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Reliability of PD-L1 Testing in NSCLC

Panelists: Suresh S. Ramalingam, MD, Emory University School of Medicine; Benjamin Besse, MD, PhD, Gustave Roussy; Marina Garassino, MD National Cancer Institute; Giorgio Scagliotti, MD, PhD, University of Turin
Published: Tuesday, Oct 17, 2017



Transcript: 

Suresh S. Ramalingam, MD: Speaking for the United States, the FDA has approved pembrolizumab for patients whose tumors expressed PD-L1 at 50% or higher at monotherapy. And that’s the only drug that’s approved in that space right now. We’ve seen chemotherapy/pembrolizumab in nonsquamous tumors, which Giorgio mentioned, with carboplatin and pemetrexed. That’s also approved. And PD-L1 expression seems to be coming around as perhaps the best determinant at this time to decide which patient gets what therapy. I’m going to ask Marina to comment on PD-L1 testing and how you look at the results from PD-L1 testing to make treatment decisions for your patients.

Marina Garassino, MD: Thank you for the question because I think that it is really an important question. And the PD-L1 is the biomarker for which we have more robust data, but it does not cover all the studies of immunotherapy. So, we know from the KEYNOTE-024 trial that that is now fundamental to test all the patients for the presence of PD-L1. But the study is quite different in second-line and further lines.

So, now the story is also complicated because of the 4 drugs that appeared on the market. They developed the drugs with different companion diagnostics. And we saw also in the past years, some tentative plans to harmonize all these tests with the immunohistochemistry. There are several papers suggesting that, starting from the Blueprint trial, at least the 3 commercial available assays are more or less the same, but 1 is quite different, which is the VENTANA SP142 assay. But again, this result is also quite controversial because in the German harmonization trial, all the 4 trials were performed in the same way, also with different cutoff.

And then, we also know that we have the difficulty to perform the PD-L1 test and go on the psychological specimen, because generally we manage with the psychological specimen during our diagnostic workups. So, there is a huge confusion. I would like also to mention the French harmonization trial in which the laboratory drive test does not perform as well as the commercial tests. It’s also important that when you do PD-L1, do PD-L1 with at least 3 antibodies commercially available.

So, the study is quite complicated because we also know that some patients with PD-L1-negative disease still benefit from immunotherapy. Not only strongly PD-L1-positive patients can benefit from immunotherapy. I think that we have to work a lot on the population at least less than 50%.

Suresh S. Ramalingam, MD: So, when we’re making decisions for our patient, if you had a frontline non–small cell lung cancer newly diagnosed metastatic diseased patient, is it fair to say, Benjamin, that for a PD-L1-high patient, we should give monotherapy with PD-1 inhibitor—in this case, pembrolizumab? Or would you consider using chemotherapy plus pembrolizumab for the patient? What’s your approach?

Benjamin Besse, MD, PhD: As Giorgio said, first-line pembrolizumab in high PD-L1 NSCLC patients is probably the standard of care because the study with pembrolizumab is really convincing. It’s a phase III study. The chemotherapy/pembrolizumab combination was tested in a phase II study. The primary objective was response rate, and it’s a very small study. I really think we cannot change our practice based on a randomized phase II study. I was quite surprised that the FDA could approve the drug based on such limited data. And it has to be stated that patients are highly, highly selected. The control arm of this phase II study completely overperformed with a PFS roughly of 9 months. It’s unseen. You expect a PFS of 6 months in this population.

Suresh S. Ramalingam, MD: For the chemotherapy alone.

Benjamin Besse, MD, PhD: So, I really think that this phase II study, as a concept study, means that you have to test the triplet in phase III studies. But in any case, I like to use this kind of data to change my practice.

Suresh S. Ramalingam, MD: So, for a squamous cell lung cancer patient, it’s clear now that the first-line paradigm is, if your tumor is overexpressed in PD-L1 at 50% or greater, you get monotherapy with pembrolizumab. If it’s not, then you give platinum-based chemotherapy. For nonsquamous, again, the panel seems to agree that for a high expressor of PD-L1, you give pembrolizumab monotherapy. For patients in the United States who don’t have high expression, you have the option of chemotherapy/pembrolizumab. In the rest of the parts of the world, chemotherapy continues to be the mainstay of treatment.

Transcript Edited for Clarity 

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Transcript: 

Suresh S. Ramalingam, MD: Speaking for the United States, the FDA has approved pembrolizumab for patients whose tumors expressed PD-L1 at 50% or higher at monotherapy. And that’s the only drug that’s approved in that space right now. We’ve seen chemotherapy/pembrolizumab in nonsquamous tumors, which Giorgio mentioned, with carboplatin and pemetrexed. That’s also approved. And PD-L1 expression seems to be coming around as perhaps the best determinant at this time to decide which patient gets what therapy. I’m going to ask Marina to comment on PD-L1 testing and how you look at the results from PD-L1 testing to make treatment decisions for your patients.

Marina Garassino, MD: Thank you for the question because I think that it is really an important question. And the PD-L1 is the biomarker for which we have more robust data, but it does not cover all the studies of immunotherapy. So, we know from the KEYNOTE-024 trial that that is now fundamental to test all the patients for the presence of PD-L1. But the study is quite different in second-line and further lines.

So, now the story is also complicated because of the 4 drugs that appeared on the market. They developed the drugs with different companion diagnostics. And we saw also in the past years, some tentative plans to harmonize all these tests with the immunohistochemistry. There are several papers suggesting that, starting from the Blueprint trial, at least the 3 commercial available assays are more or less the same, but 1 is quite different, which is the VENTANA SP142 assay. But again, this result is also quite controversial because in the German harmonization trial, all the 4 trials were performed in the same way, also with different cutoff.

And then, we also know that we have the difficulty to perform the PD-L1 test and go on the psychological specimen, because generally we manage with the psychological specimen during our diagnostic workups. So, there is a huge confusion. I would like also to mention the French harmonization trial in which the laboratory drive test does not perform as well as the commercial tests. It’s also important that when you do PD-L1, do PD-L1 with at least 3 antibodies commercially available.

So, the study is quite complicated because we also know that some patients with PD-L1-negative disease still benefit from immunotherapy. Not only strongly PD-L1-positive patients can benefit from immunotherapy. I think that we have to work a lot on the population at least less than 50%.

Suresh S. Ramalingam, MD: So, when we’re making decisions for our patient, if you had a frontline non–small cell lung cancer newly diagnosed metastatic diseased patient, is it fair to say, Benjamin, that for a PD-L1-high patient, we should give monotherapy with PD-1 inhibitor—in this case, pembrolizumab? Or would you consider using chemotherapy plus pembrolizumab for the patient? What’s your approach?

Benjamin Besse, MD, PhD: As Giorgio said, first-line pembrolizumab in high PD-L1 NSCLC patients is probably the standard of care because the study with pembrolizumab is really convincing. It’s a phase III study. The chemotherapy/pembrolizumab combination was tested in a phase II study. The primary objective was response rate, and it’s a very small study. I really think we cannot change our practice based on a randomized phase II study. I was quite surprised that the FDA could approve the drug based on such limited data. And it has to be stated that patients are highly, highly selected. The control arm of this phase II study completely overperformed with a PFS roughly of 9 months. It’s unseen. You expect a PFS of 6 months in this population.

Suresh S. Ramalingam, MD: For the chemotherapy alone.

Benjamin Besse, MD, PhD: So, I really think that this phase II study, as a concept study, means that you have to test the triplet in phase III studies. But in any case, I like to use this kind of data to change my practice.

Suresh S. Ramalingam, MD: So, for a squamous cell lung cancer patient, it’s clear now that the first-line paradigm is, if your tumor is overexpressed in PD-L1 at 50% or greater, you get monotherapy with pembrolizumab. If it’s not, then you give platinum-based chemotherapy. For nonsquamous, again, the panel seems to agree that for a high expressor of PD-L1, you give pembrolizumab monotherapy. For patients in the United States who don’t have high expression, you have the option of chemotherapy/pembrolizumab. In the rest of the parts of the world, chemotherapy continues to be the mainstay of treatment.

Transcript Edited for Clarity 
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