are probably impacted by that. So in a public session here, Krish, I’ll encourage you to try and look at your patients, and even if it wasn’t part of the statistical design, to look at whether prior wide-field chemoradiation impacted their chance of responding. Because this should be a disease that has a great response to immunotherapy. I had one patient who presented with disease during pregnancy and had Stage IV disease with supraclav nodes, and as soon as she delivered she actually went on a trial of ipi/nivo and had a complete response. Cervical cancer patient. I mean we don’t see that at all. She’d never had radiation. I think that the radiation impacts the response and explains a lot of why we don’t see good responses in cervical cancer patients to immune checkpoint inhibitor therapy. DR LOVE: Krish, any thoughts? DR TEWARI: Yeah. I think it’s definitely one of our plans to look at the people that were previously irradiated in the pelvis, and that data will be forthcoming. DR ARMSTRONG: Great. DR TEWARI: We’ve got lots of different ancillary or secondary analyses planned for this randomized trial with cemiplimab. So I think it’s really important. At the same time, radiotherapy may also upregulate PD-L1 expression. And so depending on the proximity of the radiation to the treatment you may see some responses. DR LOVE: Yeah. And Deb we talked about the use of an IO, durvalumab, after chemoradiation in lung cancer because the 5-year data came out, and they see a significant benefit after the chemoradiation. So I guess it could go either way. DR ARMSTRONG: I think this lymphopenia has to do with the broadness of the field and how many large blood vessels are radiated. So I think in lung you might not have as much lymphopenia as you do in whole-pelvic radiotherapy. DR LOVE: Good point. Good point. I didn’t even think about that. We have a question in the chat room, Krish, from Charles, asking about treatment of HER2-positive endometrial cancer. We’ve been talking about HER2-positive lung cancer, GI cancers, breast cancer, bladder cancer, endometrial cancer. We actually saw a paper at ASCO that you reviewed looking at pertuzumab plus trastuzumab, Krish. How often do you see HER2-positive endometrial cancer? And anything you want to say about this paper from ASCO, the TAPUR study, or registry? DR TEWARI: Yeah. We don’t see a lot of HER2-positive endometrial cancer. I know at Deb’s institution they did a study with HER2-positive uterine serous cancers looking at platinum/paclitaxel/trastuzumab. But this study didn’t impact me very well. I thought the objective response rate was not very high. I think the median PFS was about 4 months, which was reasonable. But I think that we need to do more work in this area because certainly for HER2-positive breast cancers we’ve got at least 6, 7 approved drugs, and they do make meaningful benefits in those patients. So there is going to be a subpopulation of HER2-positive uterine cancer patients that may be able to benefit from HER2-targeted therapy. But I don’t think the TAPUR study has identified that regimen yet, at this point. DR LOVE: So Deb, of course we’ve been talking a lot about trastuzumab deruxtecan, which is used in breast cancer and lung and GI cancers. Do we know anything about it in endometrial cancer? Is that something you would consider in a patient who runs out of options? DR ARMSTRONG: Yeah. I mean I think as Krish said, our main population in endometrial cancer that’s HER2 positive is a subset of the high-grade serous. And the data are that if you add trastuzumab to chemotherapy they have a better outcome. I would point out that even in breast cancer just using the trastuzumab and the pertuzumab, we don’t see that great of response rate. It’s really using them in combination and then as maintenance. So I wouldn’t cast this aside yet. I think the real question’s going to be is using this with chemotherapy going to improve outcomes or not. As you said, there’s now so many HER2-targeted agents to use in breast cancer. And as other HER2-targeted diseases, particularly the GI ones, they’ve moved ahead more quickly in terms of looking at those agents in the HER2-positive disease. I think we haven’t moved ahead as quickly. It’s really just a numbers thing because serous is only about 10% of uterine cancer and probably only about 20% to 30% are HER2 positive. So we have pretty small numbers. But I think that moving ahead with particularly the T-DM1, the antibody-drug conjugates, like moving ahead with those is really to me the way to go. I’m not surprised that the antibodies alone didn’t have a whopping response rate. Highlights of ASCO 2021 — Krishnansu S Tewari, MD DR LOVE: So here’s another paper, getting back to cervical cancer, Krish, looking at adjuvant chemo after chemoradiation therapy, the OUTBACK trial. Can you comment on that? DR TEWARI: Yeah, so this was a trial for locally-advanced cervical cancer patients. They’re typically treated with chemoradiation plus high-dose intracavitary brachytherapy, and the question was should we give them 4 more cycles of chemo after they complete chemoradiation and brachytherapy. And unfortunately, the study didn’t meet its endpoints, and so consolidation chemotherapy, as they call it, had no benefit on survival. This trial’s really important because there has been some perceived benefit based on smaller institutional experiences. A lot of people around the world have been giving consolidation chemo after chemoradiation. So I think the importance of this study is that it’s a negative study, but as one of my mentors always told me, the only definitive study is a negative study, and so hopefully we can now move on and start looking at the acala trial and other studies looking at novel agents in the locally-advanced cervix population. DR LOVE: So let’s talk about one more case. This is pretty unusual. I’m curious what your experience is with this, small cell cancer of the cervix. This is a 46-year-old lady who’s a patient of Dr Pavel Levin. Here’s his questions. DR LEVIN: — presented to the hospital with cough and shortness of breath and had diffuse metastatic disease in the lung. When we did a PET scan she ended up having FDG activity in the cervical area. We sent her to OB/GYN to look into her cervix and do the biopsy. They found that there was a cervical cancer. So we kind of attributed that as the primary site of disease. DR LOVE: And what, you started her on chemo right then? DR LEVIN: I did, carbo/paclitaxel. By cycle 2 she already reported significant improvement in her cough, and we gave her 6 cycles and have been monitoring ever since. DR LOVE: How long has it been? DR LEVIN: Two years. I have not seen cervical small cell. This is a remarkable response, I thought. In her case we ended up giving her carbo/paclitaxel, but I don’t know if most people would use carbo/etoposide or platinum/etoposide in this kind of situation. DR LOVE: So Krish, any experience with small cell of the cervix? DR TEWARI: Yeah. It’s a pretty aggressive cancer, and chemotherapy is a mainstay. If you can cut the cancer out and do a radical hysterectomy, we try to do that if there’s no obvious evidence of metastatic disease. But we still treat them. I’ve typically used cisplatin/etoposide following the lung small cell cancer of the lung data. But carboplatin/paclitaxel’s been studied in small cell of the cervix at Memorial Sloan Kettering, and that’s a good alternative. And this patient did great, 2 to 3 years, remarkable. DR LOVE: So one final question. We were talking about how things are changing in cervical cancer and the good news coming out from the cemiplimab study that Krish reported. I’m also curious, Deb, about the antibody-drug conjugate tisotumab vedotin and whether or not if that is approved how that’s going to fit in now that we have better data with IOs. I’ll point out Krish’s study had 350 people in it compared to the 100-patient study with pembro, so much more robust data. But how do you see tisotumab fitting in, Deb? The reported response rate’s around 20%, 25%. If it is approved how do you see it fitting in? DR ARMSTRONG: Well I think, as we disease, pembro got approved with a response rate of 14%. So response rate in the 20% to 25% range I would be surprised if this drug does not get approved. The question’s going to be can we tease out who’s going to have the best responses to the pembro or other immunotherapies in the second-line therapy and those who would. So we still have patients whose CPS score is less than 1. So that would be an obvious group of patients if this gets approved to be used. DR LOVE: So Krish, final comment? DR TEWARI: The cervix space is looking really crowded, but that’s a good thing. When we did the bevacizumab study in 2013 there was no other trials on, but now we’ve got tisotumab, we’ve got cemiplimab, we’ve got pembrolizumab, we’ve got balstilimab, we’ve got zimberelimab, we’ve got many different things. You’ve got the nivo/ipi combination that you highlighted earlier. Lots of stuff being done in cervix. We also have the TILs therapy that’s being studied. So I think things are very promising for our patients. Hopefully these medicines will be approved, and they’ll be tolerable, and we’ll learn how to use them safely, and we can help more patients. Introduction DR LOVE: We’re going to be talking about breast cancer. We’ll go through a bunch of great cases that we’ve had presented. We have a great faculty again, Dr Ginger Borges from the University of Colorado and Dr Hal Burstein from the Dana-Farber cancer institute. We’re going to have docs from the Texas Society of Clinical Oncology presenting cases today. We asked the faculty to make just one slide summarizing some of the key papers. This is an example of that. Here are the papers that we’re going to be talking about from ASCO as we go through this hour today on breast cancer. We’re going to go back and forth between cases, as well as papers. We’re going to talk about the OlympiA trial. But I’m just kind of curious, before we start roaring down this thing here, any other papers, Ginger, in addition to the OlympiA paper, that if you had to pick one that you really loved or stood out. Anything in particular about ASCO that you want to comment on? DR BORGES: Well, OlympiA was obviously a driving force for all of us. I was gratified also to see the longer-term follow up of a couple of our key trials for breast cancer, the CDK4/6 inhibitor studies in the advanced-disease setting letting us know how patients are doing long term on these trials. And one of the ones that I get to present I think is where we need to be going for our studies in the future, with really drilling down on things about the immune system and TME. So a lot of good data this year. DR LOVE: Hal, any favorites maybe that other people might not have noticed? DR BURSTEIN: Well, we’re talking about two that are there, the randomized Phase II, the GeparNuevo study, which is one of those checkpoint inhibitor in the early-stage setting trials, and then the West German Study Group, the ADAPT trial with a THP regimen that looks really good. There were a couple of smaller abstracts that I thought were important. One was on delay in breast cancer diagnosis. So UCSD has a really large catchment area in Southern California, and they showed that since the pandemic they’re seeing a smaller percentage of cases diagnosed in Stage I and a growing percentage of diagnoses in Stage III or even Stage IV. Obviously, we’re all aware of the disruption to mammograms that happened with the pandemic, and I think that’s something to monitor as people resume mammography. The second was a very sobering one on economic consequences of a cancer diagnosis. It was an interesting study. They looked not just at breast cancer, but some other tumors as well, and they looked at things like credit card ratings, credit report ratings, and mortgage delinquency. And all of those tick up after a cancer diagnosis at the population level, just a reminder that despite everything we try and do and everyone tries to do to keep it all going, that there are real consequences to a cancer diagnosis that affect families beyond the cancer itself. DR LOVE: So you mentioned the issue of the mammogram, and obviously the vaccine. I’m curious, Ginger, have you seen any cases of lymph nodes? I’ve heard cases in other solid tumors people thought they had recurrences, et cetera. Obviously, axillary nodes. Have you seen that? DR BORGES: Many, many cases. In fact, the first case I saw was an emergency room physician I was taking care of, and it was before any of this had hit the news or other reports in the literature, and thankfully as a physician we could stay calm about it since that was not a site of disease in her body. So yes, very prevalent, and I actually had one of the biggest immune reactions to the vaccine that I’ve heard of, so I started warning my patients. Because I was thrilled when my body responded so well, and then I thought wow, my office is going to get a lot of phone calls. DR LOVE: What happened with you? DR BORGES: I had swollen lymph nodes in my armpit the size of clementines, and all the way up to my ear. DR LOVE: Wow. Wow. DR BORGES: And they lasted about 5 days. DR LOVE: Wow. Interesting. All right. Cases from the Community — HER2-Positive Breast Cancer DR LOVE: Well let’s get into some cases and papers here today. We’re going to start out talking about HER2-positive disease. We’ve got a few cases, but first this is a question. We sent out a survey to the attendees of this meeting, and we said what’s your usual third-line therapy after CLEOPATRA and T-DM1 first and second line. And in this situation, we said symptomatic disease progression. As you might guess, the most common answer was trastuzumab deruxtecan, although about a quarter of the audience said HERCLIMB in that situation. Just kind of curious, Hal, how you think through third-line therapy in general. Are you using T-DXd if there are no brain mets, and brain mets tucatinib? Or like some of the audience, maybe you use tucatinib even if there’s no brain mets. DR BURSTEIN: I think either of those are the appropriate third- or fourth-line treatment, and we don’t really know which is the best. The HER2CLIMB study was a very nice, randomized Phase III. There’s a survival benefit in that study which gives it a little bit of pride of place still. The trastuzumab deruxtecan approval is still based on Phase II results, but a very active drug, with a 50%, 60% response rate even in refractory disease. So nobody really knows the optimal choice. There are a lot of data for the use of the tucatinib regimen in patients who have CNS metastases, and so I think if a patient does have brain metastases it makes it a somewhat preferred regimen, though at the ASCO meeting there was an abstract from a group that looked at trastuzumab deruxtecan and showed about a 40% response rate in the CNS with that agent. So maybe there’s even less of a distinction. I think that the sequence, as you’ve mapped it out, is correct, which is the THP is first line for us. T-DM1 or trastuzumab emtansine second line, then either trastuzumab deruxtecan or the tucatinib/capecitabine/trastuzumab regimen as third, flip it around for whatever you get next, and then you move on through the rest of the regimens. DR LOVE: So we’re going to do a case in a second that gets into that. But Ginger, any situations where, particularly with brain mets, you might use HERCLIMB as second-line therapy? And what do we know about the impact of T-DM1 on brain mets compared to HERCLIMB indirectly? DR BORGES: So there are data that T-DM1 can demonstrate benefit in brain mets, not in prospective studies, but in retrospective looks. And in the T-DM1/tucatinib Phase IB study there were patients with brain mets that were allowed on that study and/or developed brain mets and could be kept on the study after first progression, and that supports the current Phase III randomized trial that is ongoing. So I think tucatinib has really shown itself to be incredibly effective in the setting of brain mets, and I have used it in the second-line setting when I wanted to make sure of getting benefit to brain. Most often I try and stick with the HER2CLIMB regimen there, but if someone is T-DM1 naïve and not eligible for the study it’s something that certainly could be considered based on the Phase IB data. DR LOVE: I’m going to ask the audience. Have you seen a patient respond in the brain to the HERCLIMB regimen with tucatinib, audience? I’m curious. Incidentally, we asked earlier on have you seen a response to sacituzumab in breast cancer. 42% of the audience said yes, which I thought was amazing. And here, in terms of this question, it looks like it’s about 50/50. So 50% of the audience has seen a response in the brain to HERCLIMB. Wow, really interesting. Well let’s get into the next case here. This is Dr Debra Patt, who actually is the president of the Texas Society of Clinical Oncology. She has a 73-year-old woman who actually got the HERCLIMB regimen, had brain mets early on, got THP, HP, then developed brain mets, had SBRT and T-DM1. And now the question is what’s next, and specifically about the issue of HERCLIMB. Here’s Dr Patt. DR PATT: She had TCHP and enjoyed a complete response clinically in her body and has continued to enjoy a complete response clinically in her body. I even managed a little trastuzumab-induced heart failure in her that we got her through, treated her through it, and retreated her. And she’s continued to be fine. She never progressed again in her body, only in her brain. When she developed brain metastases in 2019, she was treated with SBRT focally to those areas, and also systemically had a change to ado trastuzumab. She’s had the benefit since 2019 but does have evidence of progression in her brain. So I think in this era where we have multiple new therapies, particularly HER2CLIMB, which demonstrates a lot of benefit in the brain, how do you think about her next lines of therapy? DR LOVE: Any questions specifically about HER2CLIMB? DR PATT: Had she already seen capecitabine is there a role to have capecitabine and still initiate and give her the benefit of HER2CLIMB of the tucatinib and the trastuzumab? And what is the role of other therapies, like T-DXd, like margetuximab, in this patient population? DR LOVE: So lots of things to discuss there, Hal. What about the issue of capecitabine, particularly in someone who’s had capecitabine? How do you deal with tolerability issues like hand-foot syndrome, in terms of do you reduce the capecitabine or the tucatinib? DR BURSTEIN: Yeah, so I think capecitabine’s actually an important part of the whole cocktail, especially for the brain lesions. My colleague, Nancy Lin, who’s been involved in multiple studies of CNS metastases, builds most of her regimen backbone around that or around the antibody-drug conjugates. So I think the capecitabine’s still important here, and it’s known to have CNS penetration as well. So in management of HER2-positive metastatic disease it’s not a drug we often give until this juncture. So as was described by Dr Patt, TCHP or THP is common adjuvant regimen, and then when they recur it’s taxanes and pertuzumab and trastuzumab again, and then perhaps one of the antibody-drug conjugates like trastuzumab emtansine. So a lot of these patients are actually naïve to capecitabine, and I think it’s a good choice in the case that she described. DR LOVE: So Ginger, this patient interestingly had some evidence of heart failure with trastuzumab. I’m curious what we know about the newer agents like tucatinib and T-DXd about the effects on the heart. Can you give it to somebody who’s had a history of a cardiac issue with trastuzumab? DR BORGES: Well in a patient who has recovered from their previous cardiac toxicity with trastuzumab we know we can reinitiate HER2-targeted therapy with careful monitoring, perhaps with ongoing heart support medications onboard and do that safely. With drugs like tucatinib there was not a strong signal for heart toxicity. There was some in the T-DM1/tucatinib Phase IB study, not to my recollection in the cape combination regimen. With the T-DXd, same thing. I mean it’s a trastuzumab-based compound, so we have to be careful about this. But I certainly think we know that the HER2 is such an important driver in these cancers that you have to try. I do want to add one comment to the question about prior cape with HER2CLIMB regimen. I agree with Hal that that would be an unusual circumstance. Prior cape was an exclusion criteria for that study. Prior lapatinib was eventually allowed in if it had been more than 12 months. So I think it’s an unknown, if for some reason that patient had had prior cape, but I’d probably still give it a go if you thought they were an otherwise good candidate. DR LOVE: We actually had a patient present in one of our programs who had the NALA regimen of capecitabine plus neratinib, which is effective, but then they progressed, and the question is what are you going to do about the cape when you have the tucatinib there. Hal, I’m curious. There’s a paradigm that evolved, we were talking about it in the lung cancer session with the targeted therapy, for example osimertinib and EGFR, when they see brain mets they don’t use radiation therapy, particularly whole brain. They treat systemically because they’re so confident that they’re going to get a response. What about HERCLIMB or tucatinib in that situation, holding off radiation to the brain, Hal, particularly whole brain? DR BURSTEIN: So it’s a great question, and we worry about the whole-brain radiation because many of these patients will actually do well for a long time. And you only have to see the encephalomalacia effects of late consequences of whole-brain radiation a couple times in your career to make you worry about that. Having said that, it depends on the picture at presentation. So as in the case Dr Patt described, oftentimes there will be a couple of focal lesions, and we are very liberal in using SRS or brain stereotactic radiosurgery radiation to go after multiple spots, even multiple waves of such treatment to avoid the whole-brain consequences. Other times patients present with more diffuse innumerable lesions, and one is stuck, essentially, offering whole-brain radiation to provide adequate treatment control. So it depends a lot on the actual clinical picture that comes in. But I think it’s a good point. I’ve got to say I don’t think anybody would feel so confident that if patients had extensive brain metastases that they could avoid radiation right now in favor of just drug therapy, though it’s an interesting question and one that there are clinical studies in development to compare radiotherapy versus systemic therapy approaches. And hopefully the drugs will get close enough. When you look at the ALK inhibitors in lung the response rates in the CNS are remarkable. There’s something north of 70-plus percent, and that’s still a little higher than what we’re seeing in breast cancer, even with these more effective approaches. DR LOVE: So we’re going to go on to another case here, really interesting case of Dr Martins. And Ginger if you could respond to this. There are two things that are really remarkable about this, one is the fact that the diagnosis of spinal cord compression was missed by the primary care people. But the other thing that’s really interesting is this patient actually got first-line therapy for metastatic disease with anti-HER therapy and endocrine therapy and did really well, of course triple-positive disease, prolonged response to that therapy. I want to ask the audience, in the last year have you started any patient with HER2-positive metastatic disease, triple positive, on endocrine therapy plus anti-HER therapy without chemotherapy? Have you done that in the last year? And we’re going to get into this case where this happened, and this patient actually really did well. And there was also some data that was presented at ASCO about it. It looks like about 55% of the audience has done that in the last year, so we should talk about that. But here’s this case of this 58-year-old woman who as I mentioned unfortunately presented with spinal cord compression and ended up on actually trastuzumab, anastrozole and denosumab and did great. Here’s Dr Martins discussing the case. DR MARTINS: — slipped through the cracks. She presented with bone pain and weakness. Her PCP got a bone scan and made an oncology referral. I immediately admitted her the day I met her. And she was quite weak and very frail. Neurosurgery elected to operate on her, so they were able to stabilize her spine. DR LOVE: When she presented with the cord compression did she have pain or any motor weakness? DR MARTINS: Yeah, very much so. I mean she came to my office in a wheelchair. That’s why I was shocked that her PCP didn’t recognize the severity of the situation. DR LOVE: Any questions about CHEK2 germline mutations? DR MARTINS: So CHEK2 I have a lot of questions about because I’m wondering do we have any treatment directed at that. I think I read somewhere that PARP inhibitors may be active for CHEK2 because it’s in the same pathway. So that’s one question. By the way, she’s off the brace. She’s totally ambulatory, back to normal. DR LOVE: It’s impressive how well she’s done without chemotherapy. DR MARTINS: The real question is is there a survival benefit for triple-positive breast cancer to chemo plus HER2 versus hormone plus HER2. And how do they discriminate when to do what? DR LOVE: So Ginger, I was recalling this prostate cancer program we did not too long ago, and one of the people referred to code spine that they have at their hospital. When they suspect cord compression they have their whole team, neurosurgeons, all over it. Any thoughts about what happened in this case? I should have mentioned this patient had a CHEK2 mutation, HER2-positive disease. Is PARP inhibitors ever a consideration with HER2-positive disease? And any thoughts about what happened here with the cord compression, Ginger? DR BORGES: A couple thoughts about the case itself, and the patient. I think we are seeing less cord compression in the more recent years than we used to in the past. And coincidentally my brother is a spine neurosurgeon. He’s the other Dr Borges still in Boston. So he also notes that he’s getting far fewer referrals. So there’s something about how we’re treating our patients that that presentation is less common. Obviously, it should have been picked up, and there could have been substantial improvement to how this patient would be doing now if it had been. But I think with HER2-positive disease the lessons I’ve learned over time is that it’s a very reversible disease. And so she’s 58 and previously sounds like quite healthy, so I would tend to ignore a little bit what the disease has done to the patient in front of me and still potentially be aggressive in things. But you also have to see the patient and know what you’re doing. There’s many ways to come at this. So the CHEK2 positivity is interesting. There certainly is data to look at the PARP inhibitors in CHEK2 from smaller studies. Nadine Tung, a mutual colleague of Hal and ours, has published that in the JCO. But in my view of this, again, the HER2 is such a driver of fundamentally how these cancers behave that I would not incorporate the CHEK2 into my immediate decision-making. That’s where I would go, and then in terms of her HER2-targeted therapy and what do initiate with, before we had all these snazzy new drugs, and we only had trastuzumab. Some of the early studies looking at hormonal therapy and trastuzumab were disappointing. It was about a difference between a 2-month and a 4-month progression-free survival. The study we’re going to review shortly under the ASCO session is a first-line metastatic disease trial that specifically looked at dealer’s choice chemotherapy with trastuzumab versus either an AI or an antiestrogen modulator with trastuzumab. And it shows very equal outcomes, and that’s the first time I’ve seen data like this comparing those two head to head. So it suggests this was a very reasonable course that the doctor chose based on what he was seeing in front of him that day. DR LOVE: So Hal, what about PARP inhibitors in HER2-positive disease? We’re going to talk about the OlympiA trial. I don’t know how often you see BRCA mutations in HER2 positive. What are you going to do about that? A question in the chat room was about CDK inhibitors in HER2-positive disease. Your colleague, Dr Sara Tolaney, has done some work on that. Is that the strategy you’re using? DR BURSTEIN: So all these things are really interesting. And the dominant treatment paradigm for HER2-positive disease is anti-HER2 therapy. And what’s been surprisingly challenging to study is how do you improve on that. So in the setting of BRCA1 and 2 mutations the vast majority of these are not HER2 positive. So BRCA1, as people know, most commonly gives rise to triple-negative breast cancer. And so if you look at the OlympiA trial 80% of the patients in that study actually had triple-negative breast cancer, and they actually excluded HER2-positive tumors. So we don’t know a lot about what happens there with PARP inhibitors. The question in the metastatic setting of using CDK4/6 inhibitors is an interesting one, and Shom Goel, who’s an investigator now in Australia who’d previously been in our group, had some very nice laboratory data to suggest that CDK4/6 inhibitors can be active in HER2-positive breast cancer. And so I think it’s a potential tool in the toolbox, but it’s not one that we commonly use because we have so many other options already with the antibody-drug conjugates, the small molecule tyrosine kinase inhibitors, and precision chemotherapy choices. Ginger, I know you wanted to say something here. DR BORGES: Only when you’re done, Hal. DR BURSTEIN: Okay. No. So obviously I think that those are all choices, but we do not routinely use them in HER2-driven disease I guess would be the summary. DR LOVE: So Ginger? DR BORGES: I just wanted to add in I agree with everything Hal said. We did present data last San Antonio from a Phase II clinical trial specifically for the triple-positive breast cancers that we think will hopefully move forward into a different space. It’s a combination of letrozole, palbociclib, and tucatinib, so no chemo, no IV regimen at all. We have not yet reached the median progression-free survival. The safety profile is awesome, as you might expect. You do have to dose the palbociclib at 75 mg because of a drug-drug interaction with tucatinib. So those data were presented last year. My colleague, Elena Shagisultanova, had that poster. And so it is out there that there’s data on it, and we hope it moves forward. DR LOVE: Wow. That’s a really interesting combination. Hal, coming back to this issue of the triple-positive patient, are there situations where you are okay with not using chemotherapy? Or maybe an older patient where you really want to avoid it? Or you just try to get a little bit of paclitaxel in there anyhow? DR BURSTEIN: Yeah. It’s a great question. And our practice, at least my practice, typically we start with a taxane/trastuzumab/pertuzumab regimen because we think that the survival benefit documented a long time ago now in the CLEOPATRA trial gives a rationale for that. But I think that the study Ginger alluded to at ASCO, it was a Chinese group of investigators that compared endocrine therapy with trastuzumab versus chemotherapy with trastuzumab, showing no near-term benefits for the chemo, in her own pilot study that she just referenced. I’ll make the point that you can do a lot of different things. And since most patients with HER2-positive disease are going to get 7, 8, 9, 10 lines of therapy it almost becomes impossible to imagine that you have to have a preferred regimen with chemo up front. So we still tend to do it based on how symptomatic they are. But I can easily imagine that there will be more and more patients in the future who get endocrine therapy plus anti-HER2 therapy as first line. And certainly when we don’t give it in first line we do an induction phase with the chemo and then bring in the endocrine therapy afterwards and hopefully run that maintenance for a long time. DR LOVE: So Ginger, a little bit ahead of ourselves, but Rajeshwari in the chat room has a patient, a male patient, with metastatic ER-positive disease, I guess HER2 negative, wants to know about PARP inhibitors in men. I would assume it’s the same. Do you approach that the same way in men, Ginger? DR BORGES: So you’re asking your young women’s breast cancer specialist how I treat men. So to my knowledge there was no exclusion to men in any of the PARP inhibitor trials. And so I would treat them the same, and just if they have underlying ER-positive disease go down that direction. If they’re ER negative, go in that direction. Hal, anything different? DR LOVE: So — DR BURSTEIN: Yeah. So men do get BRCA2-associated breast cancer a little more commonly, and you can use PARP inhibitors in them. And of course, PARP inhibitors work in prostate cancer when there’s a BRCA association, and in pancreatic cancer. So I don’t think it matters if it’s a man or a woman at this point. And I used that brief pause to look up the TBCRC data from Nadine Tung that Ginger referenced. So there were 8 patients with CHEK2 mutations, and not a single one had a measurable response to PARP inhibitor therapy with olaparib. And in fact, the duration of treatment in none of them exceeded 4 months. So I don’t think CHEK2 is the right pathway for PARP inhibition at the moment. But if I had a man with a BRCA2-associated metastatic breast cancer I think it is reasonable to offer olaparib or other PARP inhibitor therapy. DR LOVE: So I’ve got another yes/no question for the audience, but I really want to know whether Hal and Ginger, how they would respond to this question. Audience, here’s my question to you. When you use first-line therapy in metastatic HER2-positive gastroesophageal cancer you give chemotherapy plus trastuzumab. Do you add in pembrolizumab, an IO? First-line therapy of HER2-positive gastroesophageal cancer. Audience, would you generally add in an IO to a patient like that? And we just covered that because that was a paper at ASCO. I’m not sure you two saw that, and it was approved by the FDA, pembro, chemo, and anti-HER therapy. So have you heard that one, Hal? DR BURSTEIN: As always, you pull rabbits out of the hat. That is not routine in our practice. That’s very interesting. There was a study on immune responses in HER2-positive breast cancer at ASCO, and very modest activity. It’s not clear that in breast cancer that’s truly HER2 positive that there will be, in the near term, substantial augmentation with the checkpoint inhibitors. DR LOVE: Of course, gastroesophageal, IOs are much more part of therapy than they are in — so I think it may be just 1+1=2 rather than anything special. But we talked about that earlier today. Apparently, half the audience heard us, so that’s great. Let’s go to another case. This is a patient of Nikesh Jasani, a 55-year-old woman who got neoadjuvant therapy with TCHP. She also was triple positive, ER 95%, HER2 positive, residual disease, is getting T-DM1. Here are his questions about this situation and this case. DR JASANI: Some things we always ponder and want to have insight from the faculty is what is the threshold to add pertuzumab to your neoadjuvant therapeutic regimens, considering it adds a couple of percentage points benefit. And we do understand in node positive we’re adding it, but what about the classic T2N0 patient? And how are you incorporating the T-DM1 in the post-neoadjuvant setting, considering the guidelines are for any microscopic disease or any residual disease as opposed to triple-negative therapy, where we use capecitabine, and it is for certain subsets with significant residual disease? How does the faculty incorporate neratinib, considering its significant effects on diarrhea, predominantly effective in estrogen positive patients that are HER2 positive? How to sequence neratinib, and in what selected patients based on their clinical T size, their nodal status, and how are they making these decisions? DR LOVE: So Ginger, how important is pertuzumab in the neoadjuvant setting? You have a patient who’s having problems that you think are from the pertuzumab, diarrhea, et cetera. How important is it? And how are you thinking through post adjuvant use of neratinib, high risk patients, particularly these people who are getting neoadjuvant therapy and residual disease, ER positive? Are you thinking about neratinib? So pertuzumab, how important is it? And what about neratinib? DR BORGES: So I do use pertuzumab in all of my node-positive patients. In my node-negative patients, T2N0 has a bit of a spectrum to it. So if it’s somebody who’s 2.2 cm, not a lot of other high-risk factors, I probably would not give them TCH. Or right now we have the COMPASS-pCR that’s widely available, and I would espouse enrolling those patients to that study, which is a de-escalation study looking at a taxane plus H and P for 4 cycles. So I think that’ll be critical information for us to really land on the Goldilocks moment of not too little, not too much, just right. And if somebody is a T2 more like 4.5 cm, high risk, 35 years old or something, I’d potentially include the pertuzumab. I have definitely done that. I use the KATHERINE data on face value. If there is any residual disease I cross them over to T-DM1. And we also have the companion study, COMPASS RD, that’s widely available that will take T-DM1 with or without tucatinib as a dose escalation for anyone who does not achieve a pCR. And that’s kind of where I live right now. Off of that trial, if someone’s not eligible, I’ll just give them the T-DM1. The neratinib’s a tougher nut because we have all these other HER2-targeted drugs that show benefit, and we don’t really know where neratinib lands in that now. If I have somebody who is super high risk, inflammatory, many, many lymph nodes positive, really, really high risk to recur even after all of these other bells and whistles that we can throw at them, I’ll have a conversation and offer it to them, but at this point in time that’s kind of where I’m limited with that drug. DR LOVE: So Hal, a question in the chat room, and actually Dr Patt brought this up earlier. We didn’t address it. Nikita wants to know what about the role of margetuximab nowadays? Any thoughts, Hal? DR BURSTEIN: Yeah, so margetuximab is a very similar antibody. It has a couple of amino acid substitutions from trastuzumab, but it’s otherwise fundamentally the same. And in the randomized trial they compared chemotherapy plus trastuzumab versus chemotherapy plus margetuximab. There was a small, 1-month progression-free survival advantage in essentially a third-line experience. There is a biological subset where it looked like there was a little more activity based on mutations in the FcRγ receptor. And so for enthusiasts you have the opportunity to test for that and might identify it. I’ve got to say that I view it as largely a biosimilar trastuzumab. Nowadays we’re offering trastuzumab-based regimen in first line, and then second line we’ve spoken already today about tucatinib options, and then trastuzumab deruxtecan. There really aren’t any data for the efficacy of margetuximab-based regimens in patients who are getting fifth- or sixth-line treatment. So it has a relatively narrow role, I think, at the moment. There are neoadjuvant studies going on to see if it would be more potent than trastuzumab-based therapy alone. DR LOVE: So following up on Ginger’s comments about neratinib. In what situations, if any, are you using it, Hal? And how are you finding it tolerated nowadays with some of the new measures, dose escalation and other supportive care measures? DR BURSTEIN: Yeah. So I think our treatment algorithm sounds a lot like what Ginger’s doing. So Stage I, HER2 positives we’re using the paclitaxel/trastuzumab regimen. That seems to provide very adequate control. For Stage II or III we typically use a neoadjuvant approach, and increasingly I am omitting the carboplatin and just giving the THP-type regimens in that setting. We may come to this later, but there was a really nice study from the West German Group as part of their ADAPT trial. This was in ER-negative/HER2-positive cancers, but they saw 80% complete pathologic response with THP. So I think that you’re going to escalate up the pertuzumab here and de-escalate, if you will, the carboplatin. I really don’t like the de-escalation terms. I’ve got to say my own group talks about this relentlessly. We’re just moving off chemotherapy and adding more biologics. It’s like people, they don’t talk about CML saying we’re going to de-escalate bone marrow transplants and instead we’re going to give imatinib. It’s we have a better drug, we’re just going to give it. And that’s what’s happening in HER2-positive breast cancer. We have better drugs, and so we’re getting away from the hook on chemotherapy. And as exactly as she said, for patients who have residual disease we’re looking at trastuzumab emtansine. So then the question is on top of all that do you then add the neratinib. And because of the timing of the ExteNET study, which was done a decade ago now, none of those patients had pertuzumab. None of those patients would have had trastuzumab emtansine. It’s really hard to know if there is benefit from that regimen after a year of everything else. For extraordinarily high-risk patients with ER-positive disease we offer it. I find the patients do struggle with it, and despite a lot of vigorous diarrheal prophylaxis. Perhaps the pertuzumab therapy they’ve had in the past, which also causes diarrhea, makes it more difficult. I know it’s something we’re not commonly giving, and it’s an extremely high-risk patient that we would think about it. Highlights of ASCO 2021 — Virginia F Borges, MD, MMSc and Harold J Burstein, MD, PhD DR LOVE: So let’s go through a few papers. I think we’ve mentioned this study that was presented at ASCO looking at endocrine therapy plus trastuzumab. Ginger, anything else you want to say about this and this strategy? DR BORGES: No. I think we covered it pretty well. I would say that obviously there’s a favorable side effect profile when you’re not giving chemo, which we know this already. The one thing that did appear to matter a little bit was that chemotherapy plus trastuzumab had better outcomes if somebody was within 2 years of having progressed from their prior adjuvant treatment, which would make sense. So I looked at this study overall as really we get a little spoiled by what we have our hands on here in the United States. And when we go to our international conferences we get reminded that in some places trastuzumab is not even readily available. So for me I think either XUS, where the litany of other opportunities are not available, or like the case we reviewed earlier, where you’d be worried about adding in other HER2 agents. That’s where this data lives. And I think Hal really hit it on a very important point, which what we’ve learned since he and I were kiddos coming out of fellowship and trastuzumab was brand new, is that it really is the escalation on the HER2 side of the equation that has moved the needle for these patients, not escalation on the chemo side. It was just the partners that we had to use over time. DR LOVE: So I think we referred to this paper, and I’ve heard so many cases over the years how people had problems with TCHP. I know you all have had a big interest in using paclitaxel with pertuzumab/trastuzumab. Any thoughts about this ADAPT trial presented at ASCO, Hal? DR BURSTEIN: I thought it was a very nice little study. I mean I don’t want to make too much of it. It is an open-label study. I forget exactly the size. It was like a couple hundred folks, but it’s not like thousands of people in a randomized trial. But look at these numbers here. The first question was would biologics alone in ER-negative/HER2-positive breast cancer suffice. And fascinating, 30% of patients actually did have a complete pathologic response. But if you added the taxane that shot up to 80%. So it turns out paclitaxel’s a really important drug in combination with trastuzumab/pertuzumab. The outcomes numbers didn’t differ a lot because the patients did really well in both cohorts, but there was a numerical advantage for having had the taxane. I think the question people are asking is could you figure out who those 30% are and spare the need for the taxane. And I don’t want to trivialize giving chemotherapy because it has a lot of side effects, but the experience of giving THP is radically easier than TCHP or ACTHP or any of these others. Nowadays we’re using cold caps very liberally for these kinds of regimens, so patients are not losing their hair. And you put those combinations together, and all of a sudden chemo looks a lot different from the patient point of view than it did when you’re talking about ACTHP or TCHP and all the various more intensive chemotherapy programs. I like this regimen a lot for Stage II and higher cancers increasingly. Cases from the Community — HER2-Negative Breast Cancer DR LOVE: So let’s talk about triple-negative breast cancer. We’ve got a case from Dr Levin, a 48-year-old woman with metastatic disease, initially presented with inflammatory breast cancer with extensive skin involvement. Here’s Dr Levin with his questions about the case. DR LEVIN: She ended up having recurrence as subcutaneous nodules throughout her body. So no visceral involvement, just kind of subcutaneous nodules, completely asymptomatic, and was easily palpable on physical exam. We tested her for PD-L1, and she had 8%, so we started her on nab paclitaxel and atezolizumab, and she did not have any response to that; then carboplatin and gemcitabine, very short response to that. Then we switched her to sacituzumab, and she had a good response. DR LOVE: How did she tolerate the sacituzumab? DR LEVIN: Very well actually. Before that she had been struggling with anemia from chemotherapy, but with sacituzumab she actually felt remarkably well. No issues. Her hemoglobin has come up. Her blood indices have come up. She has a lot of energy. This is probably the only experience I have with this drug so far, and it’s proven to be great as compared to the other lines of chemotherapy. So at which point do physicians introduce sacituzumab in their management of metastatic triple negative? DR LOVE: So Ginger, today we’ve had general medical oncologists presenting cases. I sit down with these people, they present me cases of CLL, lymphoma, bladder cancer. In every one of these things there’s so much going on to keep up with. And one of the things that is kind of really challenging about new agents, we always focus on the tolerability issues that everybody has to be aware of, and sometimes it’s really hard to figure out how well things work. You can look at a trial, you see the numbers, you see hazard rates, et cetera. I’m curious, first of all how you decide upon first-line therapy in metastatic disease, which chemo, which checkpoint inhibitor you use, Ginger. And globally whether you feel like you’re seeing better responses since we started to add IOs. And the second question is what’s your next line of therapy, and what’s your experience with sacituzumab. Because I keep hearing about people who are responding. I don’t know if that’s just because people present cases to me of people responding. But again, any thoughts about triple-negative disease, Ginger, nowadays? DR BORGES: Sure. So the specific case that we were just presented is concerning because the cutaneous-only recurrences tend to be really refractory to everything, so I’m very happy to hear that there was a great response to the sacituzumab, and I hope it has some durability. We definitely struggle with those cases, and it’s very, very difficult for the patient. There’s nothing worse than a patient being able to watch their cancer progress, in my experience. But just going back to the general concept of triple-negative breast cancer first line where are we these days. It’s very important to assess the likelihood of immune response using the PD-L1 antibody and then choosing your immunotherapy, with the main regimen of the paclitaxel and atezolizumab has had great results with the IMpassion130 trial. So oftentimes I will use that one. We now also have excellent data with its partner, pembrolizumab, with a little bit more dealer’s choice of chemotherapies that you can incorporate, so I think we’re starting to have increasing choices. For a patient who is PD-L1 negative or not going to appear to benefit to IO or can’t tolerate IO or has an autoimmune syndrome, or in somebody who’s previously received that, the sacituzumab, I think’s been a really added benefit to our armamentarium of chemo agents. I’ve had a lot of experience with it, both when it was still on clinical trial and since it’s been FDA approved. And it would be my go to as well, and I’ve had some great responses, both visceral and elsewise. DR LOVE: Again, Hal, any comments about management of metastatic triple-negative disease? And your experience with sacituzumab. DR BURSTEIN: Yeah. Sacituzumab’s clearly a better drug. Remember, in the ASCENT trial they compared it against vinorelbine, capecitabine, eribulin. The response rates in refractory disease were 5% with those drugs. Those are terrible options for our patients. It’s what we give every day, but they’re dismal. And so the response rate of 30% is a big improvement. And in a patient like this, I mean she’s had 7 flavors of chemotherapy already when I was counting them, AC, carbo/tax, capecitabine, gem/carbo, nab-paclitaxel. And so I’m glad she’s having a nice response. But this is a tough disease to treat. I think it’s exciting that we’ve made some progress with the immuno-oncology drugs in triple-negative disease. In my own personal experience they are a modest step forward. I’ve got a next-door neighbor out that window there, he’s in his 60s. He’s got metastatic melanoma, and he got ipi/nivo 6 years ago, and he’s out there mowing his lawn and raking his leaves in the fall and all that. That is not what we see in metastatic triple-negative breast cancer with checkpoint inhibitors. So we need to figure out how to use that immune insight to begin to build on this because this is an incremental step forward, and it’s great that the antibody-drug conjugates are coming along behind them. A lot of interest in TROP2 targeting and all these other drugs at ASCO. Lots of drugs in early-stage development for refractory triple-negative disease. So there’s lots to build on there, but cases like this still remind you just how challenging this disease can be. DR LOVE: And Anita in the chat room wants to know do we know anything about sacituzumab, Ginger, in ER-positive disease. She says the bulk of patients in practice get tired of chemo, chemo, chemo, which is what Hal just brought up. What about sacituzumab in ER-positive disease, Ginger? DR BORGES: Well, that study’s currently ongoing, and so we’ll have to wait and see what the results will ultimately show. I have put patients on that trial, and I’ve seen nice responses. I’ve put patients on that trial who did not respond. So I think we’ll have to await the data. For right now I don’t think we understand its role in ER positive. DR LOVE: So the next case is a 40-year-old patient of Dr Dhatri Kodali. This patient has node-positive, triple-negative breast cancer and a germline BRCA mutation. Here are her questions about this case. DR KODALI: The biggest question always with triple-negative breast cancer in the germline mutation-positive setting. I am taking care of a patient now who is a 40-year-old who has left-sided, node-positive, 7 cm, triple-negative breast cancer. She’s BRCA1 mutation positive. She has N3 disease with both internal mammary, as well as axillary and infraclavicular lymph nodes. So in this scenario, what’s the role of platinum in the neoadjuvant setting? What’s the role of PD-L1 in the neoadjuvant setting? And what’s the role of PARP inhibitors? Just the recent New England Journal article, I think was just published with olaparib as adjuvant therapy for BRCA1 mutation-positive cancers. This patient of mine, once I finish her neoadjuvant therapy and get her to surgery, would I be considering PARP inhibitor in the adjuvant setting for her is what I was thinking about just looking at the study. DR LOVE: So Hal, any thoughts about this case, about OlympiA? Any comments? DR BURSTEIN: This was a beautiful and really important study. So I just want to remind people how hard it is, a randomized trial with BRCA1 and 2 mutations. I mean this is something we talk about a lot, but it accounts for only 4% or 5% of breast cancers around Europe and the United States, and even less, of course, in other parts of the world because of population demographics. Yet they pulled off a huge, randomized trial, randomizing patients after standard therapy to PARP inhibitor or not. And I thought the results were very compelling. There was an impressive difference in recurrence-free survival. There was a trend favoring a difference in overall survival. By the standards of oncologists, a very easy drug to take. The potential worries have been things like do you increase the rate of second malignancies or leukemias. Think probably too soon to say, but there was certainly no signal of that in the study. So in terms of the question we were just posed, for sure I would give the PARP inhibitor. Do they need the other stuff? That’s really an interesting question too. The study was timed so that very few of the patients had checkpoint inhibitors. The guess is that in the United States we’re going to be giving checkpoint inhibition in the neoadjuvant setting by the end of 2021 based on maturation of the KN-522 data and some related studies. We don’t technically have data on whether PARP inhibitors will work specifically in that population, but I think that will still be the temptation to use it. The role of carboplatin. This is like one of these platonic philosophy questions. Is the shadow the real thing or is it not the real thing in the man in the cave experiment? Carboplatin, it has some activity in triple negative. In a couple of studies it improved the pCR rates. Everyone got excited about BRCA. But when you actually look at those trials the benefit was not in the BRCA-associated cancers, and neither Bill Sikov’s CALGB trial nor in the GBG trials was there any signal that BRCA uniquely sensitized to platinum-based response. So if you look at the KEYNOTE-522 data it’s built around AC/TC, so they all got carboplatin anyway. The NSABP trial has a similar look. And I think you can’t say they didn’t give the maximal chemotherapy, which is the advantage of that study design. So look, this is a very high-risk patient. I certainly agree with a regimen of ACT with or without the carboplatin. And the other point I wanted to make is we know from previous studies that BRCA-associated breast cancers are just more sensitive to chemotherapy. That is part of the phenotype of these tumors. And so intensive chemotherapy certainly makes sense here. And then I absolutely would follow on with the olaparib. ASCO had a rapid guideline update approving olaparib in the adjuvant setting based on the OlympiA data. Other national guidelines are rapidly following suit. So it should be covered pretty soon, and I think it’s an important step forward. DR LOVE: So a couple questions for Ginger. First let me ask a question to the audience. Putting aside reimbursement issues, if you had a high-risk patient who had a PALB2 germline mutation would you want to give them olaparib? Yes or no. While we’re waiting to see what they say, Ginger, I’m curious how you would answer. It looks like at least three quarters of the audience says yes, they would like to. What do you say, Ginger? And also Charles in the chat room wants to know what about — this always happens when big adjuvant trials come out, what about delayed use — somebody who got adjuvant chemo, finished 3 months ago, 6 months ago, a year ago, would you start them on a PARP inhibitor, or olaparib? DR BORGES: So first question, in regards to the PALB2, I would not at this point in time use olaparib in the adjuvant setting for a PALB2 mutation. And in the setting of metastatic disease, I think there’s still clinical trial work to be done there with many of the options ongoing. As Hal mentioned earlier, sometimes we have patients who are on ninth-, tenth-, eleventh-line therapy, so I have gotten off-line approval after the usual suspects have been given, and given that a shot as single agent. But in general, that’s not where we are right now with understanding these downstream DNA damage repair mechanism genes. For the other more interesting dilemma we’re all going to be facing in about 15 minutes is how far out from prior treatment is too far before you would consider initiating a PARP inhibitor. And I think it’s going to depend on the patient’s risk. Certainly 3 months, 6 months, I feel pretty comfortable. Once we start getting out past a year, then all of a sudden what if it’s 24 months? What if it’s 36? I don’t know what my breakpoint will be yet. I’m sure I’ll define one. I think we have to be careful because we know from other agents that if you don’t initiate the therapy in a timely manner it doesn’t have the same level of benefit. Because on some point you start to select for those who are already doing well and maybe don’t need the added risk reduction. But I would say if it was only 3 to 6 months ago it’s going to be pretty hard to not offer them the therapy. DR LOVE: So Hal, great question from Dean in the chat room. Triple-negative breast cancer, neoadjuvant therapy, residual disease, with a BRCA germline, so are you going to give them olaparib, capecitabine, or both? DR BURSTEIN: Just to remind everybody, this is 2.5% of your clinic practice in triple-negative breast cancer. So I think the more important thing is that we need to be testing people now. So folks who meet the criteria for OlympiA warrant testing, so that’s Stage II or II triple-negative disease or residual disease after neoadjuvant therapy or higher-risk ER positive. There was a very complicated algorithm for who gets olaparib if it’s an ER-positive thing. But most important is to be testing. And when you do find it, as Dean’s question alludes to, I don’t know is the honest answer. My guess is I would probably give them both. So if they had residual disease I think you probably have earned a ticket to both the capecitabine and the olaparib dance, and let’s give the capecitabine first just because that’s how we usually do it. There were a handful of patients in the OlympiA trial who had that sequencing. DR LOVE: So let’s go on to another topic. Audience, I’ve got a quick case for you. You’ve got a 65-year-old clearly postmenopausal woman with 2 positive nodes, ER positive/HER2 negative. Her 21-gene recurrence score is 10. Are you going to give her chemotherapy? Yes or no. Let’s see what happens. Ginger, are you going to give that patient chemotherapy? She’s postmenopausal, recurrence score 10, 2 positive nodes. DR BORGES: I am not going to give her chemotherapy. I think she’s a great candidate for antiendocrine therapy alone based on the RxPONDER data. DR LOVE: Wow. 97% of the audience agrees with you. That’s what I call a quick turnaround. I like that. So Hal, again, of course one of the big issues here is not so much the postmenopausal women, but the premenopausal women. But before we get to that, I made this case low recurrence score. Hal, what about intermediate recurrence score in a postmenopausal woman? Chemo or not, Hal? DR BURSTEIN: So by intermediate you mean somewhere between 10 and 25. DR LOVE: Yes. DR BURSTEIN: I still think the answer is no chemotherapy. The RxPONDER data are remarkably clean data for postmenopausal women in particular. There’s absolutely no signal of benefit. And so the risk goes up as the score goes up and as the nodal involvement goes up. But the lesson from the study is that chemo doesn’t change that risk. And so I think we don’t really have data for Stage III cancer, so 4 or more positive nodes remains a black box, and we often feel obliged to give chemo there, though my guess is it doesn’t do very much. But 2 positive nodes, I think you’re done. Here’s a question back to Ginger. What if you had 2 out of 2 sentinel nodes, and you don’t know how many nodes they have? Have you done an axillary dissection to figure out if they have more extensive nodes? DR BORGES: You just outlined almost every tumor board where we debate these things. We follow the guidelines of whether somebody does or does not need an ax dissection based on all the surgical literature, and in this patient I believe the answer to that is no, she does not need an ax dissection. And unless there was something about her presurgical imaging that had me worried we are missing something I am not going to send this patient back to the morbidity of a completion ax dissection in order for me to just make sure. I’m going to take the great information and run and get her started on her aromatase inhibitor. DR LOVE: So Hal, I’m curious about your approach to node-positive patients who are premenopausal. Are you doing a genomic assay or not? DR BURSTEIN: We absolutely are. And I think that in both TAILORx and RxPONDER there’s this very interesting signal of benefit for chemotherapy in the premenopausal patients. In retrospect the studies were not designed to give optimal endocrine therapy, which was a design mistake. They didn’t include ovarian suppression. And so the confounder is how much of the benefit of treatment is really due to the ovarian suppression effects of chemotherapy as opposed to the cytotoxic chemo poisoning the cancer cell kind of benefit of chemotherapy. So I think the clinicians I’ve been speaking to since these data came out, they understand these things. For a 47-year-old who’s got a micrometastatic fleck in 1 node, absolutely I would check the Oncotype DX® Recurrence Score®, and if it’s low I would do ovarian suppression and an AI instead of chemotherapy. In the 38-year-old who has 3 out of 3 sentinel lymph nodes and a score of 22, I feel less confident that she doesn’t need chemo, though my guess is there’s still a pretty small role. And so many of these patients do end up getting chemotherapy. I’m hopeful that subset analyses will begin to tease this out. They did that pretty well in TAILORx. It was clear that the benefit of chemotherapy actually went up as you got closer to age 50, which makes no sense unless you imagine that the effect is because of ovarian suppression. It’ll be interesting to see what happens in RxPONDER further follow up and analysis. DR LOVE: All right. DR BURSTEIN: But I don’t think the default answer is to just give chemo. I don’t think the default answer is to just to give chemo to all premenopausal women with node-negative or node-positive breast cancer. That is not the lesson from TAILORx and RxPONDER. DR LOVE: So let’s finish out, if we can, with a couple quick cases and two papers I’ve got to ask you about. So we’ll try to do this fairly briefly. So we’re coming back to Dr Patt, who has a 52-year-old woman, and here’s her case. DR PATT: On exam she did have retraction of her nipple right at the periareolar region. So even though it was a small mass, by size criteria is a T1 lesion, she did have a little bit of inflammation in that skin and pullback of that tissue. After mastectomy, while it was a small tumor, 5 mm, she did have extensive dermal invasion. Obviously, chemotherapy may not be of benefit in this woman with a low-grade cancer that’s low Oncotype, but clearly this is a different cancer because it has gone already into her dermis. And how do you think about risk-reducing strategies in this patient who has, even though it’s small and low grade, really a locally more advanced cancer because of the dermal invasion? What is the role of radiation in this patient? Is there a role to augment endocrine risk reduction either with 10 years of endocrine therapy, or is this someone that you would try to add a CDK4/6 inhibitor like abemaciclib? DR LOVE: So again, Ginger, radiation therapy in this patient? Abemaciclib in this patient? And your thoughts in general about abemaciclib in the adjuvant setting. DR BORGES: Sure. So for this patient specifically what I’m hearing is that there was a concern about this lesion for a while, and with her dense breasts and her younger age by the time it came to diagnosis it had eroded into the dermis. But that’s probably more of a location issue than necessarily clearly a different biological driver. Her Oncotype Score is reassuring. For sure the local therapy with making sure the affected skin is removed to clean margins, and the radiation oncologist getting in there and doing a boost to that area makes a lot of sense and is critical. I would pursue antiendocrine therapy alone. I think we were told she is 52, right? DR LOVE: Right. DR BORGES: So 52 is in the gray zone when it comes to what her ovaries are actually doing, so I’d probably draw some blood to check, or depending on what history the patient could give me. Is she more of a still premenopausal 52-year-old with ovaries of steel, is she the more classic perimenopausal 52-year-old, or did she go through menopause quite some years ago, so you know biologically who she is would be a very important part of the history? I think the monarchE data on the abemaciclib is incredibly exciting. We have to see where that goes. We know from the other CDK4/6 inhibitor studies in the adjuvant setting there was some early signal, but that did not hold up with longer time of follow up. This patient would be pretty low risk in terms of the classic features of the size of the tumor, absence of nodal involvement, and the low Oncotype Score, so I don’t see her as coming to my mind as someone where I might think of adding in the CDK4/6. Highlights of ASCO 2021 — Virginia F Borges, MD, MMSc and Harold J Burstein, MD, PhD DR LOVE: So I want to finish out with a couple of papers, starting out, Hal, with my favorite paper of all of ASCO; not breast cancer, all of ASCO. When I saw this I literally did not believe it. I thought I was misreading what I saw on the scan. So, neoadjuvant PARP. What are your thoughts, Hal? DR BURSTEIN: So Jennifer Litton at MD Anderson led this trial, a neoadjuvant study of talazoparib in BRCA1- or 2-associated cancers. 50% pCR rate. Remarkable. DR LOVE: 50%. DR BURSTEIN: With just that drug alone. So it’s phenomenal. And I think it just speaks to what we were alluding to in the OlympiA study, which is these were really active drugs in women who have BRCA1 and 2 cancers, and it makes testing really important for not missing such cases. The question is how would it stand up against standard chemotherapy. As we said a few moments ago, these are chemosensitive tumors, and in many studies such cancers have pCR rates of 65% or more with standard chemo. Ironically, the OlympiA study makes this a little bit moot, in my mind, for the moment because they’re going to get the drug outback. And the question is could we in the future imagine giving them a PARP inhibitor, taking those patients who have a pCR and calling it quits. We’re not there yet, but I score this as a very important paper, and it tells us just how valuable PARP inhibitors are in BRCA1- and 2-associated breast cancers. DR LOVE: And Ginger, that’s why I like the paper so much, not so much about the exact implication in terms of what we’re going to do in the neoadjuvant setting, but to be honest with you, to see a 50% path CR rate from just a PARP inhibitor, I was surprised. Because I kind of didn’t have the feeling that PARP inhibitors were that effective, like what you see in targeted therapy of lung cancer, where you see almost everybody responding. And of course most people in practice don’t have that much experience with PARP inhibitors in the metastatic setting. To me it was just an endorsement, as Hal was saying, that these can be very effective drugs in the right patient. Any thoughts, Ginger? DR BORGES: Yeah, absolutely. I mean it highlights how we can use the neoadjuvant space to really explore these targeted therapies, knowing that we have all of the adjuvant space to give whatever drug we want. And we can use path CR as a readout for learning encouragement. We have seen umpteen examples of how when you hit the target effectively you really change how a breast cancer behaves, and you can really enact much higher cure rates. If things move forward, HER2’s our strongest example of that over perhaps ER as the original HER2-targeted therapy. This is super exciting for our BRCA-positive patients, and as Hal has emphasized, and I can chime in on top, is when in doubt, test. I think we don’t exactly understand who could be BRCA positive. We know some obvious markers for high risk, with strong family histories and Ashkenazi Jewish descent, but plenty of patients who didn’t necessarily potentially meet those criteria pop up. If somebody has triple-negative breast cancer up to the age of 60 we should be routinely testing them to make sure we don’t miss anybody. And as these data move forward, and other studies will come out of all of this great place we are right now with the OlympiA data, we’ll ultimately land in a different place with maybe the PARPs up front, and maybe continuing outback as well for when we also know who amongst all the BRCA carriers are going to be the ones that will completely benefit from this. So a lot of work to do, but it’s really awesome to be at this moment right now seeing the benefit. DR LOVE: And of course in ovarian cancer, you walk through the door with ovarian cancer you’re going to get not only germline panel, you’re going to get NGS as well. And so I think we’re heading that way in breast cancer, but maybe not in lower risk. We’ll see. Okay, here’s another one of my favorite papers, Hal. Durvalumab in the neoadjuvant setting. It’s mirroring what we are seeing with pembrolizumab. Any thoughts? DR BURSTEIN: Yeah, so this is a nice paper for two reasons. One is that it was a randomized trial, chemotherapy plus or minus the checkpoint inhibitor durvalumab. They had previously reported an improvement in pathologic complete response. Now with longer follow-up they actually saw a robust improvement in event-free recurrence and overall survival, on the order of 5% or 6% absolute benefit. And I think that’s beginning to tell us, as I suspect the maturation of the KN-522 data will tell us, that the standard approach is going to be chemotherapy plus a checkpoint inhibitor for Stage II or III triple-negative breast cancer. So this drug probably won’t get approved. It’s a randomized Phase II, but it’s a very compelling model. The second really interesting nugget, and Neil I know you love these kinds of nuggets, so I want to make a point of this. They looked at outcome by pCR, and as you would expect, patients who had a complete pathologic response did better than those who did not. But the pCR with chemo alone was not as good in long-term follow up as pCR with the checkpoint inhibitor as well. And they did not get adjuvant checkpoint inhibitor treatment in this trial. And that raises this really interesting finding, that maybe not all pCRs are the same. We’ve been operating on the idea if you get to pCR that’s all you need, but in this study pCR with chemotherapy was less good than pCR with chemoimmunotherapy, arguing there’s something you’re doing to train the immune system that it’s going to keep working after the fact. But that was a great little nugget in that paper. And we’ve talked about the checkpoint inhibitors in early-stage triple negative. I suspect it’s somewhere around the corner this year. That’s my guess, and we’ll just have to see how the data mature and the FDA responds. |