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Checkpoint Inhibitors in Small-Cell Lung Cancer

Panelists: Mary Jo Fidler, MD, Rush; Roy S. Herbst, MD, PhD, Yale ; Geoffrey R. Oxnard, MD, Harvard; Naiyer Rizvi, MD, Columbia; Mark A. Socinski, MD,
Published: Wednesday, Nov 11, 2015


Transcript:

Mark A. Socinski, MD: One of the data sets that I thought was most encouraging at ASCO 2015 was the immunotherapeutic data for relapsed small-cell lung cancer where there’s a huge abyss of options. Roy, what were your thoughts about those data?

Roy S. Herbst, MD, PhD: There were two papers, both presented during the oral session. One was with pembrolizumab, which is the PD-1 antibody. The approach taken there was to search for PD-L1-positive patients. The search was a tough one: I believe they screened over 140 patients to find a small group, maybe 20 patients; but, of those 20, the response rate was reasonably good. It was in the 20% or more range.

Clearly, there is activity there with pembrolizumab. Whether or not one can screen for PD-L1 is the question. I can tell you from our own work at Yale, trying to do PD-L1 staining on small-cell lung cancer tissue is very tough because of the limited biopsies and the artifacts that you get from some of the frozen sections. But, I think that it certainly is something to think about.

Equally impressive were the data for nivolumab or nivolumab plus ipilimumab. In that trial, not only were there good response rates but, for the combination, I believe in the updated ASCO data the response rate was as high as 35% or 37%. What I was most impressed by was the spider plots, which actually looked at the responses in the platinum-refractory patients—those patients for whom we all know nothing works and there was clear activity.

Now, there was more toxicity. Of course, the grade 3/4 toxicity was in the range of 40% or higher, maybe even a little bit higher. The trial unmasked some of the paraneoplastic issues. There was some limbic encephalitis, if I recall. But, I think there’s great potential there.

I know that there are some trials ongoing now or about to start, looking at these drugs in small-cell tumors, and I think that’s great because that’s clearly an area where there hasn’t been anything new in quite some time, with many failed trials. There’s clear activity there and it goes with what you were saying, Naiyer. Everyone with small-cell lung cancer smokes. I don’t think I’ve ever seen anyone who didn’t smoke; there are plenty of mutations there.

Naiyer Rizvi, MD: There’s a reason why the small-cell lung cancer trials occurred so many years after the non-small–cell lung cancer, and the reason is that everyone did PD-L1 testing on small-cell tumors and they’re mostly negative. They thought because they’re all negative, what are we going to do this for? Yet, they’re all highly mutated tumors so it didn’t make any sense.

In the pembrolizumab trial, for example, the PD-L1 positivity rate was half that of non-small–cell lung cancer. There is clearly some other immunosuppression that’s going on in small-cell cancers that is completely different than for non-small–cell lung cancer.

It’s fascinating! Both are lung cancers and both are highly mutated tumors, but the small-cell tumors are more immunosuppressed for some reason. I think you probably do need to drive immune activation harder in small-cell lung cancer than you do in non-small–cell lung cancer, which is why the combination immunotherapy worked so much better. It shows that all these tumors are not the same and you need to think about them a little differently.

Mark A. Socinski, MD: At least there was some degree of enthusiasm.

Naiyer Rizvi, MD: Absolutely.

Roy S. Herbst, MD, PhD: Tremendous enthusiasm. In fact, I’m getting requests to use it when we don’t have a protocol. You have nothing else to offer in someone who is platinum-refractory. We need new agents.

Geoffrey R. Oxnard, MD: The phenomenon of having all of these different companies developing drugs at the same time means that there is a rich variety of trials scattering out across oncology and that’s been very fun. One of the weird trials is the PACIFIC durvalumab after chemoradiation for stage III lung cancer. It’s kind of random, but a neat idea. Everyone is trying to find a niche to develop a drug for various populations.

Roy S. Herbst, MD, PhD: That’s a nice trial.

Geoffrey R. Oxnard, MD: I like that trial.

Roy S. Herbst, MD, PhD: But that’s curable disease.

Mark A. Socinski, MD: Well, they’re curable but there was a bit of a hint from the Stimuvax trial in patients who were post-chemoradiotherapy that there might be something there with an immune approach, if you will.

Geoffrey R. Oxnard, MD: I’m just trying to figure out, who’s going to thymoma first? Then we’ll really be making headway.
Transcript Edited for Clarity
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Transcript:

Mark A. Socinski, MD: One of the data sets that I thought was most encouraging at ASCO 2015 was the immunotherapeutic data for relapsed small-cell lung cancer where there’s a huge abyss of options. Roy, what were your thoughts about those data?

Roy S. Herbst, MD, PhD: There were two papers, both presented during the oral session. One was with pembrolizumab, which is the PD-1 antibody. The approach taken there was to search for PD-L1-positive patients. The search was a tough one: I believe they screened over 140 patients to find a small group, maybe 20 patients; but, of those 20, the response rate was reasonably good. It was in the 20% or more range.

Clearly, there is activity there with pembrolizumab. Whether or not one can screen for PD-L1 is the question. I can tell you from our own work at Yale, trying to do PD-L1 staining on small-cell lung cancer tissue is very tough because of the limited biopsies and the artifacts that you get from some of the frozen sections. But, I think that it certainly is something to think about.

Equally impressive were the data for nivolumab or nivolumab plus ipilimumab. In that trial, not only were there good response rates but, for the combination, I believe in the updated ASCO data the response rate was as high as 35% or 37%. What I was most impressed by was the spider plots, which actually looked at the responses in the platinum-refractory patients—those patients for whom we all know nothing works and there was clear activity.

Now, there was more toxicity. Of course, the grade 3/4 toxicity was in the range of 40% or higher, maybe even a little bit higher. The trial unmasked some of the paraneoplastic issues. There was some limbic encephalitis, if I recall. But, I think there’s great potential there.

I know that there are some trials ongoing now or about to start, looking at these drugs in small-cell tumors, and I think that’s great because that’s clearly an area where there hasn’t been anything new in quite some time, with many failed trials. There’s clear activity there and it goes with what you were saying, Naiyer. Everyone with small-cell lung cancer smokes. I don’t think I’ve ever seen anyone who didn’t smoke; there are plenty of mutations there.

Naiyer Rizvi, MD: There’s a reason why the small-cell lung cancer trials occurred so many years after the non-small–cell lung cancer, and the reason is that everyone did PD-L1 testing on small-cell tumors and they’re mostly negative. They thought because they’re all negative, what are we going to do this for? Yet, they’re all highly mutated tumors so it didn’t make any sense.

In the pembrolizumab trial, for example, the PD-L1 positivity rate was half that of non-small–cell lung cancer. There is clearly some other immunosuppression that’s going on in small-cell cancers that is completely different than for non-small–cell lung cancer.

It’s fascinating! Both are lung cancers and both are highly mutated tumors, but the small-cell tumors are more immunosuppressed for some reason. I think you probably do need to drive immune activation harder in small-cell lung cancer than you do in non-small–cell lung cancer, which is why the combination immunotherapy worked so much better. It shows that all these tumors are not the same and you need to think about them a little differently.

Mark A. Socinski, MD: At least there was some degree of enthusiasm.

Naiyer Rizvi, MD: Absolutely.

Roy S. Herbst, MD, PhD: Tremendous enthusiasm. In fact, I’m getting requests to use it when we don’t have a protocol. You have nothing else to offer in someone who is platinum-refractory. We need new agents.

Geoffrey R. Oxnard, MD: The phenomenon of having all of these different companies developing drugs at the same time means that there is a rich variety of trials scattering out across oncology and that’s been very fun. One of the weird trials is the PACIFIC durvalumab after chemoradiation for stage III lung cancer. It’s kind of random, but a neat idea. Everyone is trying to find a niche to develop a drug for various populations.

Roy S. Herbst, MD, PhD: That’s a nice trial.

Geoffrey R. Oxnard, MD: I like that trial.

Roy S. Herbst, MD, PhD: But that’s curable disease.

Mark A. Socinski, MD: Well, they’re curable but there was a bit of a hint from the Stimuvax trial in patients who were post-chemoradiotherapy that there might be something there with an immune approach, if you will.

Geoffrey R. Oxnard, MD: I’m just trying to figure out, who’s going to thymoma first? Then we’ll really be making headway.
Transcript Edited for Clarity
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