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What to Do After Progression on Immunotherapy and for Non-Driver NSCLC

Panelists: Mark A. Socinski, MD, Florida Hospital Cancer Institute; Tracey L. Evans, MD, University of Pennsylvania; Alexander Drilon, MD, Memorial Sloan Kettering Cancer Center; Vali A. Papadimitrakopoulou, MD, The University of Texas MD Anderson Cancer Center; Jared Weiss, MD, UNC Lineberger Comprehensive Cancer Center
Published: Wednesday, Apr 05, 2017


Transcript:

Mark Socinski, MD:
I do think the KEYNOTE-024 trial results are a major step forward. In my practice, I think 10% to 20% of patients are going to get pembrolizumab in the first-line setting, based on that trial. What do you do after pembrolizumab in those patients? Tracey?

Tracey Evans, MD: I’ll go back to the standard chemotherapy. I haven’t had somebody who I’ve put on it and who’s progressed on it yet. But my plan would be to go back to my standard first-line chemotherapy options.

Mark Socinski, MD: Should we get rid of first-line, second-line, and third-line, and just use next-line?

Tracey Evans, MD: Right. It’s interesting because there was a lot of angst in some of the pharmaceutical companies because their drug is approved based on line of therapy. But the way I think about it is, the only place that line of therapy applies is in cytotoxic therapy. There’s first-line cytotoxic and second-line cytotoxic. So, if they‘ve had first-line immunotherapy and they’ve progressed, then they’re going on to first-line cytotoxic therapy, and I’ll use all the usual first-line cytotoxics that I used.

Mark Socinski, MD: Others, do you all have the same thinking?

Vali Papadimitrakopoulou, MD: Yes. Maybe we should just eliminate the first-line altogether—combination cytotoxic chemotherapy—because we anticipate that it’s going to be tolerated in this setting after immunotherapy, versus single-agent chemotherapy, in later lines after progression on second-line or third-line immunotherapy.

Mark Socinski, MD: In these patients, or the greater mass that is not strongly PD-L1-positive, they don’t have an oncogenic driver, and let’s say you’ve searched high and low for any actionable sort of thing and you don’t have anything, we’re still kind of in the chemotherapy cytotoxic arena?

Jared Weiss, MD: Outside of a clinical trial, yes.

Mark Socinski, MD: Yes, outside of a clinical trial.

Tracey Evans, MD: It can be very effective. That’s the other thing that’s important to remember.

Mark Socinski, MD: Tracey, what are your go-to regimens in this population?

Tracey Evans, MD: We’re talking about in nonsquamous disease?

Mark Socinski, MD: Yes.

Tracey Evans, MD: Carboplatin/pemetrexed is my go-to regimen, plus or minus bevacizumab, depending upon the individual characteristics of the patient.

Mark Socinski, MD: And Alex?

Alexander Drilon, MD: Same thing—carboplatin/pemetrexed plus or minus bevacizumab.

Mark Socinski, MD: Vali?

Vali Papadimitrakopoulou, MD: I do the same thing.

Mark Socinski, MD: For what percentage of patients, would you say, in your practice, do you make the decision to use bevacizumab?

Tracey Evans, MD: I’d say 20% or 30%.

Vali Papadimitrakopoulou, MD: Maybe a little less.

Alexander Drilon, MD: Probably 40%.

Mark Socinski, MD: Okay. I’m probably more in the 40% range also.

Jared Weiss, MD: We really have a lack of data in the context of pemetrexed/carboplatin, as to what we add, if anything, with bevacizumab in that context. We know, for sure, that with carboplatin and paclitaxel that the addition of bevacizumab does help. But with the tolerability of pemetrexed, as well as some of the histology specific data, I think many, in both academia and community, have moved toward it in the frontline setting. And now, we just don’t know what we get.

Mark Socinski, MD: It’s something that I have a difficult time understanding, because I like to base my judgment on evidence. I’m just not quite sure where the evidence is—that in a nonsquamous bevacizumab-eligible population, giving carboplatin/pemetrexed alone is as good as the 3-drug combination of carboplatin/pemetrexed or paclitaxel with bevacizumab. We just don’t have that data to say that you aren’t compromising outcomes. We know, from a bevacizumab point of view, that for better or for worse, it’s an agent that has 4 positive phase III trials. It met every endpoint in 4 phase III trials, right? So, why wouldn’t you use it? There are lots of reasons not to use it.

Tracey Evans, MD: So, then the question becomes, if you are using carboplatin/pemetrexed/bevacizumab, what does everybody do in maintenance, where I think it becomes even muddier?

Mark Socinski, MD: Yes, it does.

Tracey Evans, MD: And talk about racking up the cost on providing care. If you have people who are on long-term maintenance pemetrexed and bevacizumab that really breaks that bank.

Mark Socinski, MD: What about use of anti-angiogenic agents beyond first-line, second-line? We know about the docetaxel/ramucirumab REVEL data. Is that part of your standard? Let’s say for some reason the patient can’t get immunotherapy. Is that your standard second-line?

Tracey Evans, MD: It’s not. I don’t like using docetaxel all that much at full Q3 week dosing. I think the benefit of ramucirumab, with some additional toxicity, is not worth the expensive cost. It’s $10,000 per month that you’re adding, and the hazard ratio is, I think, 0.84 for overall survival. So, yes, there’s an overall survival benefit, but it was quite small and it did add additional toxicity. It adds a load of expense, and it makes me feel like I need to give docetaxel in a way that I think is quite toxic. So, I’ve not adopted that.

Mark Socinski, MD: Others have different feelings?

Jared Weiss, MD: No, my feelings are very similar. I think that that was a well-run randomized phase III trial that showed an advantage for the addition of ramucirumab to docetaxel. The problem is that I share Tracey’s bias against using docetaxel. Patients feel awful on it. So, if I do have reason to pull out docetaxel in my practice, I tend to dose reduce it.

There are some Chinese data that reveal that you can go down to 60 mg/m2 without impairing efficacy in the second-line setting. And, if I do that, I’ll add ramucirumab to it. But my lack of use is primarily driven by a distaste for docetaxel. There are data looking at the combination of Taxol and bevacizumab in the second-line setting that we just got a look at. That was favorable compared to docetaxel, but it was not a very user-friendly regimen. It was a weekly regimen, if I recall, and I’m not sure that it has gotten a lot of real world uptake, but it’s certainly a valid option.

Mark Socinski, MD: In a second-line trial, the French trial, that brings up the issue that even though we know these 2 antibodies, bevacizumab and ramucirumab, have different mechanisms of action, is their biologic impact any different? The data kind of look similar.

Vali Papadimitrakopoulou, MD: It is hard to say.

Mark Socinski, MD: This has been extremely informative. Before we end this discussion, I’d like to get some final thoughts from each of our panelists. Dr. Drilon?

Alexander Drilon, MD: So, as we’ve discussed, there have been exciting developments, both in the targeted therapy arena and in the I-O arena. I think my major point is to try to get as much tissue as is safe and feasible in order to test your patients for both biomarkers.

Mark Socinski, MD: Tracey?

Tracey Evans, MD: There’s a lot of reason for hope in the treatment of advanced non-small cell lung cancer, but there are still those patients for whom none of this new stuff is going to work. And we have to keep them in our hearts and remember that early palliative care has also been shown to be very beneficial in this patient population.

Mark Socinski, MD: Good point. Jared?

Jared Weiss, MD: You can’t action a molecular altercation if you haven’t tested for it and found it. So, test every patient. And the same goes for immunotherapy in the first-line setting. You can’t offer this to patients if you haven’t tested for it.

Mark Socinski, MD: Vali?

Vali Papadimitrakopoulou, MD: I think there have been dramatic changes in the landscape of treatment of non–small cell lung cancer, and I think that’s testament to the efforts of academic community, pharmaceutical companies, and the FDA. I think the intense focus, for the next few years, is going to be combinations of immunotherapy with other agents and how to best fit them in the treatment of all of the patients, not just the minority.

Mark Socinski, MD: I think you raise a good point. The academic community, the pharmaceutical community, the NCI, and even community physicians have a vital part in advancing the bar, if you will. We all must be in this together, and it really underscores the importance of clinical trials—ones that are well designed and ones that we try to do as quickly as we can so we get the answers and move on. Thank you all for your contributions to this discussion. On behalf of our panel, we thank you for joining us and we hope you found this Peer Exchange® discussion to be useful and informative.

Transcript Edited for Clarity
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Transcript:

Mark Socinski, MD:
I do think the KEYNOTE-024 trial results are a major step forward. In my practice, I think 10% to 20% of patients are going to get pembrolizumab in the first-line setting, based on that trial. What do you do after pembrolizumab in those patients? Tracey?

Tracey Evans, MD: I’ll go back to the standard chemotherapy. I haven’t had somebody who I’ve put on it and who’s progressed on it yet. But my plan would be to go back to my standard first-line chemotherapy options.

Mark Socinski, MD: Should we get rid of first-line, second-line, and third-line, and just use next-line?

Tracey Evans, MD: Right. It’s interesting because there was a lot of angst in some of the pharmaceutical companies because their drug is approved based on line of therapy. But the way I think about it is, the only place that line of therapy applies is in cytotoxic therapy. There’s first-line cytotoxic and second-line cytotoxic. So, if they‘ve had first-line immunotherapy and they’ve progressed, then they’re going on to first-line cytotoxic therapy, and I’ll use all the usual first-line cytotoxics that I used.

Mark Socinski, MD: Others, do you all have the same thinking?

Vali Papadimitrakopoulou, MD: Yes. Maybe we should just eliminate the first-line altogether—combination cytotoxic chemotherapy—because we anticipate that it’s going to be tolerated in this setting after immunotherapy, versus single-agent chemotherapy, in later lines after progression on second-line or third-line immunotherapy.

Mark Socinski, MD: In these patients, or the greater mass that is not strongly PD-L1-positive, they don’t have an oncogenic driver, and let’s say you’ve searched high and low for any actionable sort of thing and you don’t have anything, we’re still kind of in the chemotherapy cytotoxic arena?

Jared Weiss, MD: Outside of a clinical trial, yes.

Mark Socinski, MD: Yes, outside of a clinical trial.

Tracey Evans, MD: It can be very effective. That’s the other thing that’s important to remember.

Mark Socinski, MD: Tracey, what are your go-to regimens in this population?

Tracey Evans, MD: We’re talking about in nonsquamous disease?

Mark Socinski, MD: Yes.

Tracey Evans, MD: Carboplatin/pemetrexed is my go-to regimen, plus or minus bevacizumab, depending upon the individual characteristics of the patient.

Mark Socinski, MD: And Alex?

Alexander Drilon, MD: Same thing—carboplatin/pemetrexed plus or minus bevacizumab.

Mark Socinski, MD: Vali?

Vali Papadimitrakopoulou, MD: I do the same thing.

Mark Socinski, MD: For what percentage of patients, would you say, in your practice, do you make the decision to use bevacizumab?

Tracey Evans, MD: I’d say 20% or 30%.

Vali Papadimitrakopoulou, MD: Maybe a little less.

Alexander Drilon, MD: Probably 40%.

Mark Socinski, MD: Okay. I’m probably more in the 40% range also.

Jared Weiss, MD: We really have a lack of data in the context of pemetrexed/carboplatin, as to what we add, if anything, with bevacizumab in that context. We know, for sure, that with carboplatin and paclitaxel that the addition of bevacizumab does help. But with the tolerability of pemetrexed, as well as some of the histology specific data, I think many, in both academia and community, have moved toward it in the frontline setting. And now, we just don’t know what we get.

Mark Socinski, MD: It’s something that I have a difficult time understanding, because I like to base my judgment on evidence. I’m just not quite sure where the evidence is—that in a nonsquamous bevacizumab-eligible population, giving carboplatin/pemetrexed alone is as good as the 3-drug combination of carboplatin/pemetrexed or paclitaxel with bevacizumab. We just don’t have that data to say that you aren’t compromising outcomes. We know, from a bevacizumab point of view, that for better or for worse, it’s an agent that has 4 positive phase III trials. It met every endpoint in 4 phase III trials, right? So, why wouldn’t you use it? There are lots of reasons not to use it.

Tracey Evans, MD: So, then the question becomes, if you are using carboplatin/pemetrexed/bevacizumab, what does everybody do in maintenance, where I think it becomes even muddier?

Mark Socinski, MD: Yes, it does.

Tracey Evans, MD: And talk about racking up the cost on providing care. If you have people who are on long-term maintenance pemetrexed and bevacizumab that really breaks that bank.

Mark Socinski, MD: What about use of anti-angiogenic agents beyond first-line, second-line? We know about the docetaxel/ramucirumab REVEL data. Is that part of your standard? Let’s say for some reason the patient can’t get immunotherapy. Is that your standard second-line?

Tracey Evans, MD: It’s not. I don’t like using docetaxel all that much at full Q3 week dosing. I think the benefit of ramucirumab, with some additional toxicity, is not worth the expensive cost. It’s $10,000 per month that you’re adding, and the hazard ratio is, I think, 0.84 for overall survival. So, yes, there’s an overall survival benefit, but it was quite small and it did add additional toxicity. It adds a load of expense, and it makes me feel like I need to give docetaxel in a way that I think is quite toxic. So, I’ve not adopted that.

Mark Socinski, MD: Others have different feelings?

Jared Weiss, MD: No, my feelings are very similar. I think that that was a well-run randomized phase III trial that showed an advantage for the addition of ramucirumab to docetaxel. The problem is that I share Tracey’s bias against using docetaxel. Patients feel awful on it. So, if I do have reason to pull out docetaxel in my practice, I tend to dose reduce it.

There are some Chinese data that reveal that you can go down to 60 mg/m2 without impairing efficacy in the second-line setting. And, if I do that, I’ll add ramucirumab to it. But my lack of use is primarily driven by a distaste for docetaxel. There are data looking at the combination of Taxol and bevacizumab in the second-line setting that we just got a look at. That was favorable compared to docetaxel, but it was not a very user-friendly regimen. It was a weekly regimen, if I recall, and I’m not sure that it has gotten a lot of real world uptake, but it’s certainly a valid option.

Mark Socinski, MD: In a second-line trial, the French trial, that brings up the issue that even though we know these 2 antibodies, bevacizumab and ramucirumab, have different mechanisms of action, is their biologic impact any different? The data kind of look similar.

Vali Papadimitrakopoulou, MD: It is hard to say.

Mark Socinski, MD: This has been extremely informative. Before we end this discussion, I’d like to get some final thoughts from each of our panelists. Dr. Drilon?

Alexander Drilon, MD: So, as we’ve discussed, there have been exciting developments, both in the targeted therapy arena and in the I-O arena. I think my major point is to try to get as much tissue as is safe and feasible in order to test your patients for both biomarkers.

Mark Socinski, MD: Tracey?

Tracey Evans, MD: There’s a lot of reason for hope in the treatment of advanced non-small cell lung cancer, but there are still those patients for whom none of this new stuff is going to work. And we have to keep them in our hearts and remember that early palliative care has also been shown to be very beneficial in this patient population.

Mark Socinski, MD: Good point. Jared?

Jared Weiss, MD: You can’t action a molecular altercation if you haven’t tested for it and found it. So, test every patient. And the same goes for immunotherapy in the first-line setting. You can’t offer this to patients if you haven’t tested for it.

Mark Socinski, MD: Vali?

Vali Papadimitrakopoulou, MD: I think there have been dramatic changes in the landscape of treatment of non–small cell lung cancer, and I think that’s testament to the efforts of academic community, pharmaceutical companies, and the FDA. I think the intense focus, for the next few years, is going to be combinations of immunotherapy with other agents and how to best fit them in the treatment of all of the patients, not just the minority.

Mark Socinski, MD: I think you raise a good point. The academic community, the pharmaceutical community, the NCI, and even community physicians have a vital part in advancing the bar, if you will. We all must be in this together, and it really underscores the importance of clinical trials—ones that are well designed and ones that we try to do as quickly as we can so we get the answers and move on. Thank you all for your contributions to this discussion. On behalf of our panel, we thank you for joining us and we hope you found this Peer Exchange® discussion to be useful and informative.

Transcript Edited for Clarity
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