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Upfront Immunotherapy for NSCLC

Insights From: Roy S. Herbst, MD, PhD, Yale School of Medicine; Corey J. Langer, MD, University of Pennsylvania; Vassiliki A. Papadimitrakopoulou, MD, University of Texas MD Anderson Cancer Center
Published: Monday, Jul 17, 2017



Transcript:

Vassiliki A. Papadimitrakopoulou, MD:
Data from the KEYNOTE-024 study using pembrolizumab in patients selected for PD-L1 expression of more than 50% demonstrated the superiority of pembrolizumab over chemotherapy for patients with non–small cell lung cancer. This was really a huge change in the standard of care for our patients, allowing us, for the first time, to use immunotherapy instead of chemotherapy as first-line therapy. And this has significantly changed our practice. So, for patients who represent about one-third of the group of non–small cell lung cancer patients with high expression, this would be the recommended therapy.

Corey J. Langer, MD: KEYNOTE-024 was a unique and pivotal phase III trial comparing single-agent monotherapy with a PD-1 inhibitor—in this case, pembrolizumab—to standard platinum combinations. The trial mandated a minimum PD-L1 expression of 50% or higher, based on previous phase I and phase II data that showed this group had response rates in the 45% to 50% range, and 2-year survival rates in treatment naïve individuals approaching 60%. Certainly, the homework was already done. The pre-existing data to justify this trial clearly existed.

The trial was reported by Dr. Martin Reck at the ESMO Congress in October of 2016 and published, simultaneously, in the New England Journal of Medicine. This completely transformed the therapeutic landscape for those individuals with 50% or higher PD-L1 expression, which is roughly a quarter to 30% of all individuals with advanced non–small cell lung cancer. They had a higher response rate: 45% compared to about 28% for the control group with a significantly, and I’d argue clinically meaningfully, higher progression-free survival—10.3 months versus 6 months—a hazard ratio of 0.5, and a statistically significant and rather marked survival advantage with a hazard ratio of 0.6. In fact, the median survival has not been seen yet in the experimental group. And those survival curves seem to be diverging more and more over time.

To get on that specific trial—to really be eligible for front-line pembrolizumab—you first need to be treatment naïve; have a good performance status, PS 0 to 1; and have no preexisting oncogenic drivers, so no evidence of the EGFR mutation or ALK translocation. Patients can’t have any preexisting autoimmune disease of any sort, and that eliminates folks with collagen and vascular disease, inflammatory bowel disease, etc. Criteria include no preexisting interstitial lung disease, and most specifically, a minimum PD-L1 level of 50% or higher.

Roy S. Herbst, MD, PhD: KEYNOTE-001 was a historic trial. It was a phase I study—and actually, we participated on this at Yale—that enrolled patients for lung cancer and melanoma, too. In the lung cohort, there were hundreds of hundreds of patients. Now, those patients are being followed for long periods of time. At 3 years, 15% to 20% of patients with metastatic lung cancer are still alive. What that does is shows the durability of the therapy. Immunotherapy is special because of its specificity, it’s adaptability, and its durability. We’re seeing that durability in these updates. Again, we’d love to see more patients benefit, but the fact is that 15% to 20% are alive at 3 years, and we’re seeing similar things now for nivolumab. I’m sure we’ll see it, of course, with ipilimumab. In melanoma, similar things were seen. For this population of patients that lives for a longer period of time, we need to identify them early and treat them as quickly as possible.

Vassiliki A. Papadimitrakopoulou, MD: I started using pembrolizumab in my practice upon approval of the agent, sometime in the fall of 2016. So far, my experience has been consistent with the data from the use of first-line pembrolizumab, where progression-free survival was about 10.5 months. I haven’t seen any of my patients progress on this therapy, so the experience has been really good. Toxicities have been tolerable. I haven’t seen grade 3 toxicity. For the majority of the patients, the toxicities are grade 1 and grade 2, and I can easily manage them.

In terms of differences with second-line use of checkpoint inhibitors, in the frontline setting we’re seeing a more robust group of patients who can stay on these therapies longer and derive longer-term benefit from this. I haven’t had a huge experience with the use of pembrolizumab in the front-line setting to be able to compare, in a robust way, between the 2 settings.

Corey J. Langer, MD: My own personal experience with frontline pembrolizumab is rather limited. The drug was only approved in October 2016, but my experience pretty much parallels what we’ve observed in the clinical trial. Patients are tolerating this agent quite well. Toxicity is minimal. We see occasional arthralgias—sometimes arthritis. Occasionally, we see diarrhea. Individuals are at risk for hypothyroidism, so it’s a prerequisite to check TSH levels periodically. I tend to do that during every cycle. But, by and large, this treatment is extraordinarily well-tolerated with minimal upper gastrointestinal toxicity and no hair loss to speak of. Patients feel and look normal.

The response rates, in my experience, are essentially matching what was documented in the clinical trial. But, again, I only have 6 months’ experience. It’s now June of 2017, and the drug was only approved in October. The first patient I ever treated with this agent was treated in November of 2016.

We have to make a major distinction between first-line and second-line therapy. Single agent first-line therapy is confined to individuals with higher levels of PD-L1 expression. Unsurprisingly, they are much more likely to have a response and more durable benefit, including a prolonged progression-free survival, compared to the broader population who are treated in the second-line setting—where, if we use agents like nivolumab or atezolizumab, the survival benefit’s been observed irrespective of the PD-L1 level. There, the response rates tend to be lower—about 15% to 20% progression-free survival, a median of about 3 to 4 months. But still, there is a clear survival advantage compared to our erstwhile standard, docetaxel.

Roy S. Herbst, MD, PhD: I’ve been using a great deal of frontline pembrolizumab. Of course, at Yale we’ll run clinical trials if we have them. But if someone’s PD-L1 level is high, I will try to put them on pembrolizumab. And, quite frankly, the tolerability is just as good, if not better, then when given as second-line therapy. The efficacy is just as good, if not better. It’s a little bit better because you’re selecting patients who are 50% or higher. In patients who I’ve treated at Yale myself, or in those who come to me for consultation and I’ve sent home, those are the cases where I can often get a very nice call from a patient who tells me they’re feeling well and their tumor is shrinking. I am seeing, in the short experience I’ve had since the approval late last year, that the response rate is about 40% to 50%.

Transcript Edited for Clarity
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Transcript:

Vassiliki A. Papadimitrakopoulou, MD:
Data from the KEYNOTE-024 study using pembrolizumab in patients selected for PD-L1 expression of more than 50% demonstrated the superiority of pembrolizumab over chemotherapy for patients with non–small cell lung cancer. This was really a huge change in the standard of care for our patients, allowing us, for the first time, to use immunotherapy instead of chemotherapy as first-line therapy. And this has significantly changed our practice. So, for patients who represent about one-third of the group of non–small cell lung cancer patients with high expression, this would be the recommended therapy.

Corey J. Langer, MD: KEYNOTE-024 was a unique and pivotal phase III trial comparing single-agent monotherapy with a PD-1 inhibitor—in this case, pembrolizumab—to standard platinum combinations. The trial mandated a minimum PD-L1 expression of 50% or higher, based on previous phase I and phase II data that showed this group had response rates in the 45% to 50% range, and 2-year survival rates in treatment naïve individuals approaching 60%. Certainly, the homework was already done. The pre-existing data to justify this trial clearly existed.

The trial was reported by Dr. Martin Reck at the ESMO Congress in October of 2016 and published, simultaneously, in the New England Journal of Medicine. This completely transformed the therapeutic landscape for those individuals with 50% or higher PD-L1 expression, which is roughly a quarter to 30% of all individuals with advanced non–small cell lung cancer. They had a higher response rate: 45% compared to about 28% for the control group with a significantly, and I’d argue clinically meaningfully, higher progression-free survival—10.3 months versus 6 months—a hazard ratio of 0.5, and a statistically significant and rather marked survival advantage with a hazard ratio of 0.6. In fact, the median survival has not been seen yet in the experimental group. And those survival curves seem to be diverging more and more over time.

To get on that specific trial—to really be eligible for front-line pembrolizumab—you first need to be treatment naïve; have a good performance status, PS 0 to 1; and have no preexisting oncogenic drivers, so no evidence of the EGFR mutation or ALK translocation. Patients can’t have any preexisting autoimmune disease of any sort, and that eliminates folks with collagen and vascular disease, inflammatory bowel disease, etc. Criteria include no preexisting interstitial lung disease, and most specifically, a minimum PD-L1 level of 50% or higher.

Roy S. Herbst, MD, PhD: KEYNOTE-001 was a historic trial. It was a phase I study—and actually, we participated on this at Yale—that enrolled patients for lung cancer and melanoma, too. In the lung cohort, there were hundreds of hundreds of patients. Now, those patients are being followed for long periods of time. At 3 years, 15% to 20% of patients with metastatic lung cancer are still alive. What that does is shows the durability of the therapy. Immunotherapy is special because of its specificity, it’s adaptability, and its durability. We’re seeing that durability in these updates. Again, we’d love to see more patients benefit, but the fact is that 15% to 20% are alive at 3 years, and we’re seeing similar things now for nivolumab. I’m sure we’ll see it, of course, with ipilimumab. In melanoma, similar things were seen. For this population of patients that lives for a longer period of time, we need to identify them early and treat them as quickly as possible.

Vassiliki A. Papadimitrakopoulou, MD: I started using pembrolizumab in my practice upon approval of the agent, sometime in the fall of 2016. So far, my experience has been consistent with the data from the use of first-line pembrolizumab, where progression-free survival was about 10.5 months. I haven’t seen any of my patients progress on this therapy, so the experience has been really good. Toxicities have been tolerable. I haven’t seen grade 3 toxicity. For the majority of the patients, the toxicities are grade 1 and grade 2, and I can easily manage them.

In terms of differences with second-line use of checkpoint inhibitors, in the frontline setting we’re seeing a more robust group of patients who can stay on these therapies longer and derive longer-term benefit from this. I haven’t had a huge experience with the use of pembrolizumab in the front-line setting to be able to compare, in a robust way, between the 2 settings.

Corey J. Langer, MD: My own personal experience with frontline pembrolizumab is rather limited. The drug was only approved in October 2016, but my experience pretty much parallels what we’ve observed in the clinical trial. Patients are tolerating this agent quite well. Toxicity is minimal. We see occasional arthralgias—sometimes arthritis. Occasionally, we see diarrhea. Individuals are at risk for hypothyroidism, so it’s a prerequisite to check TSH levels periodically. I tend to do that during every cycle. But, by and large, this treatment is extraordinarily well-tolerated with minimal upper gastrointestinal toxicity and no hair loss to speak of. Patients feel and look normal.

The response rates, in my experience, are essentially matching what was documented in the clinical trial. But, again, I only have 6 months’ experience. It’s now June of 2017, and the drug was only approved in October. The first patient I ever treated with this agent was treated in November of 2016.

We have to make a major distinction between first-line and second-line therapy. Single agent first-line therapy is confined to individuals with higher levels of PD-L1 expression. Unsurprisingly, they are much more likely to have a response and more durable benefit, including a prolonged progression-free survival, compared to the broader population who are treated in the second-line setting—where, if we use agents like nivolumab or atezolizumab, the survival benefit’s been observed irrespective of the PD-L1 level. There, the response rates tend to be lower—about 15% to 20% progression-free survival, a median of about 3 to 4 months. But still, there is a clear survival advantage compared to our erstwhile standard, docetaxel.

Roy S. Herbst, MD, PhD: I’ve been using a great deal of frontline pembrolizumab. Of course, at Yale we’ll run clinical trials if we have them. But if someone’s PD-L1 level is high, I will try to put them on pembrolizumab. And, quite frankly, the tolerability is just as good, if not better, then when given as second-line therapy. The efficacy is just as good, if not better. It’s a little bit better because you’re selecting patients who are 50% or higher. In patients who I’ve treated at Yale myself, or in those who come to me for consultation and I’ve sent home, those are the cases where I can often get a very nice call from a patient who tells me they’re feeling well and their tumor is shrinking. I am seeing, in the short experience I’ve had since the approval late last year, that the response rate is about 40% to 50%.

Transcript Edited for Clarity
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: 18th Annual International Lung Cancer Congress®Oct 31, 20181.5
Clinical Interchange™: Translating Research to Inform Changing Paradigms: Assessment of Emerging Immuno-Oncology Strategies and Combinations across Lung, Head and Neck, and Bladder CancersOct 31, 20182.0
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