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Advanced-Stage NSCLC: KEYNOTE-189's Role in Treatment

Panelists: Benjamin P. Levy, MD, Sibley Memorial Hospital; Sanjay Popat, PhD, FRCP, Imperial College London; Solange Peters, MD, PhD, Centre Hospitalier Universitaire Vaudois; David Planchard, MD, PhD, Institut Gustave Roussy; Suresh S. Ramalingam, MD, Winship Cancer Institute
Published: Tuesday, Oct 16, 2018



Transcript:

Benjamin P. Levy, MD: Let’s move out of the stage III setting and into the stage IV setting, where immunotherapy has been. I think we’re all using it either in the second line or in combination with chemotherapy. The single-agent checkpoint blockades are firmly cemented in the second-line after chemotherapy in the refractory setting. Of course, they have more recently moved to the frontline setting in combination with chemotherapy. We’ve got KEYNOTE-189, which was a real game changer recently published showing benefit. We’ve also had some data at this World Conference on Lung Cancer in Toronto with IMpower132. Suresh, do you want to walk us through these 2 datasets? Maybe we can try to distill how to use these data in our clinical practice.

Suresh S. Ramalingam, MD: Sure. As you started talking about the advent of immunotherapy in the second-line setting, we’ve had multiple agents approved. The field has quickly shifted to the frontline setting, and that’s where we’re trying to figure out the best way to use the immune agents, with chemotherapy or by themselves based on biomarkers. In the frontline setting, we now have multiple clinical trials that combined chemotherapy with immune checkpoint inhibition.

Now, we’ve also had trials comparing the combination of immune checkpoint inhibition with another immune-active agent like CTLA-4 [cytotoxic T-lymphocyte-associated protein 4], a targeted drug, comparing that to chemotherapy. As we focus on the chemotherapy-based combinations, the KEYNOTE-189 trial that was reported about 6 months ago and has been published in the New England Journal of Medicine clearly showed that for nonsquamous patients who received chemotherapy plus pembrolizumab compared to chemotherapy alone, there was a substantial improvement in overall survival and progression-free survival [PFS]. We were all surprised with the hazard ratio for overall survival close to 0.5, which is unprecedented.

Benjamin P. Levy, MD: Unheard of.

Suresh S. Ramalingam, MD: That really changed the landscape in North America, and I’m sure it’s going to change other parts of the world as well. It’s an approved regimen in the United States. The question then is, does every patient with non–small cell lung cancer with stage IV, nonsquamous histology need all 3 drugs? In this case it’s a platinum doublet, carboplatin/pemetrexed, with pembrolizumab.

We feel that for a subset of patients who have really high PD-L1 [programmed death-ligand 1] expression greater than 50%, pembrolizumab alone may be sufficient to get the desired outcome. Well, our desired outcome is cure. We’re not there yet. But when you look at all the available agents, which one gets you the best possible outcome at the least expensive toxicity? Therefore, in our 50% or greater PD-L1–expressing patients, the KEYNOTE-024 results still hold good, where pembrolizumab alone was superior to chemotherapy and the hazard ratio was very robust for both PFS and overall survival.

Now we’ve broken down the patients into those with high PD-L1 and those with lower or absent PD-L1 expression. In the low PD-L1 expression group, which is less than 50% expression, I think the chemotherapy plus pembrolizumab approach makes a lot of sense based on the results of the KEYNOTE-189 study. What we learned at this meeting is that another triplet—which is cisplatin or carboplatin and pemetrexed with atezolizumab, a PD-L1 monoclonal antibody—also showed favorable results compared to chemotherapy alone. In this trial, the PFS results were very strong, meaning the hazard ratio was 0.6. The results are still early for survival. The overall survival hazard ratio was about 0.8. It didn’t reach statistical significance at this point. We have to wait and see, as more follow-up matures, whether that changes or not.

But all the trials are showing us the same direction with varying degrees of benefit and this will lead to the point of what is the best way to select patients? What’s the best biomarker? Is PD-L1 expression the best biomarker? I think that as of today, that’s the best biomarker we have. The tumor mutational burden is another biomarker that’s coming up, and I’m sure we can talk about that as we proceed with this discussion. But for now, I would say that the chemotherapy plus PD-1 inhibition approach with pembrolizumab in the United States is approved for nonsquamous population in the frontline setting. It’s firmly entrenched for the less than 50% expression population. For the greater than 50% expressers, pembrolizumab alone is appropriate therapy.

Benjamin P. Levy, MD: Let me ask just 1 question on that, and then I want to get the global perspective on the triplet therapy. Is there ever a time if the patient has a PD-L1 greater than 50% that you would offer triplet therapy and not single-agent pembrolizumab? Is that the patient who’s symptomatic or who has a heavy burden of disease? Or do you generally stick by single-agent pembrolizumab for greater than 50% expressers and triplet therapy, carboplatin/pemetrexed/pembrolizumab, for the less than 50% expressers?

Suresh S. Ramalingam, MD: In conversations with colleagues and tumor boards, we talk about this a lot. If there’s a patient who has very symptomatic disease and who has a bulky disease burden, do you give all 3 drugs to maximize the chance of response? Remember that all 3 drugs together also have a higher likelihood of developing adverse events, and the patient who has a lot of symptoms and has high disease burden is also the patient who’s likely to experience some of these adverse events.

I have not felt compelled to give all 3 drugs just based on some factors. My approach has been pembrolizumab alone, which has been pretty good for these patients who have really high PD-L1 expression. Now, we can look at it and ask if a patient has 100% PD-L1 expression versus 51%, would that change? That’s a patient-to-patient decision. For a large number of patients, I feel pembrolizumab alone is sufficient for the greater than 50% expressers.


Transcript Edited for Clarity

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Transcript:

Benjamin P. Levy, MD: Let’s move out of the stage III setting and into the stage IV setting, where immunotherapy has been. I think we’re all using it either in the second line or in combination with chemotherapy. The single-agent checkpoint blockades are firmly cemented in the second-line after chemotherapy in the refractory setting. Of course, they have more recently moved to the frontline setting in combination with chemotherapy. We’ve got KEYNOTE-189, which was a real game changer recently published showing benefit. We’ve also had some data at this World Conference on Lung Cancer in Toronto with IMpower132. Suresh, do you want to walk us through these 2 datasets? Maybe we can try to distill how to use these data in our clinical practice.

Suresh S. Ramalingam, MD: Sure. As you started talking about the advent of immunotherapy in the second-line setting, we’ve had multiple agents approved. The field has quickly shifted to the frontline setting, and that’s where we’re trying to figure out the best way to use the immune agents, with chemotherapy or by themselves based on biomarkers. In the frontline setting, we now have multiple clinical trials that combined chemotherapy with immune checkpoint inhibition.

Now, we’ve also had trials comparing the combination of immune checkpoint inhibition with another immune-active agent like CTLA-4 [cytotoxic T-lymphocyte-associated protein 4], a targeted drug, comparing that to chemotherapy. As we focus on the chemotherapy-based combinations, the KEYNOTE-189 trial that was reported about 6 months ago and has been published in the New England Journal of Medicine clearly showed that for nonsquamous patients who received chemotherapy plus pembrolizumab compared to chemotherapy alone, there was a substantial improvement in overall survival and progression-free survival [PFS]. We were all surprised with the hazard ratio for overall survival close to 0.5, which is unprecedented.

Benjamin P. Levy, MD: Unheard of.

Suresh S. Ramalingam, MD: That really changed the landscape in North America, and I’m sure it’s going to change other parts of the world as well. It’s an approved regimen in the United States. The question then is, does every patient with non–small cell lung cancer with stage IV, nonsquamous histology need all 3 drugs? In this case it’s a platinum doublet, carboplatin/pemetrexed, with pembrolizumab.

We feel that for a subset of patients who have really high PD-L1 [programmed death-ligand 1] expression greater than 50%, pembrolizumab alone may be sufficient to get the desired outcome. Well, our desired outcome is cure. We’re not there yet. But when you look at all the available agents, which one gets you the best possible outcome at the least expensive toxicity? Therefore, in our 50% or greater PD-L1–expressing patients, the KEYNOTE-024 results still hold good, where pembrolizumab alone was superior to chemotherapy and the hazard ratio was very robust for both PFS and overall survival.

Now we’ve broken down the patients into those with high PD-L1 and those with lower or absent PD-L1 expression. In the low PD-L1 expression group, which is less than 50% expression, I think the chemotherapy plus pembrolizumab approach makes a lot of sense based on the results of the KEYNOTE-189 study. What we learned at this meeting is that another triplet—which is cisplatin or carboplatin and pemetrexed with atezolizumab, a PD-L1 monoclonal antibody—also showed favorable results compared to chemotherapy alone. In this trial, the PFS results were very strong, meaning the hazard ratio was 0.6. The results are still early for survival. The overall survival hazard ratio was about 0.8. It didn’t reach statistical significance at this point. We have to wait and see, as more follow-up matures, whether that changes or not.

But all the trials are showing us the same direction with varying degrees of benefit and this will lead to the point of what is the best way to select patients? What’s the best biomarker? Is PD-L1 expression the best biomarker? I think that as of today, that’s the best biomarker we have. The tumor mutational burden is another biomarker that’s coming up, and I’m sure we can talk about that as we proceed with this discussion. But for now, I would say that the chemotherapy plus PD-1 inhibition approach with pembrolizumab in the United States is approved for nonsquamous population in the frontline setting. It’s firmly entrenched for the less than 50% expression population. For the greater than 50% expressers, pembrolizumab alone is appropriate therapy.

Benjamin P. Levy, MD: Let me ask just 1 question on that, and then I want to get the global perspective on the triplet therapy. Is there ever a time if the patient has a PD-L1 greater than 50% that you would offer triplet therapy and not single-agent pembrolizumab? Is that the patient who’s symptomatic or who has a heavy burden of disease? Or do you generally stick by single-agent pembrolizumab for greater than 50% expressers and triplet therapy, carboplatin/pemetrexed/pembrolizumab, for the less than 50% expressers?

Suresh S. Ramalingam, MD: In conversations with colleagues and tumor boards, we talk about this a lot. If there’s a patient who has very symptomatic disease and who has a bulky disease burden, do you give all 3 drugs to maximize the chance of response? Remember that all 3 drugs together also have a higher likelihood of developing adverse events, and the patient who has a lot of symptoms and has high disease burden is also the patient who’s likely to experience some of these adverse events.

I have not felt compelled to give all 3 drugs just based on some factors. My approach has been pembrolizumab alone, which has been pretty good for these patients who have really high PD-L1 expression. Now, we can look at it and ask if a patient has 100% PD-L1 expression versus 51%, would that change? That’s a patient-to-patient decision. For a large number of patients, I feel pembrolizumab alone is sufficient for the greater than 50% expressers.


Transcript Edited for Clarity
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