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The Current Role for Antiangiogenic Therapy for NSCLC

Panelists: Mark A. Socinski, MD, Florida Hospital Cancer Institute; Mark Kris, MD, Memorial Sloan-Kettering; Jared Weiss, MD, UNC Lineberger Comprehensive Cancer Center; Ross Camidge, MD, PhD, University of Colorado Cancer Center; David R. Spigel, MD, Sarah Cannon Research Institute
Published: Tuesday, Jul 11, 2017



Transcript:

Mark A. Socinski, MD:
Let’s switch gears. I’m going to ask Dr Kris to chime in on his use of antiangiogenic therapy, particularly bevacizumab, in the first-line setting. What’s your current view of that landscape?

Mark G. Kris, MD: I fully feel that bevacizumab adds in terms of response, response duration, and survival to our standard therapies. It has got an approval to be given with any kind of platinum doublet, and I do think that’s the way it should be used. I use it that way. I realize I’m in a decided minority.

Mark A. Socinski, MD: No, I agree with you.

Mark G. Kris, MD: The drug is there, and it works. I have to tell you, it’s almost a drug without consequences for the average patient. Most patients are able to live with the adverse effects of it—the runny nose and things like that. But it’s just not being used. Oncologists have walked away from it. I urge people, though, to walk back to it. I think we’re seeing more and more data, by the way, by using this class of drugs with anti-PD-1 and anti-PD-L1 drugs, and the jury is out on whether that is going to be a good strategy or not. But I think it’s clear that it can be done. Whether it should be done, I think more data are going to tell us that.

David R. Spigel, MD: Mark and I talked about this recently, and I agreed with your thinking. Recently, I have seen data that said the opposite though, that many doctors in the community are actually still using bevacizumab-based regimens. It was about half of what they chose for their first-line nonsquamous setting. Now, I personally think that the KEYNOTE-021G trial is going to change that. I think if a doctor has a choice, over a bevacizumab-based Taxol (paclitaxel) regimen, he’s going to choose the carboplatin/pemetrexed/pembrolizumab regimen. We’ll have to see how that plays out, but I suspect that will happen.

Mark A. Socinski, MD: Yes, until they have a grade 4 immune-related toxicity, and then it may change. Ross, your view?

Ross Camidge, MD, PhD: I think they’re cannibalizing the same population. There’s the nonsquamous population, and it’s hard to imagine that bevacizumab’s market share is somehow going to increase. I think, if anything, it’s going to be eaten up by carboplatin/pemetrexed/pembrolizumab.

Mark A. Socinski, MD: It’s interesting. At the end of the day, I’ve always said we have 4 positive phase III trials with bevacizumab, though the design of one of those, the AVAiL trial, was less than adequate. We have the ECOG 4599 trial as one bookend and we have the BEYOND trial in China as a second bookend, all of which show the survival advantage, as you point out. It’s curious why the enthusiasm for this agent in the first-line setting has eroded.

Mark G. Kris, MD: It was never there actually. It was very, very short-lived. The drug is there. I hope doctors think about it, but I don’t think we’re going to change their minds.

Mark A. Socinski, MD: And one of the criticisms is the maintenance aspect of the use of bevacizumab, even though we’ve never really isolated that.

Mark G. Kris, MD: Again, it’s the data. That’s how it was approved. That’s what it is. Whether you need it or not…

Jared Weiss, MD: I think Dr Kris’s point about the culture of these drugs applies to that as well. People who have no problem giving pemetrexed maintenance suddenly do have a problem with bevacizumab.

Mark A. Socinski, MD: Well, this is why I was going to get your opinions on the ECOG 5508 trial. About 6 or 7 years ago, maintenance was a hot topic. We don’t talk about it anymore. We have the ECOG group looking at giving patients on the ECOG 5508 trial 4 cycles of carboplatin/paclitaxel and bevacizumab; in the nonprogressor setting, the 3 randomized arms are looking at continuation maintenance with bevacizumab, switch maintenance with pemetrexed alone with no bevacizumab, and the strategy of dual maintenance therapy with both the continuation of bevacizumab and switch to pemetrexed in the same arm. Overall survival is the primary endpoint, which is a big hurdle for that trial. Is this going to influence practice?

Ross Camidge, MD, PhD: I don’t think they’ll clear the hurdle, and if they do, I don’t think anyone is going to care.

Mark G. Kris, MD: It’s a 2013 question being answered in 2018.

David R. Spigel, MD: It’s unfortunate, because at the time—you’re right—we were all talking about maintenance value, and the design was a very laudable study. It’s just that the world has shifted around us. And it makes me worried about research in general, because things move so quickly right now that when you design studies like this that are important, by the time you get answers it may not really matter anymore.

Ross Camidge, MD, PhD: Well, it makes me worry about research in the cooperative group setting in particular.

Mark G. Kris, MD: Yes, where things move a little bit slower.

Mark A. Socinski, MD: But the good news is, if patients are living longer that’s a good thing, no matter what the reason.

Mark G. Kris, MD: Now, obviously, bevacizumab is a first-line issue. A couple of years ago we also had the approval of ramucirumab in the second-line setting—a monoclonal antibody with a different mechanism of action, and a receptor-based antibody. Jared, what are your thoughts about that agent? It was the REVEL trial that compared it using docetaxel. And then I think we forget on this side of the Atlantic that over in Europe, there’s an approval for TKIs in this space in combination with docetaxel. That might be limited to adenocarcinoma, if I remember correctly. What are your thoughts about continuing antiangiogenic therapy through multiple lines?—which brings up the AVAiL trial, which is continuation bevacizumab through multiple lines of therapy. So, what are your thoughts on this concept of continued second-line use of specifically ramucirumab and nintedanib?

Jared Weiss, MD: To me, it’s the same theme as that comment from a moment ago of an older question that’s relevant in the modern clinical context. Mostly because we’re not using as much docetaxel as we used to use. Patients are getting a platinum or triplet with bevacizumab and a PD-1 agent in the first- and second-line setting. No one’s really thinking about docetaxel in the second-line anymore, it’s a very toxic and not particularly effective drug. It probably competes for the least favorite thoracic oncology drug used. For me, it’s cisplatin, but I know you probably don’t want to get into that right now.

Mark G. Kris, MD: It’s my favorite, it cures people.

Jared Weiss, MD: But you know, joking aside, it’s not a commonly used cytotoxic any more. So, asking if you want to add a little bit to it is a less clinically relevant question. Nothing is wrong with the trial design or positive data—in a different context, nothing is wrong with it. In fact, when I use docetaxel, I do tend to add ramucirumab to it. It’s just that I don’t use docetaxel very often.

Mark G. Kris, MD: Yes, I would totally agree with that. The other thing is that I use the gastric schedule. It’s absolutely crazy that the lung and gastric regimens have totally different schedules and doses. The gastric schedule giving both drugs every 2 weeks works out so much better, and I think if you choose to do that—just like Jared said—when you’re using docetaxel, I always put ramucirumab on it.

Ross Camidge, MD, PhD: I’d like to raise this issue: let’s imagine you have somebody who didn’t get immunotherapy in the first-line setting, and now you’re in the second-line setting. Is there anyone who you would give docetaxel/dexamethasone/ramucirumab to as opposed to an immunotherapy agent, based on symptoms, age, or anything else? How do you make that decision?

Mark G. Kris, MD: Totally dead PD-L1, dead negative, low mutational burden, no microsatellite instability—I might go with the docetaxel and the ramucirumab.

Mark A. Socinski, MD: Yes. I was thinking of a never-smoker, because I always felt if you look at either the EGFR mutants—not a ton of patients to date—or the never-smokers, immunotherapy doesn’t really distinguish itself from docetaxel in those subgroups. But docetaxel/ramucirumab did distinguish itself in both responses, PFS and OS, relative to docetaxel alone. So, I would agree. I think there are some patients, not to mention the obvious, who have some autoimmune history.

Jared Weiss, MD: Which is a decent sized population.

Mark G. Kris, MD: Yes. But the next-generation report gives you a lot of information now. It gives you the mutational burden score, it gives you microsatellite instability, it can tell you if you have a driver, and it also gives you the total number of mutations found in that panel. When all those things suggest negative, that’s when you don’t use it.

Transcript Edited for Clarity

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Transcript:

Mark A. Socinski, MD:
Let’s switch gears. I’m going to ask Dr Kris to chime in on his use of antiangiogenic therapy, particularly bevacizumab, in the first-line setting. What’s your current view of that landscape?

Mark G. Kris, MD: I fully feel that bevacizumab adds in terms of response, response duration, and survival to our standard therapies. It has got an approval to be given with any kind of platinum doublet, and I do think that’s the way it should be used. I use it that way. I realize I’m in a decided minority.

Mark A. Socinski, MD: No, I agree with you.

Mark G. Kris, MD: The drug is there, and it works. I have to tell you, it’s almost a drug without consequences for the average patient. Most patients are able to live with the adverse effects of it—the runny nose and things like that. But it’s just not being used. Oncologists have walked away from it. I urge people, though, to walk back to it. I think we’re seeing more and more data, by the way, by using this class of drugs with anti-PD-1 and anti-PD-L1 drugs, and the jury is out on whether that is going to be a good strategy or not. But I think it’s clear that it can be done. Whether it should be done, I think more data are going to tell us that.

David R. Spigel, MD: Mark and I talked about this recently, and I agreed with your thinking. Recently, I have seen data that said the opposite though, that many doctors in the community are actually still using bevacizumab-based regimens. It was about half of what they chose for their first-line nonsquamous setting. Now, I personally think that the KEYNOTE-021G trial is going to change that. I think if a doctor has a choice, over a bevacizumab-based Taxol (paclitaxel) regimen, he’s going to choose the carboplatin/pemetrexed/pembrolizumab regimen. We’ll have to see how that plays out, but I suspect that will happen.

Mark A. Socinski, MD: Yes, until they have a grade 4 immune-related toxicity, and then it may change. Ross, your view?

Ross Camidge, MD, PhD: I think they’re cannibalizing the same population. There’s the nonsquamous population, and it’s hard to imagine that bevacizumab’s market share is somehow going to increase. I think, if anything, it’s going to be eaten up by carboplatin/pemetrexed/pembrolizumab.

Mark A. Socinski, MD: It’s interesting. At the end of the day, I’ve always said we have 4 positive phase III trials with bevacizumab, though the design of one of those, the AVAiL trial, was less than adequate. We have the ECOG 4599 trial as one bookend and we have the BEYOND trial in China as a second bookend, all of which show the survival advantage, as you point out. It’s curious why the enthusiasm for this agent in the first-line setting has eroded.

Mark G. Kris, MD: It was never there actually. It was very, very short-lived. The drug is there. I hope doctors think about it, but I don’t think we’re going to change their minds.

Mark A. Socinski, MD: And one of the criticisms is the maintenance aspect of the use of bevacizumab, even though we’ve never really isolated that.

Mark G. Kris, MD: Again, it’s the data. That’s how it was approved. That’s what it is. Whether you need it or not…

Jared Weiss, MD: I think Dr Kris’s point about the culture of these drugs applies to that as well. People who have no problem giving pemetrexed maintenance suddenly do have a problem with bevacizumab.

Mark A. Socinski, MD: Well, this is why I was going to get your opinions on the ECOG 5508 trial. About 6 or 7 years ago, maintenance was a hot topic. We don’t talk about it anymore. We have the ECOG group looking at giving patients on the ECOG 5508 trial 4 cycles of carboplatin/paclitaxel and bevacizumab; in the nonprogressor setting, the 3 randomized arms are looking at continuation maintenance with bevacizumab, switch maintenance with pemetrexed alone with no bevacizumab, and the strategy of dual maintenance therapy with both the continuation of bevacizumab and switch to pemetrexed in the same arm. Overall survival is the primary endpoint, which is a big hurdle for that trial. Is this going to influence practice?

Ross Camidge, MD, PhD: I don’t think they’ll clear the hurdle, and if they do, I don’t think anyone is going to care.

Mark G. Kris, MD: It’s a 2013 question being answered in 2018.

David R. Spigel, MD: It’s unfortunate, because at the time—you’re right—we were all talking about maintenance value, and the design was a very laudable study. It’s just that the world has shifted around us. And it makes me worried about research in general, because things move so quickly right now that when you design studies like this that are important, by the time you get answers it may not really matter anymore.

Ross Camidge, MD, PhD: Well, it makes me worry about research in the cooperative group setting in particular.

Mark G. Kris, MD: Yes, where things move a little bit slower.

Mark A. Socinski, MD: But the good news is, if patients are living longer that’s a good thing, no matter what the reason.

Mark G. Kris, MD: Now, obviously, bevacizumab is a first-line issue. A couple of years ago we also had the approval of ramucirumab in the second-line setting—a monoclonal antibody with a different mechanism of action, and a receptor-based antibody. Jared, what are your thoughts about that agent? It was the REVEL trial that compared it using docetaxel. And then I think we forget on this side of the Atlantic that over in Europe, there’s an approval for TKIs in this space in combination with docetaxel. That might be limited to adenocarcinoma, if I remember correctly. What are your thoughts about continuing antiangiogenic therapy through multiple lines?—which brings up the AVAiL trial, which is continuation bevacizumab through multiple lines of therapy. So, what are your thoughts on this concept of continued second-line use of specifically ramucirumab and nintedanib?

Jared Weiss, MD: To me, it’s the same theme as that comment from a moment ago of an older question that’s relevant in the modern clinical context. Mostly because we’re not using as much docetaxel as we used to use. Patients are getting a platinum or triplet with bevacizumab and a PD-1 agent in the first- and second-line setting. No one’s really thinking about docetaxel in the second-line anymore, it’s a very toxic and not particularly effective drug. It probably competes for the least favorite thoracic oncology drug used. For me, it’s cisplatin, but I know you probably don’t want to get into that right now.

Mark G. Kris, MD: It’s my favorite, it cures people.

Jared Weiss, MD: But you know, joking aside, it’s not a commonly used cytotoxic any more. So, asking if you want to add a little bit to it is a less clinically relevant question. Nothing is wrong with the trial design or positive data—in a different context, nothing is wrong with it. In fact, when I use docetaxel, I do tend to add ramucirumab to it. It’s just that I don’t use docetaxel very often.

Mark G. Kris, MD: Yes, I would totally agree with that. The other thing is that I use the gastric schedule. It’s absolutely crazy that the lung and gastric regimens have totally different schedules and doses. The gastric schedule giving both drugs every 2 weeks works out so much better, and I think if you choose to do that—just like Jared said—when you’re using docetaxel, I always put ramucirumab on it.

Ross Camidge, MD, PhD: I’d like to raise this issue: let’s imagine you have somebody who didn’t get immunotherapy in the first-line setting, and now you’re in the second-line setting. Is there anyone who you would give docetaxel/dexamethasone/ramucirumab to as opposed to an immunotherapy agent, based on symptoms, age, or anything else? How do you make that decision?

Mark G. Kris, MD: Totally dead PD-L1, dead negative, low mutational burden, no microsatellite instability—I might go with the docetaxel and the ramucirumab.

Mark A. Socinski, MD: Yes. I was thinking of a never-smoker, because I always felt if you look at either the EGFR mutants—not a ton of patients to date—or the never-smokers, immunotherapy doesn’t really distinguish itself from docetaxel in those subgroups. But docetaxel/ramucirumab did distinguish itself in both responses, PFS and OS, relative to docetaxel alone. So, I would agree. I think there are some patients, not to mention the obvious, who have some autoimmune history.

Jared Weiss, MD: Which is a decent sized population.

Mark G. Kris, MD: Yes. But the next-generation report gives you a lot of information now. It gives you the mutational burden score, it gives you microsatellite instability, it can tell you if you have a driver, and it also gives you the total number of mutations found in that panel. When all those things suggest negative, that’s when you don’t use it.

Transcript Edited for Clarity
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