Visiting Professors: Lung Cancer Edition, Issue 1, 2019
Visiting Professors: Lung Cancer Edition, Issue 1, 2019
Featuring Drs Leora Horn and Benjamin Levy’s perspectives on their time spent visiting with patients with lung cancer in the clinics of community oncologists.
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Case: A man in his early 60s, a current smoker, with metastatic lung adenocarcinoma and a PD-L1 tumor proportion score (TPS) of 80% experiences a dramatic response to first-line pembrolizumab but a recurrence of small lymphocytic lymphoma (SLL) during therapy DR LOBINS: The first patient is a 62-year-old gentleman who I saw, oh, about a year and a half ago, and he had widespread metastatic disease. His disease was so widespread, it was actually hard to figure out where the primary was — involved his right tonsil, a large, large lesion in his left lung. His esophagus was involved. And so we treat him as if he was lung cancer, because that was the bulk of his disease. He had a high PD-L1 score and was really averse to chemotherapy, so we put him on pembrolizumab. DR LOVE: What was the histology? DR LOBINS: I believe he was adenocarcinoma. DR LOVE: And how about his smoking status? DR LOBINS: He’s a current smoker. DR LOVE: Interesting. And you said that his PD-L1 level was elevated. What other biomarker assays did he have done? DR LOBINS: I believe he had a full panel, but that was the only abnormality he had. DR LOVE: Right. He got started on pembrolizumab. And what happened then? DR LOBINS: He had a complete response to the bulk of his disease. His interesting case is that in the mid-90s he had what appears to be SLL, because he was treated with chlorambucil as well, before I knew him. And during his treatment over the last several months, he started noticing a lump on the right side of his neck. And he had a palpable lymph node. But the rest of his scan was completely normal now. And so we sent him for a biopsy of his cervical lymph node, and it came back with lymphocytes on the fine needle aspiration. They’re planning to do an excisional biopsy, but it’s likely his SLL is back. DR LOVE: What’s his count doing? DR LOBINS: His white count is 8,000. His lymphocyte counts are normal. So it’s probably SLL. DR LOVE: Wow, that’s really interesting. And any tolerability issues with the pembrolizumab? Any autoimmune problems? DR LOBINS: Not at all. At all. He looks as healthy as anybody walking the street these days. Activity and tolerability of immune checkpoint inhibitors alone or with chemotherapy as first-line therapy in patients with metastatic non-small cell lung cancer (NSCLC) DR LOVE: What an interesting case, and also interesting that he’s still smoking. Wow. That is really interesting. Just kind of curious, Ben, any general thoughts as you visited this man? So many things to talk about. DR LEVY: Yes. So many things to talk about, and Ray and I were just mentioning, 5, 10 years ago, we would have never — who would have dreamt that we would be able to see this type of outcome without chemotherapy, or even with chemotherapy? This is a patient who has widespread metastatic disease and who, of course, is averse to getting chemotherapy, has a biomarker that’s predictive of outcome to single-agent immunotherapy. Has a PD-L1 that’s high, at 80%. He doesn’t have an actionable mutation. And just to see, and I agree with Ray, I mean, it’s hard to know — this guy had as much cancer as was seen on his scan, and the response to single-agent pembrolizumab — we see these, of course, in real world, and it’s been mirrored in the data. We see some of these patients that have not only responses but real depth to their response. Looking at this scan before and afterwards, seeing how much shrinkage there is on the scan with just a single-agent checkpoint inhibitor is pretty remarkable. And tolerability was not an issue for him. Many of our patients do struggle with some of these issues, maybe fatigue and some thyroid issues. Of course, it’s rare to get this autoimmune phenomenon, but tolerating it well and deriving a meaningful benefit to single-agent checkpoint inhibitor. DR LOVE: One of the things this does raise, I know if we asked as a poll question in a meeting or if we do a survey and present a case like this, even with a PD-L1 level over 50% Ben, a lot of people, even in a relatively asymptomatic patient will go with chemotherapy plus a checkpoint inhibitor. DR LEVY: Yes. DR LOVE: Any thoughts about that? DR LEVY: Yes, I think it’s a pretty nuanced decision. We, of course, have KEYNOTE-189 approval, and that is across the board, including greater than 50%. And we have KEYNOTE-024 with single-agent immunotherapy versus chemo. Cross-trial comparisons, which we say we don’t do, but we do. If you look at the hazard ratio in the subset analysis from the PD-L1 greater than 50, the hazard ratio seems to lean a little more pronounced, 0.42 with KEYNOTE-189. And so the question of whether to give chemotherapy IO or IO alone in a PD-L1 greater than 50% for me comes down to symptomatology — are patients symptomatic or not? And then patients’ wishes and desires — I think that if a patient’s asymptomatic and doesn’t want chemo, I’m okay giving that patient single-agent pembrolizumab. If a patient is more symptomatic or I think that wants to be more aggressive, we can certainly give the triplet therapy of carboplatin/pemetrexed and pembrolizumab. Both are approved. I think it’s an individualized treatment decision for patients with a PD-L1 greater than 50%. Duration of therapy with immune checkpoint inhibitors DR LOVE: I’m curious, Ray, whether the topic has come up of stopping treatment at any given point. And I don’t know what your experience is in general in your practice. I’m sure you’re using checkpoint inhibitors in all kinds of situations. Maybe you have other patients who’ve done well like this one. Has the topic come up with this man? DR LOBINS: It has. It has. And so he is about 16 months out from his disease. And his disease was extremely bulky when he first met me, and he was extremely symptomatic, and now he’s completely asymptomatic. And is really averse to chemotherapy or averse to treatments, per se. He’s not balking at all about the pembrolizumab, because it turned his life completely around. But we’ve talked about it, and I really am taking the data from melanoma, and I told him, if he’s doing well at 2 years, we could consider stopping the medications and just watch him closely. DR LOVE: What type of work is he doing? And what’s his lifestyle? DR LOBINS: I know he owns houses for a living. And he has a lot of rental properties. I don’t think he does any other work besides that at this point. DR LOVE: Does he have a family? Does he come in with anybody? Was anybody there today? DR LOBINS: Oh, he always comes in with his wife. DR LOVE: Interesting. I’m curious, Ben, what your approach has been in terms of the question of stopping therapy. There was some data, I think, a couple of years ago, suggesting maybe longer is better. DR LEVY: Yes. DR LOVE: What do you think about that? DR LEVY: We had data — this was presented by David Spigel — looking at 1 year versus continuation, and it seemed like patients who continued beyond 1 year with single-agent nivolumab did better than patients who stopped after 1 year. This trial was a little bit flawed, and I don’t know if it answered the question definitively. At least in the second line, many of the trials stopped single-agent immunotherapy after 2 years. And I think again, this is an individualized treatment decision where we really need to talk to patients. We need to look at how much response we’re really seeing and what the toxicities are. I do have a conversation with patients after 2 years. Certainly I think that’s an appropriate time to say, “Look, you’re doing well.” This comes down, I think, to patient motivation and region where you’re practicing — most of my patients are very motivated, want to stay on, have been encouraged by the results and I have no problem. But for others who want to travel, spend time with their family, I’m okay giving either treatment holiday or stopping all together and watching. This is where we get to — as Ray and I talked about this morning — the art of medicine rather than the science of it. DR LOVE: It is interesting. I mean, he did have a high PD-L1 level, but it is also stated — and I’m curious, Ben, whether even if you correct for a PD-L1 level, do smokers have more response to checkpoint inhibitors? DR LEVY: One of the first enrichment factors that we found out about, this story of immunotherapy of clinical enrichment factors, that patients who smoked the most were the ones who had the largest benefit. And there’s a lot of reasons for that. They have more somatic mutations and more, probably, higher neoantigen load that makes the immune system able to recognize these cancers. I think we do know that in data that was presented last year at ASCO that never smokers who have a high PD-L1 do as well as smokers with high PD-L1. It’s a small data set. I don’t think it’s been published yet. As Ray and I were talking about this morning, there’s still some questions rummaging around in our field about whether never smokers really respond as well as smokers do, even if you adjust for the biomarker. And I think this is something that we still need to look at, but certainly something that we discussed this morning after we saw this patient. Perspectives on the effects of recent advances in the management of lung cancer on the practice of oncology DR LOVE: When we began, you were talking about how lung cancer has changed. I don’t know. Ray, any reflections on being in general medical oncology practice in terms of — I mean, is it really different, from your point of view? DR LOBINS: Oh, it’s crazy different. And we actually talked about this today, because just a couple of years ago, I thought life was a little bit easier, because you had a game plan. You had first-line chemotherapy. You had second-line checkpoint. You had third-line docetaxel. And at the end of third-line treatment, a lot of the patients would wear out, and it wouldn’t be as big of a deal. Now you have everything up front, and you’re back to docetaxel as second line. And after second line, you’re going, okay, what am I going to do with this patient? DR LEVY: Yes. I was telling Ray right before we came on, Neil, I said, “I don’t envy you. You’ve got to keep up.” I mean, I have a hard enough time keeping up with the lung cancer data. We were talking about how challenging it is just to keep up with 1 disease state, not to say trying to keep up with all the different tumor types. I think it’s incredible — the pace of discovery has made things so exciting, but coupled with that is this incredible complexity and confusion. And so it’s a fun time to be around in the field, but it’s certainly hard and challenging. DR LOVE: Yes. Actually, Ben, we did a meeting this year for the first time. We had 32 investigators here in Miami — Ray was one of the docs there — and one of the things we put up there was what we call “Day in the Life.” And we asked the attendees to just tell us about the last 20 people they saw. And we would put this up, and they’d go from one room with melanoma to the next room with CLL, to — and every single patient, everything had changed, so pretty interesting experience. Potential correlation between recurrence of chronic lymphocytic leukemia or SLL and treatment with anti-PD-1/PD-L1 antibodies DR LOVE: One other thing about this case I want to ask you, Ben. It’s really interesting. It sounds like this node, this SLL node popped up while he was getting a checkpoint inhibitor. Ben, can you see any connection? DR LEVY: Yes. Were you in the room when we had this conversation? We walked out of the room, and I saw the node, and Ray had said that the biopsy, at least initially, was consistent with CLL. And I said to Ray, I said, it’s interesting that this node popped up on a drug that causes some sort of immune dysregulation. Is it possible that the pembro, while prolonging his life and making a meaningful impact, did something to the adaptive arm of the immune system that would allow this to reoccur? And I actually did a search as we’re waiting for the next patient, looking for reactivation of CLL. Couldn’t find anything in the literature. But we certainly see these bizarre cases and side effects, and the timing is a little bit suspicious that there may be some sort of connection here. DR LOVE: I mean, speaking about things changing. I mean, CLL, like, craziness. In December at ASH, everything changed again. But it is interesting to think about, for example, Ray, if you gave him ibrutinib, because ibrutinib does have immunological effects. I think it’s used in graft-versus-host disease. I don’t even know what would happen if you gave ibrutinib and a checkpoint inhibitor at the same time. DR LOBINS: Fortunately — we had this conversation, and we actually talked about the pathophysiology of SLL and how these indolent lymphomas, they live forever. They don’t grow real quick. And we actually talked about Bcl-2 and Bax and how that works. And fortunately right now, he doesn’t have bulky disease. He’s not symptomatic from it. But at some point, we may have to address the SLL. I’m hoping by that time he’s off the immune therapy, and then we can address 1 cancer at a time. DR LOVE: Maybe that’ll be another reason to get him off the immune therapy. Ben, are you aware of the immune effects of ibrutinib and how, theoretically — I mean, could you have somebody on ibrutinib and a checkpoint inhibitor at the same time? DR LEVY: I don’t think so. I don’t know. I didn’t know if we have any data on that or not. And as I was telling Ray today, I got an education session on CLL today — it was great. And I haven’t seen this in a while — so again, I think Ray said, “I learned a lot from you today.” I said, “Ray, I learned a tremendous amount from you in all these other disease states that I don’t treat.” It’s fascinating. DR LOVE: Yes, CLL is really fascinating. Case: A woman in her late 50s with a history of autoimmune uveitis is diagnosed with NSCLC and multiple metastases in the brain DR LOVE: Alright, let’s hear about the next patient, this 59-year-old lady. DR LOBINS: This is a very petite woman. She’s 90 pounds, to be quite honest. But she’s healthy. And about a year ago, she developed a lung cancer and was found to also have multiple brain mets. And so she was radiated. And then we talked about chemotherapy, and I talked to her about, “Do you have any autoimmune diseases?” And she said, “Oh, I was told I have autoimmune uveitis.” DR LOVE: Wow! DR LOBINS: And so I said, “Huh! Okay. In that case, we’re going to treat you with a different kind of chemotherapy,” and I put her on the Patel regimen. And she’s done extremely well on this regimen and now is on maintenance pemetrexed and bevacizumab, and this is, like, number 12 or 13 on the maintenance. No evidence of progression. Is doing extremely well. DR LOVE: She had bilateral asymptomatic brain mets? DR LOBINS: I believe so. I believe it was multiple. Side effects associated with whole-brain radiation therapy DR LOVE: And how long ago did she have the whole brain radiation? DR LOBINS: About a year ago. DR LOVE: A year ago. DR LOBINS: Yes. DR LOVE: Were you able to detect any cognitive changes or any sequelae to that? DR LOBINS: No. I mean, the only problems that she complains is, she fell in the interim, because she twisted her knee — and she’s not the world’s strongest person. She’s just a very petite lady. She’s able to take care of herself. She’s able to eat, drink, go do stuff. She has no neurological deficits whatsoever. DR LOVE: And I guess we should also mention, her PD-L1 level was zero, right? DR LOBINS: Yes. DR LOVE: And she had no targetable mutations? DR LOBINS: That’s correct. DR LOVE: She had NGS done. And I’m just kind of curious, Ben, did you see any sequelae to whole brain radiation when you talked to her today? DR LEVY: No. She looks good. I mean, I had to be reminded on your case presentation about her whole brain radiation therapy. I mean, she looks remarkably well for somebody who’s been treated with whole brain and also has remained on a maintenance chemo regimen now for quite some time with bevacizumab and pemetrexed. So no. DR LOVE: I was thinking about whole brain, because we actually did a survey — and we might have even asked you, Ben — of investigators on management of patients with EGFR-mutant disease and bilateral brain mets that are symptomatic. And every single investigator, every one, 100%, said osimertinib. That’s what we call a consensus. But amazing, again, think about how quickly that changed in the last — that’s a standard of care. Obviously that’s not the case with this lady. But that got me thinking a little bit about whole brain. When you do see neurologic sequelae? Ben, when does it occur, and what do you usually see? DR LEVY: It can occur any time right afterwards, and we’ve had a couple of patients like this without a driver mutation, where we can’t give a targeted therapy that we know will cross the blood-brain barrier, multiple brain mets. We don’t want to do whole brain, but we have to sometimes. And we usually can see problems with memory impairment. We can see ongoing fatigue. We can see problems with gait disturbances. And it’s challenging, because there’s not a lot of data out there as to how to manage this and what the best ways are pharmacologically to manage it. I would say any time 2 to 3 months after all the way up to 9 to 12 months that you can see these types of sequelae. We try very hard to avoid whole brain as best we can. And sometimes I think the lesson here is, you just can’t. You’ve got too many brain mets, and how many lesions are really SRS-able or Gamma Knife®-able? And if you have that many lesions, I think you have to default to whole brain, but you do have these sequelae afterwards. Use of immune checkpoint inhibitors for patients with preexisting autoimmune disorders DR LOVE: I want to think a little bit about where things might be heading in the future for this lady and particularly the issue of checkpoint inhibitors, in view of what you said. Do you know more about this uveitis she had? How did it present clinically? And do you know anything about it? DR LOBINS: I don’t know anything about it. But uveitis is something that I’d worry about, because vision is important. I’d hate to get inflammation and any uveal kind of scarring or something like that. Initially when she even said it, I didn’t know her when she said she had it. I don’t know much about it. I just said, “Well…” and off the top of my head, a quick decision, “I’m not going to start a checkpoint inhibitor. If you need one at the end, we’ll cross that bridge that when it comes.” DR LOVE: Yes, once you hear that word “autoimmune,” that kind of gets you thinking about it. But, I mean, suppose this lady had a PD-L1 level of 80% or — and Ben, you’re at the world center for immunotherapy, I think, there. Do you know anything about autoimmune uveitis, whether it gets worse with checkpoint inhibitors? DR LEVY: Yes. DR LOVE: And how do you generally approach patients who have some kind of autoimmune history, Ben? DR LEVY: So we were talking, Ray and I were talking about this this morning. At Hopkins, we have an autoimmune toxicity team that evaluates these patients. It consists of a rheumatologist and an endocrinologist that are referral based. And that’s kind of nice, because we have a very low threshold for turning these patients over for evaluation. I would say in the community, Ray and I were talking about how important it is to partner with your subspecialists here and get to the bottom of what’s going on in terms of their autoimmune disease. I had a patient who came in with scleroderma who was given a diagnosis of limited scleroderma and had a high PD-L1, wanted to use immunotherapy, and I referred her to the rheumatologist who said, “This is not scleroderma.” So having that partnership with your subspecialist I think is important for cases like this. I have not seen a case of autoimmune uveitis. I don’t know if there are cases out there and whether this is an autoimmune phenomenon that would ever be compatible with the delivery of checkpoint inhibitors. We do have, of course, some data to suggest that patients with an autoimmune phenomenon can be treated with immunotherapy and that the flare rate is not prohibitive. And about 25% of patients with an autoimmune disease who get treated with a checkpoint inhibitor can have a flare but is generally manageable. I think that autoimmune diseases are different, and you have to decide if you’re going to give an immunotherapy drug or not based on the type of autoimmune disease that they have. Myasthenia, I wouldn’t go there. Systemic lupus ery, SLE, a really bad SLE, probably not. But things like this, these limited scleroderma or a questionable diagnosis of uveitis or even rheumatoid arthritis, those are the ones I think you really need to partner with your subspecialists to get a real sense of whether this is safe or not to give. DR LOVE: Also, I hear people talking about whether or not they’re on treatment for it, et cetera. But I guess the other issue that I’m curious about, when you look at our experience at this point is this mainly about ipi or anti-CTLA-4, or even PD-L1 alone can exacerbate autoimmune disease? DR LEVY: I think the data we have, at least in lung, has given the limited role that CTLA-4 has played is mostly with single-agent checkpoint inhibitors with PD-L1 drugs or PD-1 drugs. I think probably adding the CTLA-4 may exacerbate it further, given that this is an additional tox that we see with the dual checkpoint blockade. But most of the data we have with autoimmune phenomenon in lung cancer is with single-agent PD-1 or PD-L1 drug. DR LOVE: And, of course, the issue of giving checkpoint inhibitors to somebody with autoimmune disease also maybe relates to setting. I hear people being a lot more conservative about the consolidation durvalumab situation, where some of these people will be cured without it, as opposed to metastatic disease, particularly this lady once she gets through, if she does have disease progression after chemo. Going to be looking at a pretty dismal prognosis. I think that could maybe affect how you approach it. Therapeutic options for patients with metastatic NSCLC in the second-line setting DR LOVE: How are you thinking about, or what do you think you’d be thinking about in terms of her next therapy? Hopefully she’ll be on this maintenance for a long time. But in general, how would you approach somebody like this in the future, Ray? DR LOBINS: One of the things that I would do — the first thing we talked about is how long to keep her on pemetrexed and the bevacizumab and when to stop the pemetrexed. Because her really only complaint is a little bit of fatigue, and prolonged pemetrexed can aggravate the fatigue. When she does recur, the question that I’ve been thinking in my head is actually who to send her to. Do I send her to ophthalmology to assess the uvea? Do I send her to rheumatology to see if it’s autoimmune in nature? I’m not 100% sure. If I don’t know, I would probably err on the side of chemotherapy/docetaxel until I had to actually use immune therapy, saying, “Hey, this is an option for you, but it does have this possible toxicity.” That’s how I would likely use her. And I’d go from the Patel regimen to docetaxel to immune therapy as a third line. DR LOVE: Docetaxel alone, Ray, or with ramucirumab? DR LOBINS: Good question. And we talked about this as well, as we’ll talk about in our cases. About half the time I use ramucirumab, and about half the time I don’t use ramucirumab. If there’s a reason I’m worried about clotting, if there’s a reason that I may be worried about some kind of bleeding or some kind of toxicities, sometimes I don’t use the ramucirumab. Other times I add it in. And so in her case, I would probably do it, but I bridged that question when it came. I think that 6 weeks in progression-free survival that it provides, it’s not automatic that you have to use ramucirumab — it’s more of weighing the toxicities and benefits. Results of the Phase III REVEL trial investigating ramucirumab with docetaxel as second-line therapy for patients with metastatic NSCLC DR LOVE: I’m curious, Ben, how you approach this question of ramucirumab. Maybe you can review the data? Also, Ray was referring to 6 weeks, but I’m also curious about hazard ratios and other things that we know about this strategy, both risks and benefits, in terms of how you see it. DR LEVY: Yes. I think the REVEL trial, one of the largest second-line trials we have, clean randomization, 1:1 in patients who were platinum refractory to single-agent docetaxel versus docetaxel plus ramucirumab, the question being asked was, if you add ram to docetaxel, was there improvement in outcome? And we did see what I call the triple threat. I mean, we saw an improvement in response rate that was modest. We saw a 6-week improvement in PFS that Ray alluded to, and we saw a 6-week improvement in OS. And so these benefit are modest. The hazard ratio, I believe, was around 0.8, 0.82, something around there. And this did come at the cost of a little bit more toxicity, a little more fatigue and cytopenias, and febrile neutropenia was there as well. And I think when you have a drug or a drug combo that provides a modest benefit in outcome at the cost of some toxicity, this is an individualized treatment decision. I mean, I’m like Ray. I try to offer my patients ramucirumab, if just for the sake of giving them an anti-angiogenesis strategy in combination with a backbone of taxane. But it’s individualized. I think that the benefits are modest at best and certainly an option for our patients, but not for all patients. Activity of ramucirumab in patients with squamous cell NSCLC and those with prior exposure to bevacizumab DR LOVE: What about patients who have squamous, Ben? We kind of had this thing with bev that evolved, and yet the story was somewhat different in terms of bleeding with ramucirumab. Can you go through that also? DR LEVY: Yes. There was a fair amount of patients in this trial, and this is a good point, that these were not just adenocarcinoma patients, which really was the ECOG-4599 histology-restricted setting — DR LOVE: For bev. DR LEVY: The bev. This was looking at patients both with adeno and squam. And speaking of bev, it also included patients who had been treated with bevacizumab this trial, the REVEL trial. Interestingly enough, patients who had gotten bev, they still derive — as first line — had still derived a meaningful benefit with the ramucirumab to docetaxel compared to docetaxel alone. I think that’s important messaging from this trial is that yes, it included squamous cell patients, and yes, it included patients who had been previously treated — some of them — with bevacizumab in combination with taxane and carboplatin. Side effects and tolerability of ramucirumab and bevacizumab DR LOVE: Ray, I’m sure you have a lot of experience with ramucirumab in gastric cancer. It’s been out there for a while. Pretty standard, usually with paclitaxel or with ramucirumab in that setting. It kind of sounds a lot like bev. Is that your experience quality of life wise? DR LOBINS: Yes. DR LOVE: No issues? It’s really hypertension, proteinuria, et cetera? DR LOBINS: As far as the RAINBOW data with paclitaxel, that is my experience, although hypertension — and I never ever had to stop either bev or ram for proteinuria. It’s the blood clot issue that I worry about the most, because that hypertension’s treatable for most people, and it’s not a reason to stop the medication. But if they have a vascular event, then it kind of stops everything in its tracks. DR LOVE: Again, there was so much excitement about checkpoint inhibitors in targeted therapy we kind of forget all the stuff that we talked about 5 years ago. But obviously we talked a lot about it. But I know there was always a lot of debate, and I think it has maybe more in the colon literature, but about this issue of bev and thrombotic events. What’s your bottom line? I mean, here this lady got bev already, and she did fine on it. I don’t know also, Ben, whether people who have long responses on bev do better on ramucirumab. You have this whole issue of continuing bev on progression that you see in colon cancer. But I’m just kind of curious in general about some of these issues related to ramucirumab, Ben. DR LEVY: I haven’t seen this, and I don’t know if it’s really mirrored in the data in terms of (1) patients who have had a long trial or a long exposure of bev, do they do better with ram? And I don’t know if that data was broken out in the REVEL. And in terms of toxicity, I will say, I have seen more bleeding and clotting with bevacizumab than I have with ramucirumab. That may be more just due to the fact that I’ve just treated a lot of patients with bevacizumab prior to the advent of checkpoint inhibitors from the 189 data. I used a lot of bev in combination with carboplatin/pemetrexed. It may be more mirroring my experience and disproportionally using bevacizumab more than I have with ramucirumab. But I haven’t seen the clotting and the bleeding that I saw with bev. DR LOVE: I don’t even know, is that reported with ramucirumab, or it’s just kind of an inference because it’s kind of like that? DR LEVY: It’s an inference. DR LOBINS: It’s an inference. DR LOVE: Yes. It’s really more indirect evidence. Case: A man in his early 50s, a current smoker, with metastatic lung adenocarcinoma and a BRAF non-V600E tumor mutation receives first-line carboplatin/pemetrexed/pembrolizumab DR LOVE: Alright, let’s go on to your next patient, the 50-year-old man. DR LOBINS: This is a very interesting gentleman. Very nice guy, and I met him in the ICU. He was recently diagnosed with a lung cancer, and he’s actually supposed to see one of my partners the following week. And I just happened to be on call. And he’s in the ICU because he had an arterial bleed from the cancer into his lungs. DR LOVE: Arterial? DR LOBINS: Arterial bleed. DR LOVE: Wow! DR LOBINS: Yes. And so they went in, they embolized it and so he stopped bleeding. And then we staged him, and unfortunately he has Stage IV disease, not only the large mass in this left lower lobe and in the hilum and the mediastinum, but he had bone disease, specifically a very large lesion in his left sacrum. And that was biopsied and proven to be lung cancer as well. DR LOVE: Before you go on, and I see here he had an adenocarcinoma. Was he a smoker, incidentally, or is he a smoker? DR LOBINS: Oh yes, he’s still a smoker. He’s trying to quit. DR LOVE: Current smoker. Okay. Hemoptysis as a presenting symptom of lung cancer DR LOVE: He’s kind of in construction. He’s working. And then, like, what happened clinically to him? How did he end up in the ICU? What happened? DR LOBINS: He started coughing up a lot of blood. DR LOVE: He was coughing — hemoptysizing. Wow! DR LOBINS: Yes. He had arterial bleed into his lungs. DR LOVE: So he starts hemoptysizing, they come in and they see he’s got a big lesion in his lung. DR LOBINS: They knew he had the lesion. He was scheduled to see my partner the following week. But in that time period, he started coughing up all this blood. He ended up in the ICU. DR LOVE: He had a biopsy already? DR LOBINS: Yes. They already knew it was lung cancer. DR LOVE: It seems like a pretty unusual scenario. I don’t know, Ben, have you seen people present like this with arterial bleeds? DR LEVY: No. Generally not. I mean, I’ve heard of this before. I mean, I’ve seen patients come in with hemoptysis and really bad hemoptysis, which is just evidence that the tumor’s eroding into some of the vasculature in the veins in the lung. But I haven’t seen having a presentation of an arterial bleed from a lung cancer. DR LOVE: What made you think that it was arterial? DR LOBINS: They told me it was. The people who embolized it. DR LOVE: Is it possible that somehow it was related to the biopsy? DR LOBINS: I don’t think so. I had radiation oncology also see him the same time I was, to be quite honest. We went in right after each other. And they think it was arterial as well. He didn’t get radiation to the mediastinum. It wasn’t, like, a venous thing where you radiate it. It was an arterial thing and you embolized it, stopped the bleeding. He spent the night over — he was able to get out of the hospital in, like, 2 or 3 days after they made sure his hemoglobin was stable and he wasn’t bleeding any more. DR LOVE: Hmm. That sounds kind of tricky. So what did his workup show? I guess at this point — how long ago did this actually happen? When did you see him the first time? DR LOBINS: January of 2019. DR LOVE: And what did his workup show in terms of PD-L1 and NGS, et cetera? DR LOBINS: He is PD-L1-negative or low, and he didn’t have any actionable mutations. We had to do that to get his treatment started, actually. DR LEVY: And he’s the one that had the BRAF non-V600E. DR LOBINS: That’s right. A BRAF mutation, but it’s 460 something. It’s not the V600E. Clinical care of patients with metastatic NSCLC and no identified targetable tumor mutations DR LOVE: You started him on carbo/pem and pembrolizumab. And what happened? DR LOBINS: Yes. Oh, he’s done extremely well in clinic. He’s finished his first 4, and his symptoms — he had a lot of pain in his hip, and it got radiated. And his other symptoms have since almost gone away. He’s going fishing this week, so he wanted a delay in his next round of treatment for an extra week. But then his house flooded, so he’s not going fishing. He’s going to clean up his house. But otherwise, he’s doing extremely well. His breathing’s better. He’s not had any more bleeding. His tumor has responded, although still there. It was quite large at the onset. DR LOVE: And you said he’s continuing to smoke also? DR LOBINS: He’s trying to quit. DR LOVE: Oh, he’s trying to quit. Ben, any comments about this case? DR LEVY: Yes, a couple of things. One is, as we’ve — extraordinary to have such complexity with these cases now. This guy has a PD-L1 that we’re not sure. His BRAF mutation is there. It can fool physicians to think, “Oh, a BRAF mutation. It’s time for targeted therapy.” But I think the important lesson here is that this is not a V600E mutation. And if you have a BRAF non-V600E mutation, which is a chunk of them, you’re not going to respond to targeted therapy with dabrafenib and trametinib. And the other issue that we talked about — he’s got a lot of bony disease. And the utility of a bone-strengthening agent like zoledronic acid or denosumab, we get so excited about the chemotherapy and the immunotherapy, this new regimen that’s fairly new and is working so well, but a reminder that patients that have bony disease, there’s still a role for bone-strengthening agents like zoledronic acid or denosumab to delay skeletal-related events and potentially improve survival. DR LOVE: How would you approach him, Ben, if he were to have disease progression? DR LEVY: I’m fortunate enough to be at a place where we do have clinical trials, and we do have a lot of trials in this space. The trial that most of our patients are going on with who progress on carbo/pem/pembrolizumab is an epigenetic trial. It’s azacitidine and entinostat with nivolumab. But outside of the clinical trial, we are in the data-free zone, and Ray and I talked a lot about this today. Even docetaxel/ramucirumab is not — no one in that trial, in the REVEL trial, had received chemotherapy with immunotherapy. We tend to extrapolate, so I’d say off of a trial, generally it’s docetaxel and ramucirumab or docetaxel alone. Other options include gemcitabine. We talked a little bit about vinorelbine as well. But this was a conversation that Ray and I again had between patients, as we’ve moved all these drugs up front — the pemetrexed, the pembrolizumab, up front. It’s leaving some gaps second line, and I would say again, off of a trial, we would probably do docetaxel with or without ramucirumab. Novel agents and approaches under investigation for lung cancer DR LOVE: I mentioned the fact that so much of the work in immunotherapy has been done at Hopkins. I don’t know if I told you, I actually went to Hopkins. I’m from Baltimore. I’m proud of what you all have been doing in these last few years. But I’m also curious where — you mention one clinical trial strategy. It’s interesting in terms of the use of hypomethylating agents. Any other new approaches, particularly people who maybe had a long response and then they start to break through and you kind of feel like — I remember when Chuck Drake was there. He was talking about other checkpoints like TIM3 and LAG3. Anything there this exciting? DR LEVY: Still in play. Yes. I think TIM3 and LAG3 are targets that we’re exploiting in the refractory setting. We have some drugs there as well. The epigenetic strategy is yet another one. We have a very large trial called HUDSON that’s looking at certain biomarkers upon resistance and then partnering off those biomarkers with certain targeted therapies, so a big umbrella trial as these begin to unfold. Patients who progress on 189 get a biopsy. Depending on the particular mutation they have or mechanism of resistance they have, they go on certain targeted therapies in combination with other checkpoint inhibitors. And that’s a very large effort globally. But I think the TIM3 and LAG3 story — Hopkins has led the way here. As Ray and I were talking about, as excited as we are about these trials, they take a lot of work, and they don’t always work. And we’re still trying to iron out the appropriate patients and iron out the appropriate biomarkers that would allow us to know which trial patients should go on. DR LOVE: Just to probe you out a little bit more about this trial, kind of like a basket trial looking for mutations. This is specifically in people who’ve gotten checkpoint inhibitors? DR LEVY: Yes. DR LOVE: So are you looking at mechanisms of resistance to checkpoint inhibitors? DR LEVY: Correct — novel mechanisms of resistance to checkpoint inhibitors and certain mutations as well. STK11 mutation is one of the arms of the trial. KRAS mutations in combination with other mutations is yet another. Most of these therapies are built on preclinical work and not necessarily clinical data, and they substitute out based on whether the drug is working or not within that particular arm — an adaptive design. And I think we really have a nascent understanding of resistance to immunotherapy. Whether these arms will pan out or not, based on the mechanism that’s being looked at, is a little unclear. DR LOVE: But it’s interesting, you’re talking about resistance to immune therapy. The kind of targeting is not the kind typically seen with lung. DR LEVY: Correct. When we think about targeted therapy, we think about genotype-directed therapies. This is not that. This is very different than any targeted agent that we have thought of before, such as ALK-directed therapy or EGFR-directed therapies. Mechanisms of resistance to immunotherapy DR LOVE: I’m just kind of curious, though, for your fellows, at a more basic level, Ben, at this point do you have any kind of intuitive concept in your own mind about what’s going on when people develop resistance to immunotherapy? DR LEVY: I think that this is one of the more common questions we get, and Ray and I talked a little bit a about this: What really is going on? And my sense is, from a very basic level, that for patients — and you have to look at progression or resistance as very heterogeneous. And I think one of the things that happens with these patients is that these tumors go cold and that they were initially recognized by the immune system and they develop adaptive mechanisms that allow them to be unrecognized. And I think there’s a lot of work going in to trying to understand (A) how these tumors go cold, but (B) how to turn the neon flashing light back on. And there are so many different ways, I think, to do that. And this is how I explain to patients and fellows. I mean, one of the major ways I think that tumors evade the immune recognition is by going cold, by going dark, by essentially recloaking themselves. And how do we figure out how to reverse that and again to turn on the flashing sign and make those tumors hot so that the immune system can recognize it again I think is one of the big strategies going on. There’s a lot of ways to do that. DR LOVE: And certainly one classic way, classic being, like, again, the last few years that you hear about, is anti-CTLA-4, and there’s a fair amount of research looking at that strategy in combination with PD-1 or PD-L1 in lung cancer. Does that look like in any way that’s going to pan out? DR LEVY: I don’t think so. I don’t know if we’re going to get to a place where dual checkpoint blockade after single-agent immunotherapy is going to lead to any meaningful responses in patients, although anecdotally I can tell you we’ve seen them. Is there a way to combine dual checkpoint blockade, or do CTLA-4 and PD-1 drug as way to reinitiate or rejump-start the immune system in patients who’ve already received a checkpoint inhibitor single agent? We’ll have data coming out. I am not confident that that will be the strategy at play. Monitoring for immune-related adverse events in patients receiving immune checkpoint inhibitors DR LOVE: One other question about this man I could ask about any of these patients, but I’m just kind of curious, Ray, you said he’s doing well, no autoimmune toxicity at this point. How do you typically follow these patients? For example, how often do you draw thyroid function? What’s your routine follow-up, Ray, for patients on checkpoint inhibitors, particularly checkpoint plus chemo? DR LOBINS: I follow the TSH for after the first dose they have it, the week after I see them, and make sure they did okay. And if they’re doing okay, I usually don’t do it every time. I usually do it about every other time — about every 6 weeks I’ll check a TSH on these people. And we catch a lot of hypothyroidism. And then if they have other things that make me worry, like Ben and I talked about one patient who has hypothyroidism, and then under review of system said, “Oh, I have a lot of frequent urination,” to me I worry about did they have high blood sugar as well? And all of a sudden, do they have a pituitary thing? And so I don’t check all those other markers on a regular basis. If they have symptomatology, I’ll kind of go there. And then in the visit I always ask about autoimmune things: Do you have a rash? Do you have any diarrhea? And those kind of issues. DR LOVE: Anything you want to add to that, Ben? DR LEVY: No, I think that’s right. I think a TSH and a T4 is important to monitor. Even 25% to 30% of patients on immunotherapy will develop some sort of thyroid derangement. But outside of that, I think just a low threshold, based on symptomatology, to work up these other autoimmune phenomenon that may occur. Case: A woman in her mid-50s with large cell neuroendocrine carcinoma of the lung and a solitary metastasis in the brain DR LOVE: Let’s go on and hear about your 54-year-old lady, Ray. DR LOBINS: All right. This is a very interesting lady as well. And so she has an atrial septal defect, and she went to get this repaired by the thoracic surgeon. And during the surgery, they noticed, “Oh, she has all these positive or big lymph nodes,” and they biopsied these lymph nodes when they did the surgery, and lo and behold, they came out to be lung cancer. And so she had her workup done, and her workup included an MRI of the head, and she had one 4-mm lesion in her brain. DR LOVE: Can you talk a little bit about this histology? DR LOBINS: She’s a large cell neural endocrine tumor. And so initially, when I saw her, I’m not — wasn’t sure if this was small cell or not, or is this a large cell with neural endocrine features, what it turned out to be. But she had Stage IIIA disease, other than the 4-mm lesion in her brain. And so we presented her at our tumor board. And what I try to push is to do stereotactic to the 4-mm lesion in the brain and treat her as a IIIA lung cancer, a la the PACIFIC data. And so that’s what we did. Now, she did get a second opinion when we were just beginning treatment at Washington University. And Washington University, their opinion was to treat her as a Stage IV tumor. And so we talked, and I gave her my opinion and went over what their opinion was, and she decided to get treated as a IIIA, and that’s what she’s doing right now. DR LOVE: And where exactly is she in her treatment? DR LOBINS: She’s on durvalumab right now, and she’s had about 7 or 8 treatments with durvalumab. DR LOVE: Again, any toxicity from the durvalumab? DR LOBINS: Oh, yes. She developed hypothyroidism, and we have to put her on levothyroxine. She also developed this achiness in her joints. It was causing lots and lots and lots of discomfort. I put her on a steroid taper, and that made her achiness go away. She’s currently today on 10 mg of prednisone, and I’ll move her to 5 mg for a week, and then she’ll be off the steroids. Perspective on the management of oligometastatic disease DR LOVE: Wow, a lot to talk about here! And I guess we should start out with the obvious, Ben. And this comes up in a lot of scenarios where people have minimal metastatic disease, oligometastatic disease. And here you have the question of obviously using really a curative therapy in design, and I guess it would be a noncurative situation. Any thoughts about the strategy here, Ben? DR LEVY: Oh, I think the strategy and paradigm is evolving rapidly based on some of the newer data we have and some of the outcomes that we’ve seen with aggressive management of oligometastatic disease, and that’s what this patient essentially has. She has IIIA lung cancer and 1 little spot in the brain. And if it’s a fit patient and is motivated and understands that while we’re going for cure, we may not get there. I think we have evidence to try to address each site aggressively and treat what’s left over at that stage. And we’re learning more and more about this. I mean, we have the data, the SABR-COMET data that’s just been published. We had other pieces of literature to support aggressive management of oligometastatic disease. I’m in favor of this for the right patient. For a patient who has 1 or 2 sites of disease, I would favor trying to do radiation or surgery to those areas and then treat what’s left over aggressively. So I was in line with — this is a fairly fit, very energetic patient and wants to be aggressive. And, interestingly, she tends to be the one patient that sticks out in my mind — really wants to get to the next stage in life. Says, “I want to get to October,” but then, “I want to keep living.” And so I think this was the right call. I mean, there’s very little right and wrong in medicine these days. But given just 1 site in the brain and the rest left over in the lung, I’m in favor of radiating the brain and then doing chemoradiation for the lung. DR LOVE: It’s funny, when you said that the patient went for another opinion to WashU, the first thing that came to my mind is they probably said not to do it. But anyhow, you have another academic who said they would do it. Therapeutic options for patients with metastatic large cell neuroendocrine carcinoma of the lung DR LOVE: What about this histology though, Ben? If this patient had clear-cut metastatic disease, how would you approach it? Would you approach it as a small cell strategy? DR LEVY: Yes. This is a large cell neuroendocrine. It’s a tough one, because it’s on a spectrum. Neuroendocrine tumors of the lung are on a spectrum of a typical carcinoid, atypical carcinoid, large cell and then small cell based on how aggressive it is. We’re getting up there to the small cell area. Large cell neuroendocrine tumors, there’s a lot of controversy: Should you treat this as a small cell, or should you treat this is a non-small cell? And I would look at some of the other features of the tumor, potentially just how hot it’s stained for or hard it’s stained for synaptophysin and chromogranin and then look at the Ki-67 — none of this is rooted in any data. This is again where medicine becomes an art and science. If it looked like it was high Ki-67, I would tend to favor treating it as a small cell, but many of these can be treated as non-small cell. In fact, I think the WashU physician recommended the KEYNOTE 189 regimen. Many of us treat these large cell neuroendocrine tumors as a non-small cell. I don’t think we have a lot of great data on this, and a lot would depend on some of the features of the tumor that would guide me towards a small cell regimen versus a non-small cell regimen. DR LOVE: When you say non-small cell regimen though, are you talking about nonsquamous regimen or squamous regimen? DR LEVY: Yes. I would talk about a nonsquamous. That’s a good point. In my mind, if we were not going to aggressively manage the brain and treat this as Stage IV, I would be debating between platinum/etoposide as a small cell regimen or carboplatin/pemetrexed/pembrolizumab as a nonsquamous non-small cell regimen, based on very little literature. DR LOVE: But in terms of the small cell, or if you go the small cell route, would that not include atezolizumab? DR LEVY: Or atezo. Yes. Exactly. So if this were small cell, based on the more recent IMpower data, yes, I would add the atezo to the platinum/etoposide. DR LOBINS: I’m not sure IMpower130 was published when I saw this patient. DR LOVE: Interesting. I mean, in a way all roads lead to checkpoint inhibitors anyhow, right? DR LEVY: Exactly. DR LOBINS: Yes. DR LOVE: Durvalumab, atezolizumab, pembro. In lung cancer — I always bring this up. When we talk about other cancers, when you really think about it, every part of lung cancer right now is chemo/checkpoint inhibitor, including small cell. DR LEVY: Yes. DR LOVE: It’s really amazing. DR LOBINS: And that’s actually how I counseled this patient is, I said, WashU’s recommendation and my recommendation were not really that dissimilar. They were dissimilar only in the sequence of the chemotherapy versus — in the immune therapy, not so much in the — if you’re going to get them or not. And then, obviously, I said, “I’m going to try to cure you. And they said they’re going to try to palliate you.” Management of metastatic small cell lung cancer in the second-line setting DR LOVE: I’ve got to ask, as long as we brought up small cell. I keep thinking about the survey we just did of pulmonary investigators. Of course, a lot of patients right now are getting atezolizumab/chemo up front, but we asked the question in the survey for a patient who didn’t. So a patient starts out and just gets chemo. What’s second line? And the results were kind of interesting. We saw a lot of ipi/nivo second-line small cell. Is that your approach right now, Ben? DR LEVY: Yes. I think for patients who have — I mean, there’s atezo with carboplatin/etoposide, is relatively new for those that have not received immunotherapy in combination with platinum/etoposide. Second line for me would be probably nivo and ipi. I’m not a fan of topotecan. That is the only FDA drug we have approved second line for small cell. We have data that nivolumab is no better than topotecan second line for small cell. To me, and I think we need to do more, it would have to be probably nivo/ipi for these patients. DR LOVE: Although I wasn’t clear exactly how strong the ipi/nivo data really are in second-line small cell. DR LEVY: It’s not. Yes. I mean, you look at the data. There’s no randomization here. It’s been a Phase I/II experience and basically showed that the responses were modest. They were higher in high TMB patients. We don’t normally test our patients with small cell for TMB, but the responses were modest. The PFS was modest. We think that that combination is a little bit better than single-agent nivolumab. DR LOVE: I’m curious, Ray, whether you used ipi/nivo second line in small cell? DR LOBINS: All the time. I have a number of people on it now. I don’t use topotecan. I use irinotecan as my second line. But I debate on using irinotecan and ipi/nivo or ipi/nivo with irinotecan. But I have a number of people on ipi/nivo right now. DR LOVE: In terms of the lung cancer patient — you probably have a bunch of people with melanoma and other — with this regimen, but how do lung cancer patients do on ipi/nivo? DR LOBINS: I have them doing extremely well. DR LOVE: What’s your experience been, Ben? I was wondering too, also — not to get too far off on a tangent, but been curious, and I like to ask people what they do if you have a small cell that’s got a paraneoplastic syndrome, either, let’s say, neuropathy, SIADH? To what extent does that deter you? DR LEVY: First of all, my experience with nivo/ipi has been mixed. I think that we have struggled some with the toxicities — rash and diarrhea, some derangements in LFTs we’ve seen. I’ve had a little bit more of a mixed experience with my patients on nivo/ipi. The patient with small cell with a paraneoplastic syndrome, I try to treat the underlying cause as best I can. And if that happens to mean that I have to give dual checkpoint inhibitor blockade to try to treat the underlying cause, so be it. I mean, I can’t think off the top of my head of any patient I’ve had with a paraneoplastic syndrome where I’m considering dual checkpoint blockade. But the paraneoplastic syndrome is probably not going to go away until you treat the cancer. You’ve just got to keep your eye on how best to treat the small cell, which is again a very unforgiving disease that — we would have thought that this would be a tumor type that would be exceptionally responsive to immunotherapy, and it really hasn’t panned out the way the non-small cell data has. Challenging disease. Case: A man in his early 80s with severe pulmonary fibrosis is diagnosed with metastatic NSCLC DR LOVE: And we’ve had a lot of young patients here, but now I see you have an 80-year-old man. How about him? DR LOBINS: He’s very interesting as well. He is a patient who has severe pulmonary fibrosis. And he is on 5 or 6 liters of oxygen at all times well before we even met him. And he developed this mass in the right upper lobe of his lung, and he was given a wedge resection/biopsy to — the biopsy itself was over 8 centimeters in size. DR LOVE: Wow! DR LOBINS: And it was a Grade 1 adenocarcinoma. We presented him at tumor board, because I really thought this was going to be adenocarcinoma in situ because of how his scans looked and how he presented. And so he was not a surgical candidate after this biopsy. The surgeon said, “No, I can’t get to it.” And he’s not a radiation oncology candidate, because you couldn’t wipe out any more of his lung and keep him alive. But he actually looks pretty good when you talk to him, other than he has a lot of oxygen going. And so I actually called Dr Govindan at Washington University and I said, “I’m worried about this guy because of his comorbidities and his cancer. What would you give to somebody like this?” Because could he even handle chemotherapy? And Dr Govindan said, “I would be giving him everything, because you’re not going to get a second shot with this guy.” And so I put him on KEYNOTE-189 and he did pretty darn well. And then he went off into maintenance with pemetrexed and pembrolizumab. He was on maintenance for about 6 months, and then he started developing some paresthesias, so we stopped the pemetrexed and he continued on pembrolizumab until March, and then he had progressive disease. And he’s a challenge on his scans because of his pulmonary fibrosis. How much of this progression is pulmonary fibrosis, and how much of it is true lung cancer? And it was a number of conversations with the radiologist saying, “Is this progression, or is this fibrosis?” And finally we said it was progression, and we put him on docetaxel. And he’s been on 3 cycles of docetaxel. And he came in for scans today. DR LOVE: And again, the issue of ramucirumab comes up. DR LOBINS: I did not give him ramucirumab. DR LOVE: Any particular reason, or…? DR LOBINS: I should have. DR LOVE: Because he was 80, or what? DR LOBINS: He’s 80. He’s at high risk for complications. He had a pulmonary emboli found on one of his scans. And so I didn’t want to aggravate any risk for him at all. I was actually quite nervous about giving him the docetaxel in and of itself with his age, his comorbidities and his history. He’s interesting, because he’s on apixaban and loves grapefruit juice and I’m saying, “Don’t take any grapefruit juice, please.” And actually, that’s what he said today is, he misses his grapefruit juice. DR LOVE: Actually, you actually counsel your patients. You ask them whether they drink grapefruit juice? DR LOBINS: Of course! It affects CYP3A4, and I can’t screw up his apixaban. DR LOVE: That’s interesting. Challenges in the management of pulmonary fibrosis in elderly patients with lung cancer DR LOVE: Again, Ben, any comments about this patient? What was the presumed ideology of the fibrosis? Smoking, or what was it? DR LOBINS: I don’t know. He had the fibrosis ever since I met him. DR LOVE: But, I mean, he’s had it all his life? Or how long has he had that? DR LOBINS: He’s had it for as long as I’ve known him, and I’ve known him for over a year now. He actually goes to Washington University for the fibrosis. DR LOVE: Huh! I see. DR LOBINS: And they’re trying to figure out what to do. But his fibrosis is, he’s more worried about his fibrosis than his cancer. DR LOVE: Hmm. Ben, any thoughts about this case? DR LEVY: Yes. A challenging case. This is a patient that is, in my mind, an ECOG performance status 2 but that wide spread of 2. Where are they on the 2? Are they 2 heading to 1 or 2 heading to 3? And he’s on the latter, I think. DR LOBINS: Yes. DR LEVY: He’s in a wheelchair. He’s on oxygen. And he has this challenge — if there’s anything more unforgiving that lung cancer, it may be IPF, or idiopathic pulmonary fibrosis. I mean, he’s got some challenges there. And we talked again whether or not to add the ramucirumab to docetaxel in this setting. He’s 80. He’s PS2. This may be a patient that I don’t do it on, although maybe he could tolerate it. He has a prior pulmonary embolism. No — I think this case highlights some of the challenges second line again. We give these patients the 189 regimen of carboplatin/pemetrexed/pembrolizumab and is reasonably well tolerated, but then upon progression we’re kind of stuck with what to do. Do we do doce? Do we do doce with ram? Can we give this in a meaningful way? This patient did have some fatigue as well from the docetaxel. And the question is, would you give him a holiday break? His scans seem to show that things are kind of stable, if not responding. These are the real-world challenges for these patients that perhaps aren’t captured in everyday clinical trial data. DR LOVE: Ray, anything else you want to say about this case? I see he had a BRAF mutation. DR LOBINS: He’s another one that has BRAF 400-something mutation, yes. DR LOVE: Anything else about this case, Ray? Any questions about this case? DR LOBINS: No. We talked to him a long time. We showed him his scans, and I show everybody their scans when I do restaging, because I think it helps the patient actually understand where they’re at. And it’s easier for them to follow your recommendations if they actually can see their pictures. And his pictures look a little bit better. And his biggest problem is, besides his lungs, is that his legs are just so weak. And so we have a long discussion between is the docetaxel causing the increased fatigue versus the benefit from it versus what to do next. Biologic rationale for and emerging data with immune checkpoint inhibitors in combination with anti-angiogenic agents DR LOBINS: There is a SWOG study — it’s called SWOG-1800 — that looks at people who had checkpoint inhibitors and you can add ramucirumab, if they’ve not had it, to the pembrolizumab. It just came to our clinic yesterday, to be quite honest. And so he would be a person — because I did not give him ramucirumab — that I could give him ramucirumab and pembrolizumab if he progresses. Because he would qualify for that trial if they’ll let him for his performance status. DR LOVE: Wow, that’s really interesting. Ben, any comments about the issue of anti-angiogenics plus checkpoint inhibitors? Obviously we’re seeing trials now with atezolizumab and bevacizumab. But this has been a story that’s kind of weaving its way through oncology. Renal cell cancer, you now have exciting data with axitinib plus pembro. DR LOVE: Again, any comments about the biology of how an anti-angiogenic might help a checkpoint inhibitor? DR LEVY: Yes. I think that VEGF may play a role in immunosuppression. And if by giving an anti-angiogenesis drug with a checkpoint inhibitor you may have synergy, I think we’re learning some data in the front line. There’s ongoing work looking at a checkpoint inhibitor just with an anti-angiogenesis drug like ramucirumab in combination with pembro. And then probably the most important data we have in combination with an anti-angiogenesis drug with a checkpoint inhibitor is the IMpower150 data looking at carboplatin/paclitaxel/bevacizumab/atezolizumab and showing that there may be potential synergy with anti-angiogenesis therapies with checkpoint inhibitors in specific genotypes. I think, as you said quite nicely, the story is still being woven here and we’re still trying to learn about who those patients are, who the right patient is to give this to and what the real synergy is. DR LOVE: It seem like an awful lot of things are being combined with checkpoint inhibitors in addition to other checkpoint inhibitors in immune therapy. You hear about PARP inhibitors and all kinds of novel agents. Any in particular that has you excited, Ben? DR LEVY: I think that the ones that we talked about earlier, potentially augmenting these immunotherapy drugs with other immunotherapy modulators, whether it be a TIM3 or LAG3 agent, I think that’s where, really, we think that the combinations that are rooted in scientific rationale may be. But I think we're just all over the place. I think we don’t really know. It’s hard for me to put my finger on 1 combination approach with immunotherapy, specifically in patients who’ve received the KEYNOTE-189 regimen, that will be the winner. Benefits and challenges of integrating early palliative care into the management of metastatic lung cancer DR LOVE: Before you go on to the next patient, I want to just bring up another issue that popped into my mind when I heard about this 80-year-old man, but I think I could have brought it up with all these patients, and that is the issue that really came out, particularly in lung cancer, the issue of early palliative care. Jennifer Temel and others have looked into this strategy. I want to ask both of you about it. Ray, starting with you, what did you think about those data, and do you refer patients earlier to palliative care? DR LOBINS: This is the 169 people with metastatic lung cancer that did better. Had actually a longer survival when palliative care was initiated. And the problem in the community in my opinion is, palliative care means different things to different places. And so palliative care in an academic center is — my understanding is another group of people that help with symptomology of the patient. Basically, another hand to help them make sure the patient’s doing okay. Unfortunately, because of, I think, financial constraints and it not being paid for in a community, palliative care a lot of times is this prehospice. And so if you get the right palliative care, it’s good. And the second thing, because it’s not reimbursed, finding palliative care at home is almost impossible. It’s really home health versus hospice. DR LOVE: Ben, I’m just kind of curious how Hopkins has integrated that concept into the care of lung cancer. DR LEVY: Ray mentions a lot of the challenges. I think the messaging has to be consistent. And we’re fortunate to have wonderful palliative care teams. I try to use the word supportive care to my patients, even though it is palliative care. And that will help them be a part of the team. But we do have a team, and that helps. We have a team that works on symptomatology, goals of care, all of those things together. And so every patient who walks through the door we try to get to see what I call a supportive care specialist, and I think that we have that discussion with them as well about the goals of care up front. But I think this is an important message. The Temel data, again, as you mentioned, from MGH, showing patients who got this had less aggressive care towards the end of life, had better quality of care. But as we’ve all said, better survival as well. Case: A man in his late 60s with metastatic NSCLC with KRAS and p53 tumor mutations experiences disease progression on multiple lines of therapy DR LOVE: Let’s move on and talk about your next patient, the 68-year-old man. DR LOBINS: This is a very nice guy who a number of years ago had a Stage I lung cancer that was cut out. He was on observation, and then he had a recurrence. And his recurrence was in the mediastinum, and it was biopsied and it was the same cancer. And so I talked to the thoracic surgeon, and it was a Stage IIIa, and it was borderline resectability, but he was healthy. And I said, “What do you want me to do?” And he said, “Give neoadjuvant chemoradiation and let’s see where we’re at.” And so we gave neoadjuvant chemoradiation. And where we stopped for the neoadjuvant dosing on radiation, we rescanned him and he had a complete response. And so the surgeon looked at him and said, “There’s nothing for me to cut out.” And so we finished up his chemoradiation. And then because he was IIIa, I put him on durvalumab. He was on durvalumab for, oh, about 6 months or so — can’t remember the exact time he was on durvalumab — but then he developed a left kidney mass. And the left kidney mass was biopsied, and it was his lung cancer. And so we took him off the durvalumab. We put him on docetaxel. And he was on docetaxel until he progressed. And then we put him on gemcitabine. DR LOVE: It looks like he actually got ramucirumab/docetaxel. DR LOBINS: Yes, he did get ramucirumab/docetaxel. That is correct. And then he progressed on that. And then we put him on gemcitabine. And he comes in today for CT scans after his first 2 cycles of gemcitabine. Therapeutic approach for patients with metastatic NSCLC in the late-line setting DR LOVE: And so can you talk a little bit, Ben, about what you saw when you came in the room with this man? DR LEVY: Yes. I think that this is a challenging case, because he’s gotten several cycles, or 2 to 3 cycles of gemcitabine — his scans showed somewhat of a mixed response. And this is challenge. I mean, there’s a little more fluid in his right lung. There’s a new spot. But everything else is kind of stable. So he’s got a new lesion. Everything else — all of his other cancer, including his left kidney, is stable. But he feels okay but not great. And this is where again, what do you do with a patient who’s now on fourth-line treatment whose scan shows potential progression where he’s kind of on the border of how he feels? And again, Ray and I talked about how difficult these decisions are. We live in the data-free world or the data-free zone at this point of what to do in these patients. Do you maybe drain the fluid and continue him on the gemcitabine? Or is this the time where you have to institute a therapeutic switch because if you don’t, 4 weeks or 6 or 8 weeks from now it may even been worse and he’s feeling lousier. I think this one of the harder cases that we went over, and a difficult one with the patient and a very loving wife trying to explain to him what we think is going on biologically with the cancer and whether or not Ray wanted to make a change in his therapy or not. We come into these problems all the time. And it tells you how challenging scans can be, coupled with patient symptoms, about what we should do at this point in time 4 lines down. DR LOVE: If you were going to use another systemic therapy, Ben, what would it be? DR LEVY: I don’t want to give a spoiler alert, but we had the conversation. Ray had turned to me and said, “What would you do here?” And I said, “You can either continue the gemcitabine. You could switch him to vinorelbine, which isn’t the easiest drug to give.” And then Ray said, “What about nivo/ipi?” We didn’t talk about his mutational analysis, but as I recall had a KRAS/p53. DR LOBINS: That’s correct. DR LEVY: And this is a mutational composite that we think there’s been some recent data, not ironed out entirely, that coalterations in KRAS and p53 may be predictive of immunotherapeutic approaches. Now, this patient didn’t do well with single-agent immunotherapy. His tumor has defined itself as perhaps immunotherapy resistant. But we are now several lines down the therapy. Is this an opportunity to give him something else, like a dual checkpoint blockade? And so, I mean, Ray can talk to you about the decision, but I think that’s also a possibility for this patient. And again, based on very little data. But based also on the fact that he doesn’t have many options left. DR LOVE: Do you have a PD-L1 or TMB analysis on him? DR LOBINS: I don’t have a TMB. He’s PD-L1-negative. Yes, his PD-L1 is zero. DR LOVE: Would a TMB be of any value, Ben? DR LEVY: I think TMB, this line of 10 mutations per megabase, that may sway me to if I had a TMB that was higher than 10. I don’t routinely use TMB in my patients. We test it in everyone at Hopkins, just based on how much immunotherapy trials we’re doing. But yes, at this point it may sway me. But I would say that if it were less than 10 mutations per megabase, I don’t know what more options — and he’s relatively fit for a guy who has seen just about every single therapy that’s known to work in lung cancer. And if you were going to make a switch, maybe this is the right time, independent of TMB. DR LOVE: It’s really interesting. I think it supports the whole idea of how much you get out of actually seeing a patient. Because I think if somebody were to look at this write-up or even listen to what you were saying, they’d be going, “What about hospice?” DR LEVY: Yes. DR LOVE: But there must be something about the patient that’s telling you no. DR LEVY: Oh, yes. And, I mean I would just say that for — it is. It is incredible. If I saw this on a piece of paper, I would be like, “What is this doc thinking?” But this patient’s motivated and fit. And the wife is supportive. And we are in the land of no data here, but I think that given the advent of all these newer therapies — and look, I’m the first to say, “Look, enough is enough. You’re not going to derive any meaningful benefit.” But for fit motivated patients who relatively still have a good quality of life, I think that our options need to be explored. Not for everybody. I mean, we can’t talk about cost here, because that’s another issue. But for this type of patient, I would have no hesitation. Case: A woman in her early 20s initially diagnosed with unresectable Stage III NSCLC with mutations in ROS1 and p53 develops metastatic disease DR LOVE: We’ll finish out with the last patient, but wow…22 years old? What’s the story there? DR LOBINS: So she is a student. And she noticed a cough. And they did a chest x-ray and they thought, “Oh, yes. You may have TB.” So they put her on TB medications. But finally they did a biopsy, and the biopsy came back lung cancer, adenocarcinoma. She’s a nonsmoker. And when her staging came about, she was a Stage IIIa. So you couldn’t surgically remove it. DR LOVE: But also, she’s ROS1? DR LOBINS: Her mutational analysis did turn out to be a ROS1. I think she has a p53 as well. And so even though she was a ROS1, she was a Stage IIIa unresectable. And so we treated her with chemoradiation. And because she was a ROS1 and I worry about immune therapies in people who have driver mutations, I gave her, after the chemotherapy and radiation, which was 2 cycles of chemotherapy, I gave her 2 more cycles of the cis/pemetrexed, because I wanted to get as much of the chemotherapy as I could. And then I talked to you guys regarding, should I give this lady durvalumab or not? And so we decided to give her durvalumab, and her liver function tests went nuts. Her bilirubin went to about 15.6. And she looked really, really, really sick. We put her in the hospital, and we found out that she had a reactivation — she didn’t even know she had hepatitis B — but she had a reactivation of hepatitis B. And so we stopped the durvalumab and we treated the hepatitis B. And we put her on observation. And then she had recurrence, and she had large recurrence in both her liver, really a single spot, but it was about 8 centimeters in size, and a large recurrence in her brain. Activity and tolerability of crizotinib and lorlatinib in patients with metastatic NSCLC and ROS1 tumor mutations DR LOBINS: And so because she was ROS1 mutated, we put her on crizotinib, and we radiated her brain with SBRT. And she doesn’t like radiation to her brain, to be quite honest. But she was doing pretty well on the crizotinib until a recent MRI. And on her recent MRI, she has 3 — I think 3, there may be 4 — but 3 small 3- to 4-mm lesions in her brain. The rest of her scans are completely at baseline. And so I talked to our radiation oncologist, and I said, she’s not real thrilled about radiation. She’s still in school. She was getting ready to take her finals for her semester. And she wanted to know if she can avoid radiation. And I said that we decided that it was reasonable to put her on lorlatinib. And so we put her on lorlatinib, and she comes today for clinic. DR LOVE: Wow. How’s she doing on the lorlatinib? DR LOBINS: She’s doing well. She’s only been on it for 9 days so far, but she’s had no symptoms whatsoever. DR LOVE: Yes, now that you mention it, I remember a couple of times over the last couple of years you bringing this up. I think initially it was even the question with do you give durvalumab to somebody with ROS1? And then the hepatitis. What are the questions you had today for Ben about her? DR LOBINS: Oh, one of the questions I have is, what do you do next? And then how would you follow her up? Ben was nice enough to look up the activity of lorlatinib, both after crizotinib and in the brain. And I’m not sure how much of that data that she has — he said it wasn’t big numbers. And these people all failed crizotinib. This patient only failed crizotinib in the brain, in those small areas. I’m not exactly sure if this is a crizotinib failure or if this is just a matter of crizotinib doesn’t do a good job in the brain. And Ben was talking, saying, “you could radiate these and keep on crizotinib,” because she really hasn’t failed systemically versus changing. And they, the patients, want to know when is the next time I’m checking that brain. That was her husband’s first question was, “When’s the next time you’re checking that brain?” DR LOVE: Hmm, wow. Difficult situation. Sequencing therapies for patients with metastatic NSCLC and ROS1 tumor mutations DR LOVE: Ben, any comments? DR LEVY: We could spend 2 hours just on this case alone given the complexity of it all. We’ve got a patient here who was initially treated with chemoradiation, on immunotherapy, has a ROS1 mutation and then develops essentially disease progression in the brain with a few sites, but the disease control below the neck is what — so you’ve got disease that’s not controlled. And the question again is, is this truly a crizotinib failure, or a PK failure in the brain? And how do we manage this? And I think one of the options would be to just radiate those spots in the brain and continue on the crizotinib, based on the dramatic response in the liver. The liver really shrunk. This is a huge lesion in the liver that had a nice response. But at some point you’re probably going to have to institute a therapeutic switch. And so I didn’t think it was unreasonable, also, just to switch the patient to lorlatinib. I mean, this tells you how complex lung cancer is. I mean, I had to kind of look at the data — again, it hasn’t been published yet — on the ROS cohort from the lorlatinib data. And it’s roughly 50 patients. The response rate in the crizotinib-refractory patients was around 30%. Interestingly, the response in the brain, independent of whether the patients got crizotinib or not, with the lorlatinib was around 50%. And so there’s a good chance this drug will cross the blood-brain barrier. It’s a good chance it will elicit meaningful responses. I think this question underscores the when do you make that therapeutic switch in a patient who has otherwise disease control below the neck on crizotinib but has new spots in the brain? And we run into this problem with every single genotype, whether it be EGFR, ALK — same rules. You’ve got an EGFR patient on a therapy who’s got progression in the brain and what do you do? And same with ALK. This is not just restricted to the ROS-rearranged world. DR LOVE: In general, right now, nowadays, Ben, what’s your first- and second-line therapy for ROS1? DR LEVY: Just as Ray, my first-line therapy for ROS1 is crizotinib, based on multiple data sets showing a reasonable response rate and competitive PFS. Postcrizotinib, we get into lorlatinib, which would be an option. Repotrectinib is a new drug that’s come out recently, otherwise known as TPX-0005 — that has high activity, and there’s an ongoing clinical trial looking at this drug in crizotinib-refractory patients. Cabozantinib is another drug that could be tried. But I think off of a trial, it would be just as Ray had done, crizotinib followed by lorlatinib. I think the big issue is, progression for genotype patients is so heterogeneous. And it’s so hard sometimes to make a decision about when that therapeutic switch should be to the next-generation agent. If you have systemic progression, it’s an easy decision. If you have oligometastatic progression or progression in the brain, it becomes a little bit harder. Case: A woman in her mid-70s with Stage IV lung adenocarcinoma and a PD-L1 TPS of 70% experiences a pathologic fracture of the right femur while receiving first-line pembrolizumab DR MA: This is a nice lady. At the time when I first met her, she was about 76 years old, and she had Stage IV poorly differentiated adenocarcinoma at the time of diagnosis. At the time, she did have more PET organ involvement: lung/liver, adrenal glands and a lot of bone mets. She had PD-L1 expression, 70%, with adeno histology. She had first-line pembrolizumab single-agent treatment. And had a pretty good response. And she did have a little up and down, would have a couple of nodes progress here and there but overall had a pretty smooth course. The major hurdle in her treatment is, in the middle of her treatment she did have a severe right thigh pain, and it looks like it was a large bone met in the right femur. At the time, we offered palliative radiation for pain palliation. And so she got a little better, but the pain recurred and got worse. And we told the radiation oncologist. They looked, had imaged her. They felt like they could offer a little more. She had a second course. And then the pain just never got better. It continued to worsen. Eventually she had a pathologic fracture in that leg and had an ER visit, admitted to the hospital. At the time, the on-call orthopedic surgeon went ahead, did a percutaneous procedure and fixed femur. If I was notified, I would have preferred to get some tissue, had open procedure. But when I saw her, it was already done. When she came back, the pain from the procedure — the procedure fixed her leg. She was able to limp on that leg, but the pain did not improve at all. At this point, her overall disease is very stable. The major concern from my standpoint is, does she have residual disease in that leg? Because she was approaching about 2 years on single-agent pembrolizumab, and I would be uncomfortable to stop her immune therapy if there is potential borderline controlled disease in that lung, or is all her pain just from radiation necrosis or well-healed fracture? To me, this leg is becoming her major morbidity, and what is the best approach to address that leg pain is her major issue right now. Yes. Pembrolizumab monotherapy versus carboplatin/pemetrexed/pembrolizumab as first-line therapy for patients with metastatic NSCLC and a high TPS DR LOVE: Before we get into that, Leora, I want to just backtrack a little bit to the original decision for her original treatment, because she was a patient who was presenting with a high PD-L1 level, and that brings up the question of how, generally, these patients would be managed, particularly whether or not they’re going to get chemotherapy. I’m just kind of curious in general where you are today with that question, Leora, and how this patient — looking back at her initial presentation — would fit into your model. DR HORN: I think you have 2 options in this cohort of patients with high PD-L1 score: are you going to do pembrolizumab alone with the KEYNOTE-024 data, or are you going to do carboplatin and pemetrexed and pembrolizumab? My bias is, in a patient who you think would tolerate single-agent pembrolizumab — so even though she had a high burden of disease, she was not particularly symptomatic. I would favor doing pembrolizumab alone. It’s very rare where a patient has a large lung mass, where they have significant liver metastases and I want to get a quicker response, so I’ll use carbo/pemetrexed/pembrolizumab, and that’s based on KEYNOTE-21G, suggesting the time to treatment response is 1.2 months rather than around 2.2 months with pembro alone. But I would have given this patient pembrolizumab alone, and that still is my preferred option for mutation-negative patients with a PD-L1 score of over 50%. DR LOVE: And just to kind of understand, because now she’s been on therapy for 2 years, Yan, where did she have the disease when she started, and what happened? What’s the situation? Did she actually respond? DR MA: She did have response, and at the beginning, she had cervical spine, right femur, bilateral jugular lymph nodes, lung/liver, left adrenal glands and the possible portal vein tumor thrombosis. Those are the sites of disease she had. And at this point, typical for immune therapy patients, she would have up and downs and a couple of nodes would get a little bigger. And sometimes we just waited. The next scan would get better. We had radiated a couple of nodes when they keep getting bigger. I wouldn’t know, if she continued therapy, those nodes would settle down or not. So we offered a little bit of local radiation here and there. But overall, she has responded. The diseases are much smaller in size. Actually, we had a couple of PET scans in between — these are mostly PET-negative, has — some of these have a little bit PET activity. The right femur, of course, had 2 courses of radiation. Had a fracture. Still has some SUV uptake in the right femur. From a scan standpoint, I cannot say for sure she has residual disease or this is just all from the radiation toxicity. Radiation necrosis as a potential cause of pathologic fractures DR LOVE: I’m curious, Leora, how did she appear to you today? Was she with anyone today? And how uncomfortable did she appear to you? What did she tell you about her quality of life, Leora? DR HORN: She’s a little bit frail, but she looks okay. I think her quality of life is diminished by her hip pain. She can’t drive, because she can’t lift that leg up well. She can’t get comfortable. She’s got a significant amount of lymphedema in that leg, which has improved with some therapy. But her quality of life seems to be determined not by her therapy and not by the disease anywhere else besides what’s going on in that right hip, which we don’t even know if it’s even cancer. DR LOVE: I’m curious, Leora, have you ever seen radiation necrosis? Have you ever seen a case like this? DR HORN: Not the hip, but what we are seeing, and we’ve seen this a few times now over the last few years in patients who get things like concurrent chemoradiation for their lung cancer, these patients are now living a long time, and I’ve seen several patients with pathologic fractures in their thoracic vertebrae, which was right in the field of where they had their radiation previously. And so for this patient, had to know if it’s radiation necrosis and, unfortunately, as Yan mentioned, the patient did not get a tumor biopsy when the surgeon went in to repair the hip. And so I think it’s important to — and we even talked to the patient about, again, today, about is it worth going to get a second opinion from an orthopedic oncologist to see if there’s utility for going in and potentially repairing this in such a manner that this hip pain goes away and you can get information of is there cancer present there or is there not. Because we talked about that she could live for years with no evidence of cancer, but very limited quality of life. She was joking about going shopping without her husband, but she can’t get to the shops without him. So that’s not going to happen. And so can we impact her quality of life by figuring out how to repair this hip properly? DR LOVE: Yan, you said she had a percutaneous procedure. What exactly did they do? DR MA: There’s a small incision, and that the rod was inserted into the femur and through the skin. And so it wasn’t — DR LOVE: Wow! Huh! DR MA: — that open procedure. There wasn’t a biopsy done. And I think the visit today is helpful for her, because we’ve been talking about this a little bit back and forth. Any patient, she’s afraid of a real surgery. She felt like she could avoid it. But coming from a different oncologist and a similar recommendation. I think she’s more convinced today, she would at least keep going and get a consultation and look into it. Yes. Yes. DR LOVE: Interesting. Really interesting case. Thyroid dysfunction and pancreatitis associated with pembrolizumab DR LOVE: Has she had toxicity, autoimmune problems at all? DR MA: I think she had 2 interesting possible — she had a little thyroid dysfunction. Her lipase — it’s very interesting. Her lipase will go very high, without a clinical pancreatitis picture. I usually just treat through it, but for her, her lipase went to close to 900 at one point. We held her immune therapy for a month or so. It came down by itself. But she was never symptomatic. No nausea/vomiting, pain or anything. And we resumed treatment. It seemed to be fine. It has not flared up. I’m not 100% sure that’s related or not. But those are the only 2 things she had so far. Yes. DR LOVE: I’m trying to remember, Leora, if I’ve ever heard of autoimmune pancreatitis. Has that been seen? DR HORN: It has been seen. There are patients who are symptomatic and asymptomatic, and for the patients who are asymptomatic, they’ve actually taken out the recommendations to hold therapy. So if you just see an isolated amylase or lipase elevation and the patients don’t have symptoms, you don’t necessarily have to hold the therapy. We’ve seen some patients with florid autoimmune pancreatitis, and they subsequently developed — I have a patient who has Type 1 diabetes as a result. You can see it. It’s just in that less than 1% group of patients. DR LOVE: That’s interesting. Does this woman have any glucose intolerance? DR MA: No. No. Her glucose level has always been fine. It seemed just to be the lipase that we can see. DR LOVE: I have heard about diabetes with checkpoint inhibitors. Do you see elevated pancreatic enzymes? DR HORN: Some of the 2 patients that I’ve had who have developed Type 1 diabetes had changes in their amylase and lipase, and they all described symptoms of pancreatitis, like bloating and fullness before they presented with their blood sugars in the 600s. DR LOVE: Wow, really interesting. And what about her thyroid dysfunction? What happened there? DR MA: I put her on a small dose of thyroid hormonal replacement, but it wasn’t very significant. It wasn’t clinically significant — no symptoms — it was just a laboratory issue. So far it has not — I think she was on — I can’t remember the exact dose, 25 micrograms or a little bit of thyroid hormone replacement. DR LOVE: Another issue brought up by this case, Leora, is duration of checkpoint therapy. She’s now been on for 2 years. Hopefully this problem in her hip is not even tumor related. What about the issue of stopping checkpoint therapy at some point in lung cancer? Where are we today with that? Where are you today? DR HORN: I think it often becomes practice specific. When I talk to Eddie Garon, he says he keeps going. I actually start preparing my patients when they hit around 18 months, but if we continue to see the response and you’re still going well when we get to 2 years that we’re going to stop your therapy. Case: A man in his early 50s with metastatic lung cancer of ambiguous histology experiences a dramatic response to first-line nab paclitaxel/carboplatin DR LOVE: Let’s go on to the second case — your patient 2. Maybe you can talk a little bit about his history. DR MA: Yes. This is a complicated case, a younger gentleman, 53. When he presented, it was in the in-patient setting. At the time, he had extensive disease, and he had extensive mediastinal nodes, bilateral cervical nodes, major pars liver. The liver was filled with metastases. He was almost going to frank hepatic failure. At the time, LFTs were sky high. When he got diagnosed, he had a biopsy. The biopsy material was very limited. The histology initially was reported as a non-small cell carcinoma favor adeno, but it was not based on a lot of stains, because the tissue was limited. At the time, because of how quickly he was deteriorating, how quickly the liver function was changing, so we decided to rush into chemotherapy. Because of the clinical presentation, I chose a histology-nonspecific regimen, so we chose carboplatin and nab paclitaxel at the beginning instead of giving him carbo with pemetrexed. He did have a very good dramatic, quick response. And he quickly recovered performance status close to 0 within about 2 cycles of treatment. And then, of course, the patient’s very happy. Tolerance, great. Later on, as more histology trickled in, we did have all the — EGFR, BRAF, ALK, all those mutation studies, they all were negative. DR LOVE: Did he have a liquid biopsy? Did he have a plasma assay? DR MA: No, he had had a nodal biopsy. It was a tissue biopsy. Yes. Utility of liquid biopsies in therapeutic decision-making for patients with metastatic lung cancer DR LOVE: Just kind of curious, we’re talking about wild-type disease, Leora, but where does liquid biopsy fit in? Do you have patients like this sometimes where it’s difficult to get adequate tissue? And how do you approach interpretation of liquid biopsies in this kind of situation? DR HORN: I think it’s reasonable to do a liquid biopsy, depending on how long it’s going to take for your tissue testing to come back. At our institution, tissue testing comes back within 7 to 10 days. A liquid biopsy takes around the same amount of time. The problem with the liquid biopsy is, if it’s positive, it’s useful. If it’s negative, it’s not useful. And there were still some patients who’ll be positive in liquid and then negative on tissue, although not as commonly. And the idea is that the liquid can give you a better idea of the whole milieu of the tumor. If he had something that was detected on liquid, it would be helpful, but if the liquid biopsy was negative, it may just be that the patient wasn’t shedding enough circulating free DNA for that to be detected on the liquid biopsy. DR LOVE: Just kind of curious though, kind of beyond the question of whether there are actionable mutations, can liquid biopsies inform about whether a tumor is a nonsquamous or squamous, Leora? DR HORN: The liquid biopsy is not going to give the napsin A/p40. But on the other hand, we wouldn’t expect to see EGFR, ALK, ROS1 in a squamous cell patient unless they were a never smoker. So it could potentially help there. p53 is going to show up in both. BRAF or MET exon 14 can show up in both. It depends on what mutation you end up detecting of whether or not it could help you or not. DR LOVE: You said BRAF and exon 14? You can see that in squamous? DR HORN: You can. BRAF has been reported in squamous, and so have MET exon 14. DR LOVE: And they respond to targeted therapy? DR HORN: The BRAF has been reported to respond. I don’t know about the MET exon 14 skipping mutations. DR LOVE: That’s really interesting. Therapy for patients with metastatic lung cancer and CNS metastases DR LOVE: Anyhow, so kind of getting back to the patients, so that’s great. The patient had a response. And what was the next step? DR MA: It’s an interesting chain of events that happened at this point. He finished the front-line treatment. We were very happy. He was very happy. On imaging has very limited disease left. At the time, we decided to not do anything or do early second-line treatment with pemetrexed or bevacizumab. He went to MD Anderson to get a second opinion on this. Had a nice visit, and they were screening him for some clinical trials, also offered a second look at his histology. Had all the original biopsy slides shipped over. In this process, he came back. On the way there, he started to notice a slight balance issue, also noticed a left abdomen and left-side numbness of the skin. He didn’t mention it at the time, because he was feeling great otherwise. He did not mention those symptoms at this visit at MD Anderson. He came back. Two things happened: MD Anderson reviewed the original slides, felt like there was a weak stain on synaptophysin. The original pathology, looked at that, felt like it was a negative stain and treated as a non-small cell histology. MD Anderson reviewed it. It felt like actually that pointed them towards a poorly differentiating neuroendocrine tumor. DR LOVE: Wow. DR MA: That’s a slight change in the histology. It is a change in his histology. We were talking about what to do about this new information. At the end of the interview, he mentioned his complaints, and we did a physical exam. It definitely raised concern for CNS and spinal metastases. So we went ahead, had MR scan of his brain and MR scan of his spine. At this time, we found out he had a small cerebellum metastasis, and also, he had a T3 cord metastasis. He still felt great. I mean, his performance status was very good, other than these neurological complaints. Of course that pushed all the other discussions about histology, about what to do next, into the backburner. We went ahead, sent him to radiation oncology. And my experience with patients with cord metastases, that they don’t do well and it significantly impacts their prognosis. We were pushing the agenda a little bit. I actually offered him concurrent immune therapy. We started him on nivolumab at the same time. And at this juncture, and he was doing the radiation. And so he actually went to Sarah Cannon, had a third opinion on this situation and taking into consideration of all the new findings of brain and cord metastases. At the moment, actually, he’s being screened and ready to start a clinical trial at this point. DR LOVE: What kind of clinical trial is he going to go on? DR MA: All his Foundation testing, he had 3 mutations. It seemed to fit this small molecule that was used in this trial, that’s targeting all 3 mutations. And the investigator felt like it’s a perfect fit. He has not started the trial yet. He’s ready to have a restaging scan for trial purposes in the next 2, 3 days. DR LOVE: Hmm. What’s your working diagnosis at this point in terms of the histology, Yan? DR MA: That’s one of the questions I was trying to get a second opinion on today, too. I mean, when I was treating him, I was thinking, this is definitely the right histology for carboplatin and nab paclitaxel, just because of the wonderful response he got. And because of the initial ambiguity, histology, I sent it out for cancer ID on the biopsy sample, and that came back actually 90% confident it’s adenocarcinoma histology. And that came about 2 cycles into treatment. My experience with cancers are not perfect testing, but between small cell, neuroendocrine and adeno, they usually have been pretty good at distinguishing. That boosts my confidence moving on. I felt, like, pretty good. I’m a little confused, actually, because I wasn’t sure that this is a difference of opinion in pathologists. Because the pathologist did a biopsy. Knew synaptophysin stain. They looked at it. They interpreted it as negative. It wasn’t a new stain obtained at MD Anderson. It was a different interpretation of the same slides. DR LOVE: Hmm, interesting. DR MA: I’m puzzled, but to me, there’re overlapping regimens between small cell and adeno. We can definitely pick some overlapping regimens in the future. But, of course, the trial right now is inserted. That changed our consideration a little bit. Yes. Therapeutic approach for patients with metastatic lung cancer of undetermined histology DR LOVE: Putting aside, Leora, this question of whether — maybe this new target or novel agent, just kind of curious how often you run into a situation where you’re not really clear about the histology, as in this one, and how would you approach management, at least moving forward, based on the information that you see there, Leora? DR HORN: Yes. It’s not common, but it’s not uncommon that you may have a patient, just because there’s a lot of crush artifact or there’s necrotic tumor, that you’re not going to have a clear idea of histology, and carbo/nab paclitaxel is a regimen that you could use both in squam and nonsquam. So I think that that was a very reasonable treatment option to consider for him. He likely has a mixed-histology tumor, given that he had such a rapid response to the platinum-based chemotherapy. And that response tells me that it probably wasn’t just purely adeno. In terms of the treatment that he’s on now, nivolumab is an option for second-line therapy for nonsquamous non-small cell lung cancer, for squamous non-small cell lung cancer as well. And then even though the CheckMate 331 data was negative, showing that nivolumab wasn’t better than topotecan or amrubicin in the second line for small cell, if you look at the subset analysis from that study, it actually showed that there was potentially some benefit in patients with chemotherapy-refractory disease. And he has chemotherapy-refractory disease, because he progressed almost immediately after completing his platinum-based chemotherapy. And so we were actually talking with the patient today, saying, we don’t even know if nivolumab has not worked. I mean, he’s feeling well. He was just tired from the radiation, but he actually said the last few days he’s been feeling better. And so he definitely needs that restaging CT scan before he goes on any study to make sure that he’s not responding to nivolumab. Because if he is, then why would you waste his time? And technically he probably wouldn’t qualify for a clinical trial, because he doesn’t have progressive disease. DR LOVE: That’s really interesting. Second-line therapy for patients with metastatic lung cancer DR LOVE: Kind of looking down the line, Leora, if he does require another line of therapy, unless he’s going to have a spectacular response to the nivolumab — it seems like that might be pretty likely — what would you be thinking about next, Leora? DR HORN: I’d probably consider something like irinotecan, which is a small cell drug, but it’s also a drug that you can use in non-small cell even though NCCN has taken it off of the guidelines. I always like to use single-agent paclitaxel as a second-line option in small cell. I know that Yan was also talking about carbo/etoposide/atezo, although I think that if he doesn’t respond to nivo, he’s not likely to respond to atezo either, but carbo and etoposide could be a reasonable option for someone who has small cell if he could tolerate more of a platinum agent. He was pretty young and robust, despite everything that he’s being going through. DR LOVE: Do you think he has small cell, Leora? DR HORN: Probably. I mean, his scans seem like small cell, just kind of the location and the rapid progression of his disease. And the fact that his tumor melted away so quickly with just 2 cycles of a platinum-based chemotherapy — I wouldn’t expect to see that in a non-small cell patient. He’s probably got a mixed histology tumor is what I think he has. Because you also wouldn’t expect this with a large cell neuroendocrine tumor. They don’t respond nicely like this patient did. DR LOVE: I was just kind of reflecting on your small cell study with the atezo, how you really didn’t have much tissue to go on. That was one of the points that came out — I think you used liquid biopsies there because, I guess, there wasn’t that much tissue. DR HORN: Yes, they have to have a confirmation of small cell histology, but they didn’t have to have enough tissue to do things like TMB. Because you can’t get it on those patients. DR LOVE: Right. And also, I guess, PD-L1? DR HORN: Correct. Yes, there was not enough tissue in the patients enrolled for PD-L1. We did blood-based TMB. DR LOVE: It was just TMB. You can’t really do blood-based PD-L1. DR HORN: There are some companies that are claiming that they can do that. We’ll have to see how well that comes out in the wash. It’s hard to imagine how you can determine the staining with just a few circulating free DNA. But right now, it’s not ready for prime time, for sure. DR LOVE: Just kind of curious a little bit about him as a person, Yan. What’s his lifestyle like? Was anyone with him today in clinic? DR MA: Nobody was with him today. I was surprised. He has a very, very supportive wife. And they’re a very outgoing, fun-loving couple and travel a lot. He’s a very happy person and looking for positive feedback. So when he did better, he would tell he gets better and want to hear you tell him how exciting, how happy you are for him and that reinforces him to feel even better. At the beginning of the treatment, he was very depressed. And as he got response, the response itself actually made him feel more positive. He’s a person I think definitely does better with positive outcomes. And I can see him get depressed easier if there is any setbacks, yes. DR LOVE: You mentioned, Leora, that you kind of felt like a med student going around in clinic today. You’re used to seeing your own patients. I’m kind of curious how it was like kind of looking over Yan’s shoulders and seeing the same kind of patients you see but from a different perspective. How did he come across to you as a patient in terms of how he’s facing this situation, Leora? DR HORN: He definitely trusts her. I think all of her patients do. They were full of compliments. I think he was probably the one who was the probably the most reluctant to have me there, or he was very clear, like, “I’ve seen someone else. I have a plan.” Wasn’t as interested in what we talked about. DR MA: I think my take on that is, I think he was presented with several options. I think he struggled a little bit to get on trial or not. He finally made a decision. I don’t think he’s 100% sure, but he wants to be sure. He’s afraid of you talking him out of it. DR HORN: Got it. Okay. DR MA: Because I think Leora was wonderful bringing up the importance of imaging. To me, that is a very good point for him. When she first brought it up, he was a little scared, actually, thinking, this is something she tried to talk him out of. We had actually repeated a couple of times to say, “How wonderful that would be. Two cycles of nivo would have caused an effect. This is something wonderful.” Then he fed on the positive information — he felt a lot better. DR LOVE: The other thought I had just kind of listening to the two of you relevant to your point, Leora, before we got started about the challenge of being in general medical oncology, I’m listening to Yan go through lung cancer, which she’s obviously totally on top of, I think, in terms of literature, but I’ve done programs with her in breast cancer and a bunch of other tumors, and I can tell she would be equally comfortable going through that. So it’s just really amazing how people like Yan can actually keep up with all these things. DR HORN: Yes, absolutely. Case: A woman in her mid-80s with metastatic lung adenocarcinoma and a PD-L1 TPS of 30% receives pemetrexed/pembrolizumab and experiences dyspnea DR LOVE: Let’s hear about your third patient, this older lady. How old is she? DR MA: Let’s see — she’s 85 now. So when I saw her, she was 80, 82. So it’s a really sweet lady, and this is from one of my satellite clinics I go to an hour away from my main clinic 1 day a week. So she lives far away. When we first saw her 2 years ago, February 2017, she was diagnosed with Stage IV disease. It was adenocarcinoma. At her age, I would say her performance status was probably between 1 and 2 at the time. Her PD-L1 at the time was 30%. So her disease was caught at the moment. Initially there was no data for chemo combo with pembrolizumab. I gave her single-agent pemetrexed, and then we added pembrolizumab later on, based on that PD-L1. And so she tolerated reasonably okay. My principle treating her is, I want her to have as much quality of life as possible, not to make her too sick. As we progressed with treatment, she had a moderate response. But then she started to develop a little bit more shortness of breath, especially on exertion. A little bit more cough. It wasn’t clear it’s for sure immune therapy-related pneumonitis, but at the time, she was approaching finishing 6 cycles of treatment. We decided just to hold off. We stopped treatment, just left her alone for a while. And then I think she had a little bit of progression. We decided to give her pembrolizumab alone. And then she had a little more cough, a little more worsening dyspnea on exertion. We halted, again, in case this is any possible immune therapy-related pneumonitis. And she was okay for a while. Then, most recently, she had a little more aggressive progression. Had an enlarging hilar lymph node but nowhere else. Just isolated. The most recent development is, we decided to do a little bit of targeted radiation to that lymph node and just resumed immune therapy again in the last 6 weeks or so. She got 2 doses in right now. Perspective on the approach to metastatic lung adenocarcinoma in elderly patients DR LOVE: Leora, I’m kind of curious what your impression was of her. How healthy of an 85-year-old did she appear to be? And what do you think about the course up to this point? DR HORN: She was pretty frail. She said she was tough, and she must be tough to have gone through so much therapy. She was there in clinic with her daughter today, and she said at home she was doing some things but had to pause. So she could make her bed, but then she’d have to sit down for a little bit. I’m not sure if I’d seen her up front if I might have just rode out the pemetrexed and stopped it when she got fatigued and then started pembrolizumab at the time of progression, although I don’t think that there was any harm in combining. But then when patients get toxicities — and this is what’s so hard about when you do the carboplatin/pemetrexed/pembrolizumab up front — when patients hit about 8 or 9 months of therapy, they’re tired. And you’ve then worked them up. They don’t have hypothyroidism. They don’t have any adrenal insufficiency. Are they benefiting from the pemetrexed? Or if they’re benefiting from the pembrolizumab, and which drug do you stop? And we more often will discontinue the pemetrexed and continue on with the pembrolizumab. She has an isolated era of recurrence, so I would have approached it the same. We’re pretty aggressive in biopsying those people. I have diagnosed 1 metastatic colon cancer and 1 breast cancer in a patient who looked like they were progressing. I do try to biopsy those folks. But I would have also gone for radiation in this patient for a single site of recurrence to see if we could continue to ride out the immunotherapy for a while. DR LOVE: I saw a paper you did, Leora, also on small cell, in terms of progressing on a checkpoint inhibitor. Did I read that right? DR HORN: Yes, those were 2 patients who were KRAS mutant-positive who were on IO. And when they progressed, one was biopsied for study, and we found out that they had had a transformation to small cell, and the other patient came in with rapidly progressing disease, and when we did the thoracentesis, that patient had small cell. And so the hard thing that we don’t know is, those patients had been on a checkpoint inhibitor for more than a year. Had they developed a second tumor, or had they had true transformation of their tissue? And one of the patients, the KRAS mutation was still present in the small cell specimen, suggesting potential transformation of the tissue. DR LOVE: That is really interesting. Leora, what was your take about the, I guess, shortness of breath or pneumonitis that she had? DR HORN: Yes, it’s hard to know. Her sats were pretty good, and she got better with a methylprednisolone dose pack. That tells me that if she did, it was a really Grade 1 or, I guess, Grade 2, because it was symptomatic pneumonitis. And so those patients I would definitely rechallenge. We talked earlier — another patient who had a florid toxicity from a checkpoint inhibitor that you wouldn’t want to rechallenge them. And if this patient had a drop in her oxygen saturations and had pneumonitis on imaging, I would not necessarily have rechallenged. The other part that I think is harder in the community, and we were talking with some of Yan’s colleagues, is when I send someone for a scan, I immediately get the results. I can look at their images. They have to rely on an outside group who is doing the images and to get those images quickly. It’s not as easy to get that quick CT scan in clinic as it is when you’re in a big hospital with multiple scanners. DR LOVE: Yan, what would you be thinking in terms of future therapy for this patient? At what point would you consider hospice for this patient? DR MA: That’s why I’m in about 2 years now for her. Since we started treatment, her performance status right now is not any worse than when we started. I’m happy of that. I think, actually, the way I developed a relation was this patient — I think she’ll be very outspoken, in her mind, when her performance status deteriorated and she feels like the treatment offered to her is not worthwhile for the — she will let me know. That’s what we have figured out. I think if she progresses on immune therapy, I might consider single-agent something else to try. I mean, I think with her, she is where she was in the beginning with — I think I would try something. And I’m confident she will let me know if she feels like her quality of life will deteriorate and not worthwhile to continue treatment or anything. Yes. DR LOVE: Leora, any thoughts about her future therapies? DR HORN: Yes. We talked a little bit about docetaxel. And so I’ve never given full-dose 75 of docetaxel outside of a study. We talked a little bit about either weekly, like 36 mg/m2 2 weeks on/1 week off, or 60 mg/m2 every 3 weeks. I probably wouldn’t add ramucirumab in an 85-year-old, because there are more toxicities with the combination, but single agent, I think it could be a good option for her if she has further progression. Efficacy of ramucirumab as second-line therapy for patients with metastatic NSCLC DR LOVE: How about in a younger patient in better condition? How do you think through the issue of adding ramucirumab, Leora? DR HORN: I have to say, I was a little bit of a naysayer when the data came out, but that’s probably because the data came out as checkpoint inhibitors were entering the trials. But now, when you’re back to chemo/IO up front and you get to second line, I do do quite a bit of docetaxel at 60 mg/m2, the Japanese dose, with ramucirumab in patients. And a lot of them do really well for quite a while. DR LOVE: Do you tend to use it more, Leora, in someone who’s never had bev, or does that not really enter into it? DR HORN: I was never a big up-front bev user after the pemetrexed data came out. I used to do a lot of carboplatin, paclitaxel and bevacizumab. But then when carbo/pemetrexed came along, it just was such an easier regimen to give. And because the carbo/pemetrexed/bev data was no better, I used to use carbo/pemetrexed on its own and just do maintenance pem. It didn’t come up as often, although the data from that study would suggest that ramucirumab, because it targets VEGF in a slightly different manner, did have efficacy even in patients that had bevacizumab. REVEL: Results of a Phase III trial evaluating the addition of ramucirumab to docetaxel after disease progression on platinum-based therapy for patients with Stage IV NSCLC DR LOVE: Can you talk a little bit about the data that supports the use of ramucirumab? I know, as you say, we’ve been talking about checkpoint inhibitors so much the last couple of years, all those old discussions that we use to have a couple of years ago seem like a long time ago. But many of these patients, most of them end up getting to that decision point. Can you talk about the data, in particular, one of the things that was interesting about those data was the fact that it looked at squamous as well as nonsquamous. DR HORN: Yes. That trial enrolled patients with squamous and nonsquamous non-small cell lung cancer who had progressed on a platinum-based regimen and were given docetaxel at the 75 mg/m2 with or without ramucirumab. And there was improvement in response rate. So the response rate went up to — I think it was around 25% or 20% with combination therapy. And there was a 6-week improvement in progression-free survival and overall survival, which is why a lot of people pooh-poohed the data and said, “It’s only 6 weeks, and so it’s not such a significant benefit.” But for patients, it is a tolerable regimen. It’s safe in both squamous and nonsquamous, and so I have adopted it as one of the treatment options that I’ve included in my patients. Interestingly, when a lot of the trials were out with the checkpoint inhibitors, KEYNOTE-010, the CheckMate trials, the POPLAR and the OAK trials, those were not docetaxel and ramucirumab compared to the checkpoint inhibitors — it was just docetaxel. And that’s because ramucirumab did not get approval in many parts of the world, including the EU, where they use more docetaxel and nintedanib than they do ramucirumab. DR LOVE: Yan, I’m trying to remember whether you and I have done any programs on gastric cancer or HCC, where ramucirumab is starting to come into HCC finally, but gastric cancer I think was really where things started out. What’s your experience with ramucirumab in general, Yan? And are you using it in non-small cell? DR MA: I used in some patients and had a good experience with it. I think ramucirumab does add — it’s not like bevacizumab. It does add a little more toxicity into the regimen. But usually, I mean, I had a pretty good tolerance in it. And we use it in GE junction in the gastric a lot more as well. I do. It’s a drug I go to a lot. Comparison of the activity and tolerability of ramucirumab to that of bevacizumab in patients with metastatic squamous cell carcinoma of the lung DR LOVE: Just kind of curious, Leora. I was surprised when I saw that they studied it in squamous. Backtracking on why bev was pushed out of squamous and why ramucirumab with pretty similar mechanism is being utilized, can you kind of talk about that? DR HORN: The Phase I data with bev actually came out of Vanderbilt, and Dave Johnson was leading a lot of the work. And he noted that there was a high incidence of death in patients with squamous cell histology who were treated with bevacizumab. A high incidence of fatal hemoptysis, probably because the patients who got bevacizumab were maybe responding too well — their tumors were melting away. And so for that reason the Phase III trial, ECOG 4599, allowed patients with nonsquamous or patients who had predominantly nonsquamous histology. For our patients with mixed tumor it was allowed. When ramucirumab came along, they did not see the same safety signals in patients with squamous cell histology, which allowed it to be evaluated in that patient population. And maybe it is something unique to bev, or maybe it’s just too good in that disease. Because when you look at some of the VEGF TKIs, most of them have been evaluated both in squamous and nonsquamous non-small cell lung cancer. In fact, the only TKI right now that is not allowing patients with squamous histology on study is with sitravatinib. The trial with nivo and sitravatinib has only been in nonsquamous non-small cell lung cancer. But many of the other VEGF TKIs have allowed patients with both squamous and nonsquamous to receive therapy. Ongoing clinical investigation of novel combination approaches with immune checkpoint inhibitors and anti-angiogenic agents DR LOVE: We’re hearing more and more about anti-angiogenics, Leora, in combination with checkpoint therapy. There was a big renal cell paper that was just presented at ASCO GU, which was — I think it was pembro/axitinib. TKIs have been looked at, that kind of a strategy. We have bev in lung cancer — atezo/bev. I’m just kind of curious what you think about that idea. I don’t know, is ramucirumab being looked at also combined with checkpoint inhibitors? DR HORN: There is a trial that’s looking at pembro and ramucirumab, and Roy Herbst had that initial data with pembro and ramucirumab and in patients with non-small cell lung cancer. I think the data is interesting. I was recently at a meeting, and I put up a sarcastic slide that I called the “obligatory synergy” slide, where drug X increases T cell and causes immune death. And I think you can rationalize almost any combination. I think the axitinib data with IO is definitely exciting compared to what we saw with sunitinib alone in renal cell. And I think the sitravatinib data in IO failures has been interesting, where we're seeing responses with sitravatinib and nivolumab in patients who’ve progressed on either checkpoint inhibitor. And so I think it’s still to be determined where it fits into the lung cancer patient treatment regimens. We have an IIT at Vanderbilt with nivolumab and vorolanib in non-small cell lung, squamous and thymic. And for the non-small cell we’re including IO failures. And so there definitely is a hint of efficacy there. Whether or not we’ll move it to the first-line setting or which combination to give it with I think is something that is going to be sorted out in the next few years. DR LOVE: Really interesting. Case: A man in his mid-70s, a former smoker, with Stage III NSCLC initially treated with adjuvant chemoradiation therapy develops metastatic disease and is found to have a RET tumor mutation DR LOVE: Let’s hear about your next patient, Yan, this elderly man. DR MA: Yes. This is a 76-year-old gentleman — he’s still working full time. When I initially saw him about 3 years ago, he was at a curative Stage III disease. He had his surgery. Then he had adjuvant chemoradiation. So he was in remission between June 2016 until about November 2017. That’s when he developed pleural recurrence and Stage IV disease. He quit smoking back in the year 2000 after about 30 years. When the disease recurred, we did the biopsy, and he had a well-differentiated adenocarcinoma histology. Did not have any unique mutations. And he had a very high PD-L1 expression — I think it was about 90%. We were very excited to put him on a trial at the time as an external beam radiation smoker — put him on nivolumab and ipi combination trial in January 2018. And I was telling him, “Oh, how great immune therapies are. We’re hopeful you’re going to be the lucky few patients who have long-term responses.” But he did not have any response, despite the high PD-L1 expression level. Then he proceeded with second-line treatment with carboplatin/pemetrexed and bevacizumab, started in June of 2018. And he mostly worked through the chemotherapy. He probably took a little bit of time off. He was definitely fatigued, but not to a level for him to stop working completely. And then we followed that with pemetrexed and bevacizumab maintenance. So during this time when he had Stage IV disease, we did send off FoundationOne testing for his tumor biopsy — pooled biopsy sample, and it came back — he did have a RET mutation. And that data for the LOXO-292 came out. I did send him to Sarah Cannon for a clinical trial evaluation for the oral agent. At the time, he was having a good response to carboplatin and pemetrexed and bevacizumab. In his mind, after hearing both sides of it, his position is to stay with what has been working and not change course in the middle of it. We continued therapy, and now he’s on maintenance therapy. DR LOVE: It’s a really interesting case. A few questions I want to ask Leora. Backtracking to the beginning, Leora, this man got chemoradiation therapy, and most likely, if he presented today, he would have had consolidation with durvalumab. Just kind of curious how you are thinking through the approach to patients who relapse after that kind of a strategy as this man did, but he didn’t have the durvalumab. Are you repeating checkpoint therapy at some point in these patients? DR HORN: I think it depends on when they relapse. And I’ve had a few patients who’ve relapsed on durvalumab, and I just go to platinum-based chemotherapy, or, if they have driver, would treat them based on what their driver mutation is. I think if they’re off durvalumab and they’re 6 months later and they relapse, I would rebiopsy and potentially consider a combination checkpoint inhibitor with chemotherapy in those patients. But if they’re progressing on one IO, another IO is not likely to make much of a difference, and I would have gone to a platinum-based regimen similar to what he had. Effects of tumor mutation burden and PD-L1 expression on response to immune checkpoint inhibitors DR LOVE: Any comments on the fact that, as Yan was pointing out, he had high PD-L1 level but yet did not respond to checkpoint therapy, in this case combinations? I noticed that he had low TMB when he had the FoundationOne assay. Do you think that might be part of why he didn’t respond? And also, does TMB stay the same, incidentally, during the patient’s treatment course? DR HORN: I think we’re learning more about TMB and how it changes, but yes, we were talking — because he was MSI stable, those patients don’t tend to respond to checkpoint inhibitors, TMB low. Although as you know, the nivo/ipi data keeps evolving, because first the original filing was with TMB high, and then when they gave more information to the EU that wanted the information of TMB-low patients, those patients appeared to be benefiting as well. I think it just proves that we don’t know what the appropriate biomarker is. We’re using surrogates with PD-L1 in TMB, and I’m still convinced someone’s going to find a true marker that would suggest “use this therapy” or “don’t use this therapy” in patients, similar to KRAS and EGFR monoclonal antibodies in colon cancer. But the reality is, checkpoint inhibitors only work in about — the response rate is 50%, but if you look at the long tail of the curve of trials like KEYNOTE-024, the numbers continue to decrease to where you get to around 30% of patients are long-term responders. And so it does work in some patients, but in the majority it does not work. DR LOVE: This man got ipi/nivo. Yan, any toxicity there? DR MA: No, he didn’t. And he progressed quite significantly, so — he didn’t have it for long. I think he had it for about 2 months or so, maybe 3 months. It wasn’t a long treatment course. But he did not have any issues with it. No toxicities, no. DR LOVE: Interesting. Perspective on the use of targeted therapy as first-line treatment for patients with metastatic NSCLC DR LOVE: Any comments about the new generation of RET inhibitors that it looks like this man is going to be eligible for at some point, Leora? There’s a lot of excitement about it. If you know up front that the patient has that, will you actually use targeted therapy up front? DR HORN: Yes. I actually saw someone in clinic on Wednesday who came with her test that said she was RET-positive, and she was showing me an immunotherapy trial that she was being offered somewhere else. And I said, “We have LOXO-292, and that’s what I would do,” and that’s what she thinks. She’s starting next week. Although, this patient was interesting. He was there with his family, and he said he tried a clinical trial — it didn’t work. He’s on chemo. He said, “It ain’t broke. Don’t fix it.” And I agree with him. The TKI data has shown us in the EGFR and ALK patients that overall survival is not really impacted. And so whether you get your TKI first versus chemo first and switch around, we just know the quality of life is different on the TKI versus chemo. And so I would ride out his chemo the same way as he’s doing, and maybe by the time he needs a TKI there may be a better drug out there, or he can just get LOXO-292 through Dr Ma’s office and not have to go somewhere for a clinical trial. DR LOVE: I’m curious, this patient that you saw, Leora, what was the PD-L1 level? DR HORN: Her PD-L1 was low. It was, like, 10% or — it was less than 20%. Sequencing targeted therapy and immune checkpoint inhibitors for patients with metastatic NSCLC and actionable tumor mutations DR LOVE: When you have patients with known targetable mutations like EGFR, ALK, the classic ones, where do you bring in checkpoint inhibitors in terms of metastatic disease, Leora? That’s been a point of contention over the years. And where does RET fit in? Is RET now part of that group? DR HORN: I think that RET does fit in in that group — that if you have a target that — and we saw data at ASCO last year from the French data that looked at multiple different mutations showing lower PD-L1 responses in patients with driver mutations. I think we have to add RET to that cohort of patients. If a patient has EGFR, ALK, ROS1, MET exon 14, NTRK, we can add RET, BRAF. I would give them their TKI up front. At the time of progression, specifically for patients who are ALK-positive, there are multiple ALK inhibitors. The problem with EGFR right now is, we’re using osimertinib up front. They progress. All we’re left is with chemo. And then at the time of progression, for those patients on targeted therapies, for the EGFR patients I do think about the IMpower150, the carbo/paclitaxel/bevacizumab/atezo data. I think it’s interesting. I’d like to see more data with the true randomized studies that are ongoing. But a checkpoint inhibitor is reasonable to consider. I think an important thing to remember, though, is that if you give the checkpoint inhibitor and you want to go back to targeted therapy, you may cause more harm to the patients. Memorial just had that retrospective review of patients who got checkpoint inhibitors and then went on to osimertinib, and 15% of those patients got immune-related toxicities. Many of them had to be hospitalized to treat their toxicities. Even though you stop the checkpoint inhibitor, the drug is still in the patients. It has made changes to the patient’s immune system. And so we can see toxicities impacting further lines of therapy even though the drug has been discontinued, whereas they didn’t see that issue when osimertinib was given first and then a patient got a checkpoint inhibitor. DR LOVE: Wow! That was really interesting. I didn’t know about that. Somehow the osimertinib is in some way interacting with the immune therapy? DR HORN: Yes. And we saw that with TATTON and the CORAL trial that closed early. There were higher incidences of pneumonitis in patients on combinations. DR LOVE: Right. Right. DR HORN: And we’ve seen that. Doug Johnson from Vanderbilt published, several years ago, in patients who got BRAF inhibitors having horrible skin toxicities when they got them after receiving a PD-1 inhibitor. Even though that drug has stopped, that drug has not stopped its effects on the patient that was receiving it. DR LOVE: Oh, that’s really interesting. Yes, I’m hearing more and more people talk about that IMpower regimen on relapse with osimertinib patients. Yan, was he a smoker, or is he a smoker? DR MA: He was a 30 pack-year smoker and quit in the year 2000. I mean, that’s why I felt like he had a decent chance of responding to immune therapy as an ex-smoker. But I guess he quit 17 years at the time when he started it. DR LOVE: I was just trying to think. I know, like, EGFR and ALK, typically nonsmokers, not always, but typically. But Leora, you hear about BRAF. I hear more about smokers. What about RET? Do you see smokers with RET? DR HORN: You can see smokers with EGFR and ALK as well. Normally you would have a never smoker more commonly with RET, but you do see patients. And in November 2017, the LOXO drug wasn’t really around. Then all you were thinking, you could give vandetanib for a 40% response rate or nivo/ipi. Nivo/ipi in a high PD-L1 in 2017, it’s amazing how the treatments are evolving and things are coming out fast and furious in terms of what we do. DR LOVE: Right. No, I was just — my understanding is that BRAF you see pretty commonly with smokers. Is that your take? DR HORN: Correct. Yes. BRAF is something that we’ll see in the smoking patient population. DR LOVE: Right. Any other questions or points about this man, Yan? DR MA: Just a small question. At the time, we struggled a little bit. He got carboplatin and pemetrexed in his adjuvant setting. About a year and a half later, he recurred. We chose and we used pemetrexed. I was wondering about Leora’s input on that. What’s her thought on that? DR HORN: That’s a good question. I mean, he had an intervening therapy with the nivo/ipi, so don’t know if that’s driving some of the response that you're seeing even though he progressed on the nivo/ipi. But again, he was more than a year out. I don’t think it would be unreasonable. If he had recurred within 6 months, I would have definitely gone to a different regimen. But clearly you chose the right thing, because it’s working. DR MA: Yes. Retrospective, at the time we talked about it, we had it before, is a year, year and a half long enough? He felt he wanted to go with the safer — and he had it before. He had a really good time with it. DR HORN: Yes, he knew what to expect. DR MA: Not a big deal, so he was a lot more comfortable with using that. I think just coming off failing the immune therapy, he wanted something more, sure. I think that’s what we decided to do. Yes. Case: A woman in her early 60s with lung adenocarcinoma and oligometastatic disease in the brain receives first-line chemoradiation therapy DR LOVE: Let’s go on and hear about your 63-year-old lady. DR MA: Oh, yes. This has been quite a long journey with her. We started this about, oh, not quite 4 — 3 and a half years ago. At the time, she was 63 years old, and initial diagnosis was Stage IV disease. She had disease that involved the mediastinum. She also had 3 small brain metastases at the time. We debated about how aggressive we should approach her initially. Even though she had 3 brain mets, we still went ahead — had SRS to the brain mets, then had concurrent chemoradiation for her locoregional disease in the chest. Later on, so I think about a year later, she had progression with bone progression. We did the rebiopsy of that bone lesion. At the time, PD-L1 was 0. Despite being that — because at the time she only had that bone lesion, so PD-L1 was 0 and we were trying to decide something maybe gentle and not as aggressive, with immune therapy. We actually did give her immune therapy. We gave her pembrolizumab single agent at that time just to see how she’s going to respond because, really, she has no other sites of disease. She got 2 doses. Then she developed profound fatigue. And I was in the workup trying to figure out why she’s so tired. Her thyroid function was fine. Cortisol level was fine. Her sugar was fine. Then we did an echocardiogram. Her ejection fraction came back about 20%. We decided she had immune therapy-related cardiomyopathy, so we aborted the immune therapy and gave her high-dose steroid. Reversed that. DR LOVE: Before you go on, can we just backtrack into a few of these points? It’s a really interesting case. First I want to ask you, Leora, what you think about the initial management using chemoradiation in the face of brain mets. DR HORN: Yes. So we saw 2 different patients today who presented with lung mass, mediastinal node, and this patient had 3 brain mets. The other patient had 1 brain met. And the definition of oligometastatic disease continues to expand. And so for this patient, it was reasonable to do stereotactic radiation to those 3 brain mets and then try to do concurrent chemoradiation. Back in 2015 we didn’t have as many options for these patients. Now if we saw this patient with 3 brains mets, we might have done stereotactic radiation and then done something like carbo/pemetrexed/pembro, because in 2019 you have slightly different therapeutic options for these patients. But the treatment of localized or oligometastatic disease, it was very reasonable to do SRS and concurrent chemoradiation and observe the patient. And clearly she did well for 18 or 17 months after that treatment approach. Cardiomyopathy associated with checkpoint inhibitor therapy DR LOVE: The other question, obviously, here is the cardiomyopathy. I saw you were on a paper in the JAMA — I think it was JAMA Oncology or JAMA — about lethal side effects or autoimmune problems that have been observed, obviously very, very uncommon. And, fortunately, this lady’s weren’t. But certainly cardiomyopathy was on that list of potentially catastrophic problems. Can you talk about what we know, Leora, about cardiomyopathy related to checkpoint inhibitors and how you make the diagnosis? Do you think that’s what happened here? DR HORN: It’s a great question. It definitely sounds like it’s what happened, given that she responded to steroids and her ejection fraction improved on therapy. Javid Moslehi with Doug Johnson and a group of collaborators at Vanderbilt actually were there first to describe it in The New England Journal of Medicine a few years ago. We don’t know all of the causes of the cardiomyopathy, and unfortunately the patients that they initially described had fatal cardiomyopathy and died as a result. And so we had biopsies on those patients and found that they had no cancer, and their hearts were just full of T cells. DR LOVE: Wow! DR HORN: And so what that has led to at our institution is, a lot of these patients automatically get troponins and EKGs with their therapy so that we can potentially catch it early. It was a great catch by Dr Ma, because the first thing you think about with fatigue is their adrenal and thyroid function, and then you kind of think, “They’re having symptoms from their cancer.” But there are so many grants and different agencies that are trying to define how best to predict which patients will develop these autoimmune toxicities. What’s interesting is, there’s also data that some of these patients that develop autoimmune toxicities actually have better outcomes. It’s kind of how do you reconcile the two? Yes, let’s give you a bad side effect. But that just means that you’re going to live longer and, hopefully, it’s a side effect you can live with. DR LOVE: I just want to pick up on that last point, because I’ve been asking that question ever since I first heard about checkpoint inhibitors. And there’s been a lot of debate and controversy. Where are we today? Because when you made that statement, it sounds like maybe we have more definitive data on this question of correlation of autoimmune toxicity and benefit. DR HORN: Most of it’s still retrospective reviews. Most of it is still case series that we’re seeing coming out. And what’s interesting is, depending on the disease, it can actually determine — so in GI tumors, recently there was data presented that maybe in GI tumors the patients who get arthralgias have better outcomes with autoimmune therapy, whereas in other disease types the patients who get rash with pembrolizumab, maybe they’ll have a better outcome with their immune checkpoint inhibitors. I don’t think we know enough to definitively say who develops what. DR LOVE: I’m kind of curious, Yan. When you say she had fatigue, did she also have any symptoms or signs of heart failure? DR MA: She did not have lower-extremity edema, and she — I mean, as far as I can remember, she did not have significant dyspnea on exertion. I mean, she’s tired. I mean, it’s hard to tell. Nothing dramatic. Just profoundly fatigued at the time. DR LOVE: Really interesting. Prolonged responses to anti-PD-1/PD-L1 antibodies after cessation of therapy DR LOVE: What happened next? And what’s her current situation? DR MA: There are 2 tracks for her. After that, when we moved on to third-line treatment, we gave her carboplatin and the nab paclitaxel starting in April 2017. She had a good response. And then she had a severe allergic reaction to carbo in that — unusual. It developed in the middle. We aborted carbo. She has been on single-agent nab paclitaxel since that time. One other reason I was asking Leora about this is, she has been on single-agent — combo and the single-agent treatment on this line for about a year, actually longer than a year now. That’s unusual to me to have not progressed at this point. My question was, could it be she’s actually riding out immune therapy effect, even though she got only 2 doses of pembro? And a lot of these benefits she’s enjoying was, completely controlled systemic disease outside her brain is coming from pembro. Maybe I should stop her nab paclitaxel because she’s starting to have neuropathy affecting her quality of life. That’s one part of her disease. The other part is separate — is her CNS disease. She had 3 mets at the beginning. I know immune therapy does not have as consistent a response in the CNS. Her CNS disease has been slowly progressing. We have been getting away with — about every 4 to 6 months she would have a new met that’s slowly enlarging above a centimeter. We’ll do SRS again. She had at least 3 more SRS treatments. Actually, during the clinic visit today on her brain MRI she has 1 more lesion that’s going to be treated with SRS. These 2 separate parts of her disease seem to be following 2 separate courses. DR LOVE: Leora, first, any thoughts about what’s going on here and the possibility that somehow there’s a delayed benefit from the immune therapy? And also kind of where you see things heading with these brains mets. DR HORN: Yes, it’s hard to know. She’s been on nab paclitaxel for almost 2 years. And so we were talking about — I have a couple of patients and one that came to mind in clinic who got nivolumab in the second line, and at about 6 months it looked like she was progressing. I gave her docetaxel. And after about 8 or 9 months she said, “I’m tired of docetaxel. I have neuropathy, and I just want a break.” And she’s been on a break now for 18 months. DR LOVE: Wow. DR HORN: And she’s had no progression, and I think that she probably was responding to the checkpoint inhibitor or had pseudoprogression, although we don’t use that a lot. And maybe she never needed to get the docetaxel. And this is a little harder, because everything below the CNS is controlled. And Sarah Goldberg’s data and some of the other series that have come out with the CNS suggest that the response in the CNS is pretty similar to what you see systemically. Sarah had that study in patients with untreated brain mets who got pembro and showing around a 30% response, which is what she was seeing systemically in those patients. What’s interesting about this patient is, she doesn’t have new brain mets, from what I understand — it’s brain mets that have been present, and they’re growing. And so is it because the checkpoint inhibitor did work from below? And so we even talked to this patient, that the nab paclitaxel is not going to stop further progression in her brain. And she asked Yan if she could get a checkpoint inhibitor again, and she said, “Absolutely not. We don’t want to be doing CPR on you because of what happened. You had a severe toxicity.” But if she held her nab paclitaxel, she may continue to have occasional CNS progression but continue to maintain her systemic response, and that observation would not be unreasonable, because neuropathy again becomes that quality-of-life issue. DR LOVE: Wow, really interesting. PD-L1 expression as a predictor of response to immune checkpoint inhibitors DR LOVE: Any other questions about this case, Yan, or any other points you want to make? DR MA: Another thing is, her PD-L1 was 0. At the time, because she had only 1 lesion, that’s why we felt like — of course, I thought it would be a lighter treatment, gave her heart failure, but that’s why we did not want to — I thought it was a good thing to use immune therapy, because we do think immune therapy can work slow, and she got plenty of time to wait. I mean, Leora, in your practice, patients with 0% PD-L1, I guess they still could potentially respond. DR HORN: Yes. And we saw that. It’s interesting that you were able to get pembrolizumab, because in the FDA label they’ve got to be greater than 1% to get the drug, but the trials with atezolizumab and nivolumab enrolled patients regardless of PD-L1 score. And what we saw was that it depended — so, for example, in the CheckMate 017 study in the squamous patients, PD-L1 didn’t appear to predict for response, whereas in the CheckMate 057 with the nonsquamous, you saw incremental increase in response in the patients who are PD-L1 greater than 1%. But we did see responses, although they were lower in the PD-L1 0%. And I think it just points to that imperfect biomarker. If you’re a 0, you’ve got a 10% chance of responding. If you’re greater than 1%, you’ve got a 30% response rate. Very different from the RET patient. If they’re 0, 0% response versus a 70% response. So it’s just not a great discriminator. And so I still would use a single-agent checkpoint inhibitor. It’s changed a little now, right, because up front, from KEYNOTE-189 and 407, we’re giving platinum/pick your doublet with pembro in the less-than-50% patients. That includes the 0% patients, although in 189 there was no PFS benefit in those patients. I don’t think we really know what to do while this biomarker continues to plague everybody. Case: A man in his early 70s with metastatic NSCLC develops a severe carboplatin-related allergy during treatment with carboplatin/nab paclitaxel/pembrolizumab DR LOVE: Let’s hear about your next patient, the 71-year-old man. DR MA: This is a gentleman who saw me with actually considered a curative-stage disease, Stage IIIa. At the time, he had the T4 7.1-cm tumor, got resected, the tumor actually abutting 2 lobes. And he, interestingly, had 0 out of 19 nodes resected there. There was no nodal involvement at the time. He just had a lot of fear of chemo and was very frail. Had existing lung disease. Breathing was borderline. He had admitted later on, was dragging his feet. He did not want to start adjuvant treatment. He saw me, and everything was diagnosed in June, and by the time eventually he made it back to clinic to proceed with adjuvant treatment, it was almost 4 months later. I said, we’ve got to do a restaging scan. It’s too far out. We need to make sure the cancer is still under control. When we did that scan, of course at this point he had Stage IV disease. He now had multiple lung metastases, pleural metastases, and so it was not curative. At this point we decided to put him on carboplatin, nab paclitaxel and pembrolizumab. And so his performance status is 2, maybe actually a little more at the time because of his breathing status and everything. So I actually gave him carbo/nab paclitaxel on the weekly basis. I don’t think he would have tolerated a larger dose — and he actually slowly improved. His performance status now is close to 1 now. His breathing is a lot better, still not perfect. And most recently what happened was, he developed carboplatin allergy, allergic reaction during treatment and pretty severe. We aborted it. He’s now just on single-agent nab paclitaxel with pembrolizumab. My question for Leora was, so he has not gotten platinum in the last 2 cycles of treatment. Should I just move on to pembrolizumab maintenance or should I consider adding nab paclitaxel to the maintenance? Or would she have replaced — I did not continue platinum — would she have used cisplatin in the case with the carboplatin allergy? That patient would have a platinum doublet in his regimen. DR LOVE: Those are all really awesome questions. Leora, how do you answer them? DR HORN: I probably would not have replaced the cisplatin with the carboplatin, especially in her patient who had a poor performance status and we can’t guarantee that he’s not going to have the same reaction to cisplatin that he had with the carboplatin. As far as the nab paclitaxel maintenance, there was recently a study that looked at that of carbo/nab paclitaxel compared to carbo/nab paclitaxel maintenance with nab paclitaxel in patients with squamous cell histology, and the data was negative. I would have done just 4 cycles of the platinum doublet with nab paclitaxel with the pembro and then drop the chemotherapy and continue with maintenance pembrolizumab alone. We were talking about 4 versus 6 cycles, and I don’t think that there’s a right or wrong answer there. Most of the studies did 4 cycles. I know that there are a lot of oncologists who have a preference to do 6 cycles of the platinum doublet. And I think with him, this was going to be his last cycle with chemo/pembro before he got his restaging scans, and he continues on pembrolizumab maintenance therapy. DR MA: And he had a weekly dose. He initially only did 2 weeks on/1 week off because he was so weak. Then eventually we did 3 weeks on. So not a standard dosing for him. DR HORN: For the nab paclitaxel, we abandoned day 15 a while back. We, actually, the regimen we have at our institution is the full-dose carbo day 1 with the nab paclitaxel, a week later nab paclitaxel and then a week off. And so we have adopted that 3-week regimen, which more fits with the pembrolizumab scheduling, because the pembro is every 3 weeks, as it was in KEYNOTE-407. DR LOVE: Any other comments about this case? Again, maybe just to go back to a similar question I asked you before: How do you find interacting with him as a person, Yan, and his family? DR MA: Oh, I mean, I think the biggest interaction with him initially is persuading him to consider a little bit of treatment. I think, actually, he had a lot of hesitation initially. When he came back with Stage IV disease, he was ready just to quit. That’s why we started in such a gentle fashion for him, because we had a long back and forth, several discussions. He needed a long time to think — he really said, “Do you think I can tolerate it? Or should I just go on hospice?” And so that was the back-and-forth discussion. We decided to do a weekly dose and just to — I told him I really don’t think he will have dramatic toxicity to a weekly dose, and he can have a taste of what chemo’s like. And then I find that a lot of times patients can get rid of their fear, just in general of chemotherapy, by starting with a low dose like that, especially palliative patients. Benefits of early palliative care in the management of metastatic NSCLC DR LOVE: I’m going to ask Leora in a second about the issue of early palliative care that’s been studied in lung cancer. But I’m just kind of curious. In your situation, Yan, do you have access to a palliative care team? Now, I’m not talking about hospice, but palliative care team. DR MA: We do. That’s a recent change incorporated, I think, in our practice. Now we have a palliative care nurse in our clinic. DR LOVE: Really? DR MA: Yes. And this started about a year ago, and she’s there 1 day week, and now that’s going to be expanded to 3 days a week. She’s a nurse practitioner that sees all the patients for our location. And it’s going to be expanded to practice wide. All the practice locations eventually will have a palliative care nurse. Yes. DR LOVE: So did this man see that nurse practitioner? DR MA: At the time, I did not refer him, because I felt like it’s my response — at the time, I don’t think his — a palliative care issue is more the gold treatment. I mean, I don’t think it’s wrong for him to be deciding. I always tell patients, “It’s his life — his quality of life.” It’s his decision to make. I don’t think it would be wrong for him to not get any treatment, so I’m not offering a cure, per se. But my feeling always is, since he had this fear, why not try and see how the treatment’s going to be, and then he can make his decision. He got much better now. At this second, actually, he has not been seeing a palliative care nurse at this time. DR LOVE: I’m kind of curious what your take is on this, Leora. Because a lot of people equate palliative care to hospice care, and yet if you really look into what they looked at in the study, the initial study by Jennifer Temel, these patients were seeing them at diagnosis, so they weren’t end of life by any means. They felt like there was a benefit that kind of went beyond end-of-life type issues in terms of, I guess, clinical management of the patient. I’m curious, Leora, what your take is on this. DR HORN: I think it can be very helpful. We also have palliative care available at our clinic. I think the biggest issue for the patients is convenience. And so initially when palliative care was implemented, they were also only there a couple of days a week, and patients didn’t necessarily want to come back and make another visit. And something a patient brought to my attention, which I really didn’t think about is, they have multiple co-pays then. They have to — $30 co-pay for me and then their $30 co-pay for palliative care. And maybe they’re seeing radiation oncology, so they’ve spent $100 seeing 3 different doctors that day, which can really have its impact on a patient and their livelihood, especially for — many of these patients, they’re elderly. They’re on fixed incomes. But I do think that it does have that benefit. Obviously the Temel study showed us that there was an improvement in survival with palliative care. The palliative care folks are better, I think, than oncologists. They have longer clinic visits with the patients. They block off more time. They spend more time sometimes talking to the patients. We have a lot of patients who are followed by palliative care. And, in fact, we’re participating in the follow-up study that Dr Temel’s doing right now looking at telemedicine and patients in palliative care. We have a bunch of patients who are enrolled on her study that is evaluating how that can impact palliative care delivery to cancer patients. DR LOVE: Wow, telemedicine for palliative care. I like that a lot. That sounds great. Really interesting. |