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Immune Checkpoint Inhibitors in Squamous Non-Small Cell Lung Cancer

Panelists:Edward S. Kim, MD, FACP, Carolinas HealthCare System; Benjamin Levy, MD, Mount Sinai Hospital; Paul K. Paik, MD, Memorial Sloan Kettering Cancer Center
Published: Thursday, Mar 17, 2016


Transcript:

Benjamin Levy, MD
: Let’s move on to perhaps one of the most exciting therapies to land in the lung cancer space ever. Nivolumab and pembrolizumab have been complete game changers for the treatment of not just squamous non-small cell lung cancer, but I’d say all non-small cell lung cancer. I would argue that every patient is a candidate for these drugs (either adenocarcinomas or squamous cell tumors), either under the umbrella of a clinical trial or a standard of care. But we’ll focus a little bit on the data with squam today and talk about two of these drugs, nivolumab and pembrolizumab. Interestingly, these drugs are showing gangbuster survival advantages in phase III studies but also come with their own adverse events that we have to re-acquaint ourselves with and learn how to manage. So I’ll briefly go over the nivolumab data and then maybe I can get both your impressions on the data.

CheckMate 017 compared nivolumab versus docetaxel in a chemotherapy-refractory patient population that was squamous cell. And we saw the triple threat. We saw an improvement in response rate, we saw an improvement in PFS, and we saw this improvement in OS, with a hazard ratio that we don’t really see of 0.59. We saw that the grade 3/4 AEs were much more manageable in the nivolumab arm, obviously, than the docetaxel arm. I think importantly, PD-L1 was neither predictive nor prognostic of the effect that we saw in this study, and I certainly will get to PD-L1 and if it is a meaningful useful biomarker for the selection of patients. So clearly game changing. Also in its design, by not employing docetaxel plus nivolumab versus docetaxel, I think that was the beauty of it is that patients were randomized to a non-cytotoxic drug arm and that arm did show a robust survival advantage. Maybe I can get both of your thoughts on this and where we see this heading and the future of nivolumab in the squamous cell population or checkpoint inhibitors in the squamous cell. Ed?

Edward S. Kim, MD, FACP: I don’t want to diminish the impact of what immunotherapy has done as far as our perspective as clinicians, our perspective as patients, as far as opportunities. When you still look at the raw numbers, they are good, they’re positive. But this is not EGFR mutations and erlotinib, gefitinib, or afatinib. I think our excitement has been primed by the previous success in melanoma and renal cell carcinoma. Again, I think they’ve made a major clinical impact and we certainly use them and encourage people to use them. But I don’t want to put a ceiling on these drugs because of this excessive hype and the thought that everybody is going to do well on them. When you look at the numbers, 9.2 months median survival is good compared to a docetaxel arm that was just squamous. Again, in the ramucirumab data in both non-squamous and squamous, it was 9.1 months. I think you would expect a median survival in squamous patients of somewhere between six and eight months. This is better but it’s not 15 months, it’s not 20 months; the response rates are decent, but again Paul just quoted a number in squamous with a response rate of a combination. So I think we have to put them in context. What makes them really attractive to me is the lower side effects. They are so easily taken as long as you’re monitoring the right endocrine labs up front. That is what makes it very attractive over a cytotoxic and to me, that aspect of it is more of a game changer than the actual efficacy numbers.

Benjamin Levy, MD: Yeah, I piggyback on that just in the setting of a patient who has a response. Some of these responses are so durable, and that’s something that we just haven’t seen in a squamous cell population, median durations of response of over a year. I agree with you, 20% response rate, that means 80% are not garnering a benefit up front, although they may have stable disease. I’m not sure response rate is the best surrogate for this drug because we’ve had many patients on trial who haven’t had a response, have had stable disease but their tumor has just halted. The brakes have been put on and there’s no further growth. So I agree, I think everything has to be put in context. These are not cures. Historically speaking though, we have not had a drug like this in squamous cell in quite some time. It’s a welcome change and mostly, I think, patient-centric for the AEs.

Edward S. Kim, MD, FACP: And, again, based on the chronicity of which you can deliver this drug, because it does not confer a lot of side effects, you can give patients this drug for years which is very unusual for any other therapeutic that we’ve had.

Benjamin Levy, MD: Yeah. It’s patient-centric not only in its AE profile but the fact that it actually harnesses the patient’s own immune system. I think patients are behind this, advocacy groups are behind this. Paul, your thoughts on this drug and your use and where this is going.

Paul K. Paik, MD: Yeah, we use it quite a bit. It is the de facto standard now in the second-line setting for patients who can take it. But I think Ed is completely right.

Edward S. Kim, MD, FACP: I didn’t pay him to say that.

Paul K. Paik, MD: There’s been a lot of positive press out there from any number of groups, not just industry, about this class of medications. And while I think it’s definitely warranted in melanoma where it approaches the efficacy that we’ve seen with targeted therapy, we haven’t yet seen that for non-small cell lung cancer. The attraction of course has to do with the subset that has this very durable response which we rarely have seen. And, as Ed had said, the rate of grade 3/4 toxicity from nivolumab over docetaxel was almost nine times less. That’s enormous, 55% rate of grade 3/4 for docetaxel, 7% for nivolumab. And so that’s astounding by itself. I think what this speaks to is that a lot more of effort needs to be put into place and people are doing this now, to figure out exactly who the durable responders are going to be and to figure out whether or not we can manipulate that microenvironment and whatever the patient’s own immune system complexity is to gain that for them. I think that really is the next step, so this is really the tip of the iceberg which is a good tip, but there’s a lot more depth I think that’s there.

Benjamin Levy, MD: I’m hearing from both of you exciting but let’s remain grounded about this drug and what it can and cannot do.

Edward S. Kim, MD, FACP: I’ve called nivolumab the new docetaxel because you can use it in anyone and it does better than what docetaxel did back in 2000 when it was first approved, based on Frances Sheppard and Frank Fossella, but I want it to be a docetaxel plus. I want there to be a biomarker subset that is enriched that we routinely go after to try and improve things with because if we’re just satisfied, give it to everybody and some of them will do really well and a lot of them won’t, I don’t want that. I think we’re taking two steps back if we accept that.

Transcript Edited for Clarity
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Transcript:

Benjamin Levy, MD
: Let’s move on to perhaps one of the most exciting therapies to land in the lung cancer space ever. Nivolumab and pembrolizumab have been complete game changers for the treatment of not just squamous non-small cell lung cancer, but I’d say all non-small cell lung cancer. I would argue that every patient is a candidate for these drugs (either adenocarcinomas or squamous cell tumors), either under the umbrella of a clinical trial or a standard of care. But we’ll focus a little bit on the data with squam today and talk about two of these drugs, nivolumab and pembrolizumab. Interestingly, these drugs are showing gangbuster survival advantages in phase III studies but also come with their own adverse events that we have to re-acquaint ourselves with and learn how to manage. So I’ll briefly go over the nivolumab data and then maybe I can get both your impressions on the data.

CheckMate 017 compared nivolumab versus docetaxel in a chemotherapy-refractory patient population that was squamous cell. And we saw the triple threat. We saw an improvement in response rate, we saw an improvement in PFS, and we saw this improvement in OS, with a hazard ratio that we don’t really see of 0.59. We saw that the grade 3/4 AEs were much more manageable in the nivolumab arm, obviously, than the docetaxel arm. I think importantly, PD-L1 was neither predictive nor prognostic of the effect that we saw in this study, and I certainly will get to PD-L1 and if it is a meaningful useful biomarker for the selection of patients. So clearly game changing. Also in its design, by not employing docetaxel plus nivolumab versus docetaxel, I think that was the beauty of it is that patients were randomized to a non-cytotoxic drug arm and that arm did show a robust survival advantage. Maybe I can get both of your thoughts on this and where we see this heading and the future of nivolumab in the squamous cell population or checkpoint inhibitors in the squamous cell. Ed?

Edward S. Kim, MD, FACP: I don’t want to diminish the impact of what immunotherapy has done as far as our perspective as clinicians, our perspective as patients, as far as opportunities. When you still look at the raw numbers, they are good, they’re positive. But this is not EGFR mutations and erlotinib, gefitinib, or afatinib. I think our excitement has been primed by the previous success in melanoma and renal cell carcinoma. Again, I think they’ve made a major clinical impact and we certainly use them and encourage people to use them. But I don’t want to put a ceiling on these drugs because of this excessive hype and the thought that everybody is going to do well on them. When you look at the numbers, 9.2 months median survival is good compared to a docetaxel arm that was just squamous. Again, in the ramucirumab data in both non-squamous and squamous, it was 9.1 months. I think you would expect a median survival in squamous patients of somewhere between six and eight months. This is better but it’s not 15 months, it’s not 20 months; the response rates are decent, but again Paul just quoted a number in squamous with a response rate of a combination. So I think we have to put them in context. What makes them really attractive to me is the lower side effects. They are so easily taken as long as you’re monitoring the right endocrine labs up front. That is what makes it very attractive over a cytotoxic and to me, that aspect of it is more of a game changer than the actual efficacy numbers.

Benjamin Levy, MD: Yeah, I piggyback on that just in the setting of a patient who has a response. Some of these responses are so durable, and that’s something that we just haven’t seen in a squamous cell population, median durations of response of over a year. I agree with you, 20% response rate, that means 80% are not garnering a benefit up front, although they may have stable disease. I’m not sure response rate is the best surrogate for this drug because we’ve had many patients on trial who haven’t had a response, have had stable disease but their tumor has just halted. The brakes have been put on and there’s no further growth. So I agree, I think everything has to be put in context. These are not cures. Historically speaking though, we have not had a drug like this in squamous cell in quite some time. It’s a welcome change and mostly, I think, patient-centric for the AEs.

Edward S. Kim, MD, FACP: And, again, based on the chronicity of which you can deliver this drug, because it does not confer a lot of side effects, you can give patients this drug for years which is very unusual for any other therapeutic that we’ve had.

Benjamin Levy, MD: Yeah. It’s patient-centric not only in its AE profile but the fact that it actually harnesses the patient’s own immune system. I think patients are behind this, advocacy groups are behind this. Paul, your thoughts on this drug and your use and where this is going.

Paul K. Paik, MD: Yeah, we use it quite a bit. It is the de facto standard now in the second-line setting for patients who can take it. But I think Ed is completely right.

Edward S. Kim, MD, FACP: I didn’t pay him to say that.

Paul K. Paik, MD: There’s been a lot of positive press out there from any number of groups, not just industry, about this class of medications. And while I think it’s definitely warranted in melanoma where it approaches the efficacy that we’ve seen with targeted therapy, we haven’t yet seen that for non-small cell lung cancer. The attraction of course has to do with the subset that has this very durable response which we rarely have seen. And, as Ed had said, the rate of grade 3/4 toxicity from nivolumab over docetaxel was almost nine times less. That’s enormous, 55% rate of grade 3/4 for docetaxel, 7% for nivolumab. And so that’s astounding by itself. I think what this speaks to is that a lot more of effort needs to be put into place and people are doing this now, to figure out exactly who the durable responders are going to be and to figure out whether or not we can manipulate that microenvironment and whatever the patient’s own immune system complexity is to gain that for them. I think that really is the next step, so this is really the tip of the iceberg which is a good tip, but there’s a lot more depth I think that’s there.

Benjamin Levy, MD: I’m hearing from both of you exciting but let’s remain grounded about this drug and what it can and cannot do.

Edward S. Kim, MD, FACP: I’ve called nivolumab the new docetaxel because you can use it in anyone and it does better than what docetaxel did back in 2000 when it was first approved, based on Frances Sheppard and Frank Fossella, but I want it to be a docetaxel plus. I want there to be a biomarker subset that is enriched that we routinely go after to try and improve things with because if we’re just satisfied, give it to everybody and some of them will do really well and a lot of them won’t, I don’t want that. I think we’re taking two steps back if we accept that.

Transcript Edited for Clarity
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