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Emerging Checkpoint Inhibitors for Lung Cancer

Panelists:Benjamin Levy, MD, Mount Sinai Health Systems, ; John W. Longshore, PhD, Carolinas Pathology Group; Gregory J. Riely, MD, PhD, Weill Cornell Medical College; Mark A. Socinski, MD, University of Pittsburgh; Thomas E. Stinchcombe, MD, University of North Carolina at Chapel Hill; Jared Weiss, MD, University of North Carolina School of Medicine
Published: Thursday, Jun 16, 2016


Transcript:

Mark A. Socinski, MD:
So, nivolumab and pembrolizumab are antibodies to PD-1. We have a couple of antibodies to PD-L1, one of the ligands for PD-1. Jared, a) is there a difference? And b) tell us about durvalumab as one of the anti–PD-L1 agents.

Jared Weiss, MD: I have no head-to-head data to answer you as to whether there’s a difference. I think in terms of efficacy, there really isn’t any great hint of difference. Toxicity profiles, they may be marginally different. There may be a little less pneumonitis with these agents that may be significant when we start to talk about combination trials, in particular, such that they may be easier to combine. But I think it would be fair to say that they look more similar than they do look different. I will say that the naming of the trials with this agent are quite cool. We have all kinds of neat oceanographic-type names. We’re seeing a lot of combination trials with this agent trying to answer some unanswered questions. So, one of the major limitations of these agents is the failure to improve the response rate over what we’ve traditionally seen, at least in unselected patients. I think we’re quite impressed with those tails of the curve, and we’re craving that for a greater proportion of our patients.

And so, in two of the durvalumab trials—in addition to comparing against standard of care chemotherapy—they are comparing against the combination with tremelimumab, which is a CTLA4 inhibitor, the same class of agent that we’ve seen efficacy with in melanoma. The idea is that you have a portion of these cancers that are going to be resistant because they’re simply not infiltrated by T cells. You’re not having interferon-gamma signaling going on there. The idea is you add a little bit of CTLA4 inhibition, maybe you can bump up that response rate to numbers that we’re going to be happy with. The other major unmet need, of course, is trying to bring these agents up into the curative intent setting. That’s what we do in cancer research. If something works in heavily pretreated patients, we bring it up to first-line. If it works there and we get appropriately greedy, can we cure more people? And there’s an ongoing study after chemoradiotherapy for stage III patients looking to do just that.

Mark A. Socinski, MD: I’m actually optimistic about that PACIFIC trial. I thought we got a little bit of a hint with the BLP25 vaccine trial, that maybe there’s something there in that population. We need something in the chemoradiotherapy because we do chemotherapy radiations, and then 75% of our patients die after that. We don’t have a good strategy, so I think that’s a very important trial. Ben, the second PD-L1 drug, atezolizumab. We’ve seen the BIRCH trial, the POPLAR trial. I guess this is like trees versus the oceans.

Benjamin P. Levy, MD: So, I’ll start with the BIRCH trial, a single-arm study, which was looking at single-agent atezolizumab as either first-line or subsequent lines of therapy for patients who were PD-L1–positive either by immune-cell or tumor-cell positivity. And, interestingly, in the treatment-naïve patient population that were PD-L1 expressers, the response rate was around 25%, which I thought was a little disappointing given that we have response rates in the 40%-range with pembrolizumab from the KEYNOTE study. Interestingly, the response rates in second-line and third-line were also around 25%. So, it didn’t matter when you got the drug, whether you got it in the treatment-naïve setting or refractory: the response rates seemed to be about the same. And, interestingly, in the first-line setting, the median PFS was around 6 months, which again underwhelmed me somewhat.

But we also have the POPLAR data, which—similar to the KEYNOTE-010 data—was randomizing patients who were PD-L1 expressers, or at least looking at patients who were PD-L1 expressers getting atezolizumab versus docetaxel. And, in that study, we saw a survival advantage that was meaningful in the second-line. So, we’ve got now two drugs—pembrolizumab and atezolizumab—that show meaningful improvements in the second-line for an enriched group of patients, and it will be difficult to kind of sort out which ones to use given that most of these agents are fairly similar in their efficacy.

Mark A. Socinski, MD: Yes. But it is interesting that in immune therapy, we’re more interested in the right-hand side of the Kaplan-Meier curve, how those tails going to sort out.

Benjamin P. Levy, MD: Sure.

Jared Weiss, MD: Because our patients care more about the right side of the curve, that’s why we care about it.

Mark A. Socinski, MD: Greg, Jared brought this up, but I wanted to kind of get back to the combination approach, particularly the PD-L1, CTLA4 inhibitors. Some initial concern about toxicity there, certainly some hints of efficacy benefit.

Gregory J. Riely, MD, PhD: This strategy, you mentioned durvalumab, tremelimumab; that’s clearly a path forward. With drugs we know a bit more, nivolumab and ipilimumab, that’s being widely explored. I think, as Jared suggested, this combination strategy really can hopefully increase the response rate, make tumors that were not immunogenic, and therefore really bring this option to far more of our patients than before. I think you’re right: toxicity is the issue. We learn a lot more about managing immune-related toxicities as we go forward, and I think the better we get at managing those toxicities, the better luck we’re going to have combining drugs. Hopefully, we can actually derive some efficacy benefit from that.

Mark A. Socinski, MD: We’re very enthusiastic. There are a number of thoracic malignancies that we all deal with. Now, the standard of care in small cell mesothelioma. People’s thoughts about [the] use of immune therapies in these diseases.

Gregory J. Riely, MD, PhD: So, for small cell, the early data is really promising. When we look at second- and third-line data for either nivolumab as a single agent or ipilimumab and nivolumab, we see response rates, we see durations of progression-free survival.

Mark A. Socinski, MD: In refractory disease.

Gregory J. Riely, MD, PhD: In refractory disease, patients we’ve never seen really benefit before. So, I think it’s really exciting in that space.

Mark A. Socinski, MD: Cautiously exciting. I mean, there were a few cases of myasthenia that were reactivated as a limbic encephalitis. You have to be very careful.

Gregory J. Riely, MD, PhD: And I’ll add that that scares me away from one thoracic malignancy that I deal with regularly, which is thymomas. I never treat patients with thymoma with immunotherapy, though there is an ongoing trial for patients with thymic carcinoma who don’t typically have any autoimmune phenomena getting pembrolizumab. So, I’m excited about that.

Benjamin P. Levy, MD: I’ll just say the data does look promising for small cell. I was hoping for a little bit higher response rate, given how genetically complex small cell is, and we think that may predict sensitivity of these drugs. Unfortunately, we’ve used checkpoint inhibitors in our patient population for compassionate use off-clinical trial. I haven’t seen the benefit I’m looking for. Certainly, the data are preliminary and it looks promising, and it has to be exploited and looked at carefully. Unfortunately, our experiences have not mirrored what the data has suggested, but a small number of patients that we’ve treated by compassionate use with small cell—refractory, by the way.

Mark A. Socinski, MD: Tom?

Thomas E. Stinchcombe, MD: So, I think if I remember, the nivolumab and the nivolumab/ipilimumab, the single-agent response for nivolumab in small cell was around 10%. I think that response rate is similar to topotecan, and that’s not an area that you want to be similar to topotecan in response. Now, those responses are more durable. I think it’s going to really require some prospective trials in small cell.

Mark A. Socinski, MD: A number of those are ongoing.

Transcript Edited for Clarity
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Transcript:

Mark A. Socinski, MD:
So, nivolumab and pembrolizumab are antibodies to PD-1. We have a couple of antibodies to PD-L1, one of the ligands for PD-1. Jared, a) is there a difference? And b) tell us about durvalumab as one of the anti–PD-L1 agents.

Jared Weiss, MD: I have no head-to-head data to answer you as to whether there’s a difference. I think in terms of efficacy, there really isn’t any great hint of difference. Toxicity profiles, they may be marginally different. There may be a little less pneumonitis with these agents that may be significant when we start to talk about combination trials, in particular, such that they may be easier to combine. But I think it would be fair to say that they look more similar than they do look different. I will say that the naming of the trials with this agent are quite cool. We have all kinds of neat oceanographic-type names. We’re seeing a lot of combination trials with this agent trying to answer some unanswered questions. So, one of the major limitations of these agents is the failure to improve the response rate over what we’ve traditionally seen, at least in unselected patients. I think we’re quite impressed with those tails of the curve, and we’re craving that for a greater proportion of our patients.

And so, in two of the durvalumab trials—in addition to comparing against standard of care chemotherapy—they are comparing against the combination with tremelimumab, which is a CTLA4 inhibitor, the same class of agent that we’ve seen efficacy with in melanoma. The idea is that you have a portion of these cancers that are going to be resistant because they’re simply not infiltrated by T cells. You’re not having interferon-gamma signaling going on there. The idea is you add a little bit of CTLA4 inhibition, maybe you can bump up that response rate to numbers that we’re going to be happy with. The other major unmet need, of course, is trying to bring these agents up into the curative intent setting. That’s what we do in cancer research. If something works in heavily pretreated patients, we bring it up to first-line. If it works there and we get appropriately greedy, can we cure more people? And there’s an ongoing study after chemoradiotherapy for stage III patients looking to do just that.

Mark A. Socinski, MD: I’m actually optimistic about that PACIFIC trial. I thought we got a little bit of a hint with the BLP25 vaccine trial, that maybe there’s something there in that population. We need something in the chemoradiotherapy because we do chemotherapy radiations, and then 75% of our patients die after that. We don’t have a good strategy, so I think that’s a very important trial. Ben, the second PD-L1 drug, atezolizumab. We’ve seen the BIRCH trial, the POPLAR trial. I guess this is like trees versus the oceans.

Benjamin P. Levy, MD: So, I’ll start with the BIRCH trial, a single-arm study, which was looking at single-agent atezolizumab as either first-line or subsequent lines of therapy for patients who were PD-L1–positive either by immune-cell or tumor-cell positivity. And, interestingly, in the treatment-naïve patient population that were PD-L1 expressers, the response rate was around 25%, which I thought was a little disappointing given that we have response rates in the 40%-range with pembrolizumab from the KEYNOTE study. Interestingly, the response rates in second-line and third-line were also around 25%. So, it didn’t matter when you got the drug, whether you got it in the treatment-naïve setting or refractory: the response rates seemed to be about the same. And, interestingly, in the first-line setting, the median PFS was around 6 months, which again underwhelmed me somewhat.

But we also have the POPLAR data, which—similar to the KEYNOTE-010 data—was randomizing patients who were PD-L1 expressers, or at least looking at patients who were PD-L1 expressers getting atezolizumab versus docetaxel. And, in that study, we saw a survival advantage that was meaningful in the second-line. So, we’ve got now two drugs—pembrolizumab and atezolizumab—that show meaningful improvements in the second-line for an enriched group of patients, and it will be difficult to kind of sort out which ones to use given that most of these agents are fairly similar in their efficacy.

Mark A. Socinski, MD: Yes. But it is interesting that in immune therapy, we’re more interested in the right-hand side of the Kaplan-Meier curve, how those tails going to sort out.

Benjamin P. Levy, MD: Sure.

Jared Weiss, MD: Because our patients care more about the right side of the curve, that’s why we care about it.

Mark A. Socinski, MD: Greg, Jared brought this up, but I wanted to kind of get back to the combination approach, particularly the PD-L1, CTLA4 inhibitors. Some initial concern about toxicity there, certainly some hints of efficacy benefit.

Gregory J. Riely, MD, PhD: This strategy, you mentioned durvalumab, tremelimumab; that’s clearly a path forward. With drugs we know a bit more, nivolumab and ipilimumab, that’s being widely explored. I think, as Jared suggested, this combination strategy really can hopefully increase the response rate, make tumors that were not immunogenic, and therefore really bring this option to far more of our patients than before. I think you’re right: toxicity is the issue. We learn a lot more about managing immune-related toxicities as we go forward, and I think the better we get at managing those toxicities, the better luck we’re going to have combining drugs. Hopefully, we can actually derive some efficacy benefit from that.

Mark A. Socinski, MD: We’re very enthusiastic. There are a number of thoracic malignancies that we all deal with. Now, the standard of care in small cell mesothelioma. People’s thoughts about [the] use of immune therapies in these diseases.

Gregory J. Riely, MD, PhD: So, for small cell, the early data is really promising. When we look at second- and third-line data for either nivolumab as a single agent or ipilimumab and nivolumab, we see response rates, we see durations of progression-free survival.

Mark A. Socinski, MD: In refractory disease.

Gregory J. Riely, MD, PhD: In refractory disease, patients we’ve never seen really benefit before. So, I think it’s really exciting in that space.

Mark A. Socinski, MD: Cautiously exciting. I mean, there were a few cases of myasthenia that were reactivated as a limbic encephalitis. You have to be very careful.

Gregory J. Riely, MD, PhD: And I’ll add that that scares me away from one thoracic malignancy that I deal with regularly, which is thymomas. I never treat patients with thymoma with immunotherapy, though there is an ongoing trial for patients with thymic carcinoma who don’t typically have any autoimmune phenomena getting pembrolizumab. So, I’m excited about that.

Benjamin P. Levy, MD: I’ll just say the data does look promising for small cell. I was hoping for a little bit higher response rate, given how genetically complex small cell is, and we think that may predict sensitivity of these drugs. Unfortunately, we’ve used checkpoint inhibitors in our patient population for compassionate use off-clinical trial. I haven’t seen the benefit I’m looking for. Certainly, the data are preliminary and it looks promising, and it has to be exploited and looked at carefully. Unfortunately, our experiences have not mirrored what the data has suggested, but a small number of patients that we’ve treated by compassionate use with small cell—refractory, by the way.

Mark A. Socinski, MD: Tom?

Thomas E. Stinchcombe, MD: So, I think if I remember, the nivolumab and the nivolumab/ipilimumab, the single-agent response for nivolumab in small cell was around 10%. I think that response rate is similar to topotecan, and that’s not an area that you want to be similar to topotecan in response. Now, those responses are more durable. I think it’s going to really require some prospective trials in small cell.

Mark A. Socinski, MD: A number of those are ongoing.

Transcript Edited for Clarity
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