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Upfront Use of Immunotherapy for NCSLC

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: Monday, Mar 27, 2017


Transcript:

Mark Socinski, MD:
On October 9, 2016, the world changed, right? At the European Society for Medical Oncology annual meeting, during the immunotherapy session, we saw KEYNOTE-024. Do we have consensus amongst the panel that PD-L1 testing is now standard of care in the first-line setting?

Tracey Evans, MD: Absolutely.

Alexander Drilon, MD: Yes.

Vali Papadimitrakopoulou, MD: No question.

Jared Weiss, MD: Absolutely, but with a mild anxiety of the limitations and operating characteristics of that test.

Mark Socinski, MD: We’ll come back to that. Vali, tell us why.

Vali Papadimitrakopoulou, MD: The data of the KEYNOTE-024 study were presented. It was a highly anticipated clinical trial result because we already had an announcement, prior to the official presentation of the data, that it was positive. And it really changed the landscape, dramatically, because up until that day, all the options that we had in this setting were chemotherapy or chemotherapy combinations with bevacizumab. I don’t think anybody dreamed of a day where we would have a single-agent therapy beating chemotherapy in this setting, so it was a quite important advance in non–small cell lung cancer treatment for our patients.

To simply present the data, the trial adopted a test that was prospectively tested and retrospectively tested by Merck in its development for characterization of PD-L1 expression in tumor cells. And the cut-offs were positivity defined in a scientific way. The patients that were selected for this first-line trial had expression of more than 50%. The trial demonstrated superiority of pembrolizumab against standard chemotherapy in terms of both progression-free survival and overall survival. The response rate was also higher. So, this defines a group of patients in our practice—we need to test them to find them—that may benefit from up-front immunotherapy, may derive deep and long-lasting responses, and may not need to be exposed to cytotoxic chemotherapy for a long time.

Mark Socinski, MD: Right. We know, from KEYNOTE-024, that just north of 1900 patients were enrolled or screened, 305 were randomized, and 1600 patients didn’t make it. So, when you think about clinical practice, this is applicable to a minority of your patients. But for those patients today, this blew chemotherapy out of the water. We’ve never seen 1 drug do as well as 2 drugs, as long as they’re active drugs, in this setting. It was actually quite impressive. The question is, which patients are going to benefit greater relative to chemotherapy? In the CheckMate-026 trial, nivolumab was not worse than chemotherapy in terms of overall survival. We have some issues to sort out about selection of patients. Jared, your former mentor and your current colleague, Dr. Corey Langer, was also a presenter in that section with KEYNOTE-021. And even though this was a randomized phase II trial, I was pretty impressed with the results.

Jared Weiss, MD: So was I. To a sense, this trial flies a little bit in the face of the culture of immunotherapy.

Mark Socinski, MD: It does.

Jared Weiss, MD: The culture of immunotherapy is to get the chemotherapy out, right? We’ve already spoken of that. But this trial said, “Okay, for the roughly three-quarters of patients who are not going to be high expressors, what could we do for unselected patients?” This was a trial of pemetrexed and carboplatin, alone or with the addition of the PD-1 antibody, pembrolizumab. The response rate was improved from 29% to 55%. The progression-free survival was improved from 8.9 to 13 months. And I know you’d call me out if I didn’t give you the hazard ratio: it was 0.53. Overall survival was statistically similar between the arms, but trended in the right direction.

Mark Socinski, MD: Very early.

Jared Weiss, MD: It was 0.9 in the early results and certainly trended the right way. Importantly, given that we’re adding to the standard, the treatment-related adverse events weren’t much worse with the addition of pembrolizumab. Mark Socinski, MD: Is that a general feeling across the panel, that the toxicity profile was not prohibitive adding pembrolizumab?

Tracey Evans, MD: It was good.

Vali Papadimitrakopoulou, MD: Yes.

Mark Socinski, MD: I have a point to make. That’s why I’m asking.

Jared Weiss, MD: It was a little worse across-the-board, if you look at all of the bars. It was a little bit worse, and you saw your immune-related adverse events. There are certainly patients for whom immunotherapy is either contraindicated or relatively contraindicated, but it was rather tolerable, in the global perspective, for the treatment-related advantage that it offered.

Mark Socinski, MD: We have a seasoned panel of lung cancer people here who are used to giving, probably, a lot more toxic stuff than what this trial showed, right? Where I was going with that is one of the impressive things about KEYNOTE-021 was they did have 20 patients that were greater than 50% PD-L1-positive, and their response rate was 80%. Now, response rates with cytotoxic chemotherapy haven’t driven survival endpoints, but we know that response rates with immunotherapy can be very durable. So, for the first time in my life, I looked at KEYNOTE-024 when it was presented and said, “Wow, they had a 70% 1-year survival.” And then, Dr. Corey Langer got up there and showed that data. I asked, “Why shouldn’t we expect a 90% 1-year survival with pembrolizumab/carboplatin/pemetrexed in the high-expressors if you have an 80% response rate?” I was very optimistic about this. There has been this groundswell, if you will, to ditch the chemotherapy in the era of immunotherapy, but I’m not sure that that’s the right strategy. I’m involved with the IMpower trials; Vali is also. I felt much more optimistic about those trials after seeing that phase II data. Now, again, I commented before that the oncologic highway in lung cancer is littered with positive phase II trials that never made it in phase III, but this was impressive.

Vali Papadimitrakopoulou, MD: The FDA thinks so as well because there is a consideration. It’s not an approval, but there is a consideration of these data for potential change in the label with the addition of chemotherapy to pembrolizumab. I think many in the academic community felt that these data indicated that we had an option for the patients that are not high-expressors because there appears to be benefit across the board—even for patients that have lower expression. So, that may be another way to look at these data.

Mark Socinski, MD: I was a little surprised by that FDA opinion, to be honest with you, because, again, at the end of the day, this is 120 patients on a phase II trial. To make that was a bit surprising.

Tracey Evans, MD: And if that happens, what do we do with that information?

Mark Socinski, MD: Did Dr. Corey Langer have anything to do with this?

Tracey Evans, MD: No, I don’t think so. I think he was as surprised as anybody. If it does get approval, what do we do with that information in the over 50% of expressors? Should we limit them to pembrolizumab as a single agent? Then do we do the combination in the greater than 1% but less than 50%? It will be a little confusing.

Vali Papadimitrakopoulou, MD: I think we’ll have to think about that.

Jared Weiss, MD: And speak to the patients, right? Patients have different values.

Transcript Edited for Clarity
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Transcript:

Mark Socinski, MD:
On October 9, 2016, the world changed, right? At the European Society for Medical Oncology annual meeting, during the immunotherapy session, we saw KEYNOTE-024. Do we have consensus amongst the panel that PD-L1 testing is now standard of care in the first-line setting?

Tracey Evans, MD: Absolutely.

Alexander Drilon, MD: Yes.

Vali Papadimitrakopoulou, MD: No question.

Jared Weiss, MD: Absolutely, but with a mild anxiety of the limitations and operating characteristics of that test.

Mark Socinski, MD: We’ll come back to that. Vali, tell us why.

Vali Papadimitrakopoulou, MD: The data of the KEYNOTE-024 study were presented. It was a highly anticipated clinical trial result because we already had an announcement, prior to the official presentation of the data, that it was positive. And it really changed the landscape, dramatically, because up until that day, all the options that we had in this setting were chemotherapy or chemotherapy combinations with bevacizumab. I don’t think anybody dreamed of a day where we would have a single-agent therapy beating chemotherapy in this setting, so it was a quite important advance in non–small cell lung cancer treatment for our patients.

To simply present the data, the trial adopted a test that was prospectively tested and retrospectively tested by Merck in its development for characterization of PD-L1 expression in tumor cells. And the cut-offs were positivity defined in a scientific way. The patients that were selected for this first-line trial had expression of more than 50%. The trial demonstrated superiority of pembrolizumab against standard chemotherapy in terms of both progression-free survival and overall survival. The response rate was also higher. So, this defines a group of patients in our practice—we need to test them to find them—that may benefit from up-front immunotherapy, may derive deep and long-lasting responses, and may not need to be exposed to cytotoxic chemotherapy for a long time.

Mark Socinski, MD: Right. We know, from KEYNOTE-024, that just north of 1900 patients were enrolled or screened, 305 were randomized, and 1600 patients didn’t make it. So, when you think about clinical practice, this is applicable to a minority of your patients. But for those patients today, this blew chemotherapy out of the water. We’ve never seen 1 drug do as well as 2 drugs, as long as they’re active drugs, in this setting. It was actually quite impressive. The question is, which patients are going to benefit greater relative to chemotherapy? In the CheckMate-026 trial, nivolumab was not worse than chemotherapy in terms of overall survival. We have some issues to sort out about selection of patients. Jared, your former mentor and your current colleague, Dr. Corey Langer, was also a presenter in that section with KEYNOTE-021. And even though this was a randomized phase II trial, I was pretty impressed with the results.

Jared Weiss, MD: So was I. To a sense, this trial flies a little bit in the face of the culture of immunotherapy.

Mark Socinski, MD: It does.

Jared Weiss, MD: The culture of immunotherapy is to get the chemotherapy out, right? We’ve already spoken of that. But this trial said, “Okay, for the roughly three-quarters of patients who are not going to be high expressors, what could we do for unselected patients?” This was a trial of pemetrexed and carboplatin, alone or with the addition of the PD-1 antibody, pembrolizumab. The response rate was improved from 29% to 55%. The progression-free survival was improved from 8.9 to 13 months. And I know you’d call me out if I didn’t give you the hazard ratio: it was 0.53. Overall survival was statistically similar between the arms, but trended in the right direction.

Mark Socinski, MD: Very early.

Jared Weiss, MD: It was 0.9 in the early results and certainly trended the right way. Importantly, given that we’re adding to the standard, the treatment-related adverse events weren’t much worse with the addition of pembrolizumab. Mark Socinski, MD: Is that a general feeling across the panel, that the toxicity profile was not prohibitive adding pembrolizumab?

Tracey Evans, MD: It was good.

Vali Papadimitrakopoulou, MD: Yes.

Mark Socinski, MD: I have a point to make. That’s why I’m asking.

Jared Weiss, MD: It was a little worse across-the-board, if you look at all of the bars. It was a little bit worse, and you saw your immune-related adverse events. There are certainly patients for whom immunotherapy is either contraindicated or relatively contraindicated, but it was rather tolerable, in the global perspective, for the treatment-related advantage that it offered.

Mark Socinski, MD: We have a seasoned panel of lung cancer people here who are used to giving, probably, a lot more toxic stuff than what this trial showed, right? Where I was going with that is one of the impressive things about KEYNOTE-021 was they did have 20 patients that were greater than 50% PD-L1-positive, and their response rate was 80%. Now, response rates with cytotoxic chemotherapy haven’t driven survival endpoints, but we know that response rates with immunotherapy can be very durable. So, for the first time in my life, I looked at KEYNOTE-024 when it was presented and said, “Wow, they had a 70% 1-year survival.” And then, Dr. Corey Langer got up there and showed that data. I asked, “Why shouldn’t we expect a 90% 1-year survival with pembrolizumab/carboplatin/pemetrexed in the high-expressors if you have an 80% response rate?” I was very optimistic about this. There has been this groundswell, if you will, to ditch the chemotherapy in the era of immunotherapy, but I’m not sure that that’s the right strategy. I’m involved with the IMpower trials; Vali is also. I felt much more optimistic about those trials after seeing that phase II data. Now, again, I commented before that the oncologic highway in lung cancer is littered with positive phase II trials that never made it in phase III, but this was impressive.

Vali Papadimitrakopoulou, MD: The FDA thinks so as well because there is a consideration. It’s not an approval, but there is a consideration of these data for potential change in the label with the addition of chemotherapy to pembrolizumab. I think many in the academic community felt that these data indicated that we had an option for the patients that are not high-expressors because there appears to be benefit across the board—even for patients that have lower expression. So, that may be another way to look at these data.

Mark Socinski, MD: I was a little surprised by that FDA opinion, to be honest with you, because, again, at the end of the day, this is 120 patients on a phase II trial. To make that was a bit surprising.

Tracey Evans, MD: And if that happens, what do we do with that information?

Mark Socinski, MD: Did Dr. Corey Langer have anything to do with this?

Tracey Evans, MD: No, I don’t think so. I think he was as surprised as anybody. If it does get approval, what do we do with that information in the over 50% of expressors? Should we limit them to pembrolizumab as a single agent? Then do we do the combination in the greater than 1% but less than 50%? It will be a little confusing.

Vali Papadimitrakopoulou, MD: I think we’ll have to think about that.

Jared Weiss, MD: And speak to the patients, right? Patients have different values.

Transcript Edited for Clarity
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