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Pembrolizumab: Monotherapy Versus Combination Therapy

Panelists: Mark A. Socinski, MD, Florida Hospital Cancer Institute; Karen Kelly, MD, UC Davis Comprehensive Cancer Center; Corey J. Langer, MD, FACP, University of Pennsylvania; Benjamin P. Levy, MD, Sibley Memorial Hospital
Published: Friday, Jun 29, 2018



Transcript: 

Mark A. Socinski, MD: What are your thoughts about that greater than 50% population with PD-L1 expression?

Karen Kelly, MD: You know, I think that is a significant question to be asking. I think most patients don’t want to take chemotherapy, if they can avoid taking chemotherapy, and would favor taking the monotherapy for many reasons, including because of the side effect profile. However, there is a group of patients for whom I do think chemotherapy needs to be given. Those are the patients who are really symptomatic, where you want to be able to get a response sooner. There was a slight difference in time to response if you got the triplet option versus if you got the monotherapy in KEYNOTE-024. So, there’s a slight, slight difference, and I think you really do want to give chemotherapy with the immunotherapy in those patients. But if you have somebody with more indolent disease, you may not want to give that chemotherapy. Like everything, you have to have these discussions with the patient who is sitting in front of you and need to make an informed decision. But for the most part…

Mark A. Socinski, MD: If I remember correctly, if you look at 1-year survival…

Corey J. Langer, MD, FACP: Not much different.

Mark A. Socinski, MD: It was 73% versus 70%.

Karen Kelly, MD: That’s correct.

Mark A. Socinski, MD: Identical. Ben, do you have anything to add to that?

Benjamin P. Levy, MD: I would just echo what Karen said. I think that for these patients, especially the over-50% group, treatment decisions need to be individualized. For those patients who need to be debulked and they’re symptomatic, I would go with the triplet therapy. And for my patients who don’t have many symptoms, or have more indolent disease, if we have an understanding of how to assess this in the clinic, I may go with single-agent pembrolizumab. I think one of the questions that comes up in this trial, that I don’t really know the answer to, is, do we need to test for PD-L1 at all? Will the community receive this as an all-comers regimen?

Mark A. Socinski, MD: Well, I hope that doesn’t happen.

Karen Kelly, MD: Right.

Benjamin P. Levy, MD: Given how precious tissue is, and the need for genotyping, I certainly would advocate for PD-L1. I throw this out there to be more provocative than anything else, but I think this is a message that the community oncologist is a little confused on, given that it benefitted every single patient population, across the board.

Corey J. Langer, MD, FACP: It’s such a small expenditure of tissue to do a PD-L1 test as opposed to next-generation sequencing or some of the other assays.

Karen Kelly, MD: It is, but it can take time in a community setting. If you have to send it out, placing the order, having pathology cut the slides, and then sending it out does take time. That is still an issue. Certainly, we have a 24- to 48-hour turnaround time, but I do think we have to be respectful to our community colleagues, where it is a little bit more challenging to do that. And remember, everybody still needs to get EGFR, ALK, and ROS before they…

Mark A. Socinski, MD: And BRAF.

Karen Kelly, MD: And BRAF. In reality, they need next-generation sequencing. They need that first, and that takes a little bit more tissue. So, I think that the tissue still remains to be a challenge.

Mark A. Socinski, MD: And to Corey’s point, EGFR and ALK-positive patients were excluded.

Karen Kelly, MD: Exactly.

Corey J. Langer, MD, FACP: Do the math. We’ve excluded squamous, which is roughly a quarter to a third of patients, and we’ve excluded the EGFR and ALK population amongst the nonsquamous, which is probably about 20% of that group. This study probably only applies to maybe half of the patients that we see.

Mark A. Socinski, MD: Corey, are there any safety issues?

Corey J. Langer, MD, FACP: Toxicity was heightened somewhat, but not overwhelmingly. There was some renal toxicity that we hadn’t necessarily anticipated from the randomized phase II study, but the rates were low. Grade 3 and grade 4 toxicity was only minimally higher. And beyond that, there were the usual immunotherapy-related toxicities: thyroid disease, rash, arthritis.

Mark A. Socinski, MD: Nothing unexpected though?

Corey J. Langer, MD, FACP: Certainly nothing unexpected. By and large, for the most part, this was a fairly well-tolerated regimen.

Benjamin P. Levy, MD: That mirrors my clinical experience with this triplet regimen. I don’t see that many toxicities that are unexpected with the triplet combination.

Mark A. Socinski, MD: Right.

Karen Kelly, MD: I wanted to add that when we have the debate about monotherapy versus triplet therapy, there are many patients with low creatinine clearance, which doesn’t make them eligible for pemetrexed or cisplatin. We tend to give carboplatin, but it’s really a pemetrexed, I think, concern.

Corey J. Langer, MD, FACP: That’s going to be another 10% to 15% of patients who can’t get on this.

Karen Kelly, MD: That is a bigger percent of patients than we realize.

Corey J. Langer, MD, FACP: We consider pemetrexed to be one of the least toxic agents that we have, but there’s enormous respect for that drug. It’s FDA approved in people with a creatinine clearance of 45 or higher. When we think about our older patients, maybe a 75- or 80-year-old woman, she looks normal. It’s 1.2 or 1.3. She only weighs 100 pounds. I guarantee that her creatinine clearance is below 45. And I agree with Karen. I’d give a taxane, preferentially. And there, the data don’t apply.

Mark A. Socinski, MD: Yes. Is this a new standard of care for all of us?

Benjamin P. Levy, MD: In my mind, yes.

Karen Kelly, MD: Yes.

Corey J. Langer, MD, FACP: Oh, absolutely.

Benjamin P. Levy, MD: I had some concerns before I saw the subset analysis about these never-smokers. We tend to believe that these never-smokers don’t derive a benefit from immunotherapy approaches. We saw, in the 70-something subset analysis, that the never-smokers did benefit, and the benefit was quite pronounced even though the confidence interval was wide. This changed my practice a little bit. Yes, we need to genotype these patients to look for actionable mutations. But outside of that, I’m starting to consider using the triplet regimen for these patients.

Transcript Edited for Clarity

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Transcript: 

Mark A. Socinski, MD: What are your thoughts about that greater than 50% population with PD-L1 expression?

Karen Kelly, MD: You know, I think that is a significant question to be asking. I think most patients don’t want to take chemotherapy, if they can avoid taking chemotherapy, and would favor taking the monotherapy for many reasons, including because of the side effect profile. However, there is a group of patients for whom I do think chemotherapy needs to be given. Those are the patients who are really symptomatic, where you want to be able to get a response sooner. There was a slight difference in time to response if you got the triplet option versus if you got the monotherapy in KEYNOTE-024. So, there’s a slight, slight difference, and I think you really do want to give chemotherapy with the immunotherapy in those patients. But if you have somebody with more indolent disease, you may not want to give that chemotherapy. Like everything, you have to have these discussions with the patient who is sitting in front of you and need to make an informed decision. But for the most part…

Mark A. Socinski, MD: If I remember correctly, if you look at 1-year survival…

Corey J. Langer, MD, FACP: Not much different.

Mark A. Socinski, MD: It was 73% versus 70%.

Karen Kelly, MD: That’s correct.

Mark A. Socinski, MD: Identical. Ben, do you have anything to add to that?

Benjamin P. Levy, MD: I would just echo what Karen said. I think that for these patients, especially the over-50% group, treatment decisions need to be individualized. For those patients who need to be debulked and they’re symptomatic, I would go with the triplet therapy. And for my patients who don’t have many symptoms, or have more indolent disease, if we have an understanding of how to assess this in the clinic, I may go with single-agent pembrolizumab. I think one of the questions that comes up in this trial, that I don’t really know the answer to, is, do we need to test for PD-L1 at all? Will the community receive this as an all-comers regimen?

Mark A. Socinski, MD: Well, I hope that doesn’t happen.

Karen Kelly, MD: Right.

Benjamin P. Levy, MD: Given how precious tissue is, and the need for genotyping, I certainly would advocate for PD-L1. I throw this out there to be more provocative than anything else, but I think this is a message that the community oncologist is a little confused on, given that it benefitted every single patient population, across the board.

Corey J. Langer, MD, FACP: It’s such a small expenditure of tissue to do a PD-L1 test as opposed to next-generation sequencing or some of the other assays.

Karen Kelly, MD: It is, but it can take time in a community setting. If you have to send it out, placing the order, having pathology cut the slides, and then sending it out does take time. That is still an issue. Certainly, we have a 24- to 48-hour turnaround time, but I do think we have to be respectful to our community colleagues, where it is a little bit more challenging to do that. And remember, everybody still needs to get EGFR, ALK, and ROS before they…

Mark A. Socinski, MD: And BRAF.

Karen Kelly, MD: And BRAF. In reality, they need next-generation sequencing. They need that first, and that takes a little bit more tissue. So, I think that the tissue still remains to be a challenge.

Mark A. Socinski, MD: And to Corey’s point, EGFR and ALK-positive patients were excluded.

Karen Kelly, MD: Exactly.

Corey J. Langer, MD, FACP: Do the math. We’ve excluded squamous, which is roughly a quarter to a third of patients, and we’ve excluded the EGFR and ALK population amongst the nonsquamous, which is probably about 20% of that group. This study probably only applies to maybe half of the patients that we see.

Mark A. Socinski, MD: Corey, are there any safety issues?

Corey J. Langer, MD, FACP: Toxicity was heightened somewhat, but not overwhelmingly. There was some renal toxicity that we hadn’t necessarily anticipated from the randomized phase II study, but the rates were low. Grade 3 and grade 4 toxicity was only minimally higher. And beyond that, there were the usual immunotherapy-related toxicities: thyroid disease, rash, arthritis.

Mark A. Socinski, MD: Nothing unexpected though?

Corey J. Langer, MD, FACP: Certainly nothing unexpected. By and large, for the most part, this was a fairly well-tolerated regimen.

Benjamin P. Levy, MD: That mirrors my clinical experience with this triplet regimen. I don’t see that many toxicities that are unexpected with the triplet combination.

Mark A. Socinski, MD: Right.

Karen Kelly, MD: I wanted to add that when we have the debate about monotherapy versus triplet therapy, there are many patients with low creatinine clearance, which doesn’t make them eligible for pemetrexed or cisplatin. We tend to give carboplatin, but it’s really a pemetrexed, I think, concern.

Corey J. Langer, MD, FACP: That’s going to be another 10% to 15% of patients who can’t get on this.

Karen Kelly, MD: That is a bigger percent of patients than we realize.

Corey J. Langer, MD, FACP: We consider pemetrexed to be one of the least toxic agents that we have, but there’s enormous respect for that drug. It’s FDA approved in people with a creatinine clearance of 45 or higher. When we think about our older patients, maybe a 75- or 80-year-old woman, she looks normal. It’s 1.2 or 1.3. She only weighs 100 pounds. I guarantee that her creatinine clearance is below 45. And I agree with Karen. I’d give a taxane, preferentially. And there, the data don’t apply.

Mark A. Socinski, MD: Yes. Is this a new standard of care for all of us?

Benjamin P. Levy, MD: In my mind, yes.

Karen Kelly, MD: Yes.

Corey J. Langer, MD, FACP: Oh, absolutely.

Benjamin P. Levy, MD: I had some concerns before I saw the subset analysis about these never-smokers. We tend to believe that these never-smokers don’t derive a benefit from immunotherapy approaches. We saw, in the 70-something subset analysis, that the never-smokers did benefit, and the benefit was quite pronounced even though the confidence interval was wide. This changed my practice a little bit. Yes, we need to genotype these patients to look for actionable mutations. But outside of that, I’m starting to consider using the triplet regimen for these patients.

Transcript Edited for Clarity
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