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The Ever-Evolving Treatment Paradigm 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 Online: Thursday, Jul 13, 2017



Transcript:

Roy S. Herbst, MD, PhD:
In the last 20 years, we’ve seen a truly dramatic change in how lung cancer is treated, especially non–small cell lung cancer. We went from an era of chemotherapy only, regardless of histology, to chemotherapy focused on histology. At the same time, we learned more about molecular profiles and mutations. And such genes as epidermal growth factor and rearrangements in ALK were discovered. And, of course, now we treat patients with EGFR and ALK inhibitors.

But, really, that left about 85% of patients without an actionable mutation until the last 4 or 5 years with the advent of the immune checkpoint inhibitors. With these agents, we’re seeing about 15% to 20% of patients having long-term benefit from these drugs. It really is a new era because, in multiple metastatic sites including brain and liver and other places, patients with these very advanced lung cancers are now living a long time. Again, this is a small number, but enough that we have great hope. Research is looking at new combinations and new ways to integrate immunotherapy, targeted therapy, and chemotherapy into this paradigm, as well as even adding radiotherapy.

Vassiliki A. Papadimitrakopoulou, MD: There are a number of recognized driver mutations for nonsquamous histology that we have successfully targeted over the past decade. For these patients, the outcomes with targeted therapy are quite good, and their overall survival has been lengthened significantly. However, at least one-third of the patients with nonsquamous histology harbor KRAS mutations in their tumor. They are recognized as drivers, but not as targetable.

Also, we have a large number of patients, about 25% of patients with non–small cell lung cancer with squamous histology, who do harbor mutations in their tumor, but the driver status of these mutations is still unknown or remains to be ascertained. For these patients, we still are lacking targeted therapies, and there is a need to improve their outcomes. Immunotherapy has been incorporated into our therapeutic armamentarium, improving the outcomes of the patients with nonsquamous histologies who have no driver mutations in their tumor.

Corey J. Langer, MD: PD-L1 testing has become increasingly critical in the management of our patients. KEYNOTE-010, the phase III trial that showed a benefit for pembrolizumab versus our former standard, docetaxel, mandated a minimum IHC expression level of 1% or higher. It’s intriguing. If you look at even higher levels, 50% or higher, the survival benefits were more pronounced. Where it’s really become absolutely essential is in the frontline setting. This is based on KEYNOTE-024, which compared single-agent pembrolizumab monotherapy to standard platinum-based doublets—essentially chemotherapy de jour. Eligibility for that study required a minimum expression level of 50% or higher. If you look at the overall population of non–small cell lung cancer, that’s probably about 25% to 30% of our patients. That trial showed a statistically significant—¬and I’d argue clinically meaningful — survival advantage, as well as a major response in progression-free survival advantage.

Roy S. Herbst, MD, PhD: I would test everyone for PD-L1. In fact, at Yale, we have a reflex PD-L1 test. When I see a patient for the first time, if they’ve just had a biopsy or surgery, the PD-L1 test is there. At the same time, I know whether or not it’s squamous or adenocarcinoma. It takes a little bit longer to get the next-generation sequencing for the EGFR and ALK, but of course, that’s important too. PD-L1 is critical, because positive PD-L1 at a high level—more than 50% of the tumors and cells being positive—indicates the patient who should get pembrolizumab in the front-line setting as a single agent. It’s only 20% of the population, but that’s the 20% we want to find.

Vassiliki A. Papadimitrakopoulou, MD: Based on the approval of pembrolizumab in front-line therapy for non–small cell lung cancer, using PD-L1 expression and the overall consistency of the assay across clinical trials, the recommended test for assessment of PD-L1 expression is the 22C3 antibody assay.

Roy S. Herbst, MD, PhD: In my opinion, there’s no need to reorder PD-L1 testing if you’ve done it in the first-line setting, if someone’s had chemotherapy or another intervening treatment. In fact, the data from KEYNOTE-010—a trial which we actually presented on last year at the ASCO Annual Meeting and updated at ESMO Congress—revealed that in patients who have biopsies that are either fresh or archival, the results did not change. We still saw benefit from the immunotherapy over the controlled chemotherapy, this being in the second-line setting. So, I would use the old biopsy and only get a new biopsy if there was none available.

Transcript Edited for Clarity
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Transcript:

Roy S. Herbst, MD, PhD:
In the last 20 years, we’ve seen a truly dramatic change in how lung cancer is treated, especially non–small cell lung cancer. We went from an era of chemotherapy only, regardless of histology, to chemotherapy focused on histology. At the same time, we learned more about molecular profiles and mutations. And such genes as epidermal growth factor and rearrangements in ALK were discovered. And, of course, now we treat patients with EGFR and ALK inhibitors.

But, really, that left about 85% of patients without an actionable mutation until the last 4 or 5 years with the advent of the immune checkpoint inhibitors. With these agents, we’re seeing about 15% to 20% of patients having long-term benefit from these drugs. It really is a new era because, in multiple metastatic sites including brain and liver and other places, patients with these very advanced lung cancers are now living a long time. Again, this is a small number, but enough that we have great hope. Research is looking at new combinations and new ways to integrate immunotherapy, targeted therapy, and chemotherapy into this paradigm, as well as even adding radiotherapy.

Vassiliki A. Papadimitrakopoulou, MD: There are a number of recognized driver mutations for nonsquamous histology that we have successfully targeted over the past decade. For these patients, the outcomes with targeted therapy are quite good, and their overall survival has been lengthened significantly. However, at least one-third of the patients with nonsquamous histology harbor KRAS mutations in their tumor. They are recognized as drivers, but not as targetable.

Also, we have a large number of patients, about 25% of patients with non–small cell lung cancer with squamous histology, who do harbor mutations in their tumor, but the driver status of these mutations is still unknown or remains to be ascertained. For these patients, we still are lacking targeted therapies, and there is a need to improve their outcomes. Immunotherapy has been incorporated into our therapeutic armamentarium, improving the outcomes of the patients with nonsquamous histologies who have no driver mutations in their tumor.

Corey J. Langer, MD: PD-L1 testing has become increasingly critical in the management of our patients. KEYNOTE-010, the phase III trial that showed a benefit for pembrolizumab versus our former standard, docetaxel, mandated a minimum IHC expression level of 1% or higher. It’s intriguing. If you look at even higher levels, 50% or higher, the survival benefits were more pronounced. Where it’s really become absolutely essential is in the frontline setting. This is based on KEYNOTE-024, which compared single-agent pembrolizumab monotherapy to standard platinum-based doublets—essentially chemotherapy de jour. Eligibility for that study required a minimum expression level of 50% or higher. If you look at the overall population of non–small cell lung cancer, that’s probably about 25% to 30% of our patients. That trial showed a statistically significant—¬and I’d argue clinically meaningful — survival advantage, as well as a major response in progression-free survival advantage.

Roy S. Herbst, MD, PhD: I would test everyone for PD-L1. In fact, at Yale, we have a reflex PD-L1 test. When I see a patient for the first time, if they’ve just had a biopsy or surgery, the PD-L1 test is there. At the same time, I know whether or not it’s squamous or adenocarcinoma. It takes a little bit longer to get the next-generation sequencing for the EGFR and ALK, but of course, that’s important too. PD-L1 is critical, because positive PD-L1 at a high level—more than 50% of the tumors and cells being positive—indicates the patient who should get pembrolizumab in the front-line setting as a single agent. It’s only 20% of the population, but that’s the 20% we want to find.

Vassiliki A. Papadimitrakopoulou, MD: Based on the approval of pembrolizumab in front-line therapy for non–small cell lung cancer, using PD-L1 expression and the overall consistency of the assay across clinical trials, the recommended test for assessment of PD-L1 expression is the 22C3 antibody assay.

Roy S. Herbst, MD, PhD: In my opinion, there’s no need to reorder PD-L1 testing if you’ve done it in the first-line setting, if someone’s had chemotherapy or another intervening treatment. In fact, the data from KEYNOTE-010—a trial which we actually presented on last year at the ASCO Annual Meeting and updated at ESMO Congress—revealed that in patients who have biopsies that are either fresh or archival, the results did not change. We still saw benefit from the immunotherapy over the controlled chemotherapy, this being in the second-line setting. So, I would use the old biopsy and only get a new biopsy if there was none available.

Transcript Edited for Clarity
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