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Nondriver mNSCLC: Incorporating Trial Data into Practice

Insights From: Hossein Borghaei, DO, Fox Chase Cancer Center; Corey J. Langer, MD, Perelman School of Medicine; Vassiliki Papadimitrakopoulou, MD, MD Anderson Cancer Center
Published: Thursday, Aug 16, 2018



Transcript: 

Corey J. Langer, MD: Grappling with this tsunami of data has become quite difficult. I don’t think I’ve attended an ASCO meeting where we’ve seen so many positive phase III trials, really back to back. First at AACR and now ASCO, we’re witnessing 5, 6, even 7 strongly positive phase III trials. Oncogenic drivers are still the initial determinant in the nonsquamous population. If an individual has an EGFR mutation, they get a TKI. Osimertinib, based on the FLAURA data, has displaced the first-generation drugs erlotinib and gefitinib. If they have an ALK translocation, they get a TKI, specifically alectinib, which looks significantly better than crizotinib. In fact, the PFS data have been updated at ASCO 2018, and it’s 3-fold better. We’re seeing a PFS of roughly 35 months versus 11 to 12 months in the control group: unprecedented findings.

For those with ROS1 mutations, crizotinib is the standard. For BRAF mutations, it’s combination dabrafenib and trametinib. But that’s probably about 20% of our patients; for the much larger population that does not have readily identifiable oncogenic drivers, PD-L1 becomes our new standard of testing. If the patient has PD-L1 expression of 50% or higher, we have the choice of either pembrolizumab or combination pembrolizumab and chemotherapy, pemetrexed/carboplatin. If it’s less than 50%, the combination has benefit, and that includes the 0% group. For those individuals who are eligible for angiogenesis inhibition or who are no longer sensitive to TKIs—they have an oncogenic driver, but they’ve exhausted their benefits from TKIs, and that may happen 1, 2, or 3 years into their treatment—we have now the emergence of a new combination that has generated survival advantage. It hasn’t been formally FDA approved, but I suspect, based on the results generated at ASCO 2018, that paclitaxel/carboplatin/bevacizumab plus atezolizumab will be a new standard.

My question is whether we can slot in pemetrexed in exchange for paclitaxel in that setting. I’m not really sure of that. It would be an extraordinarily expensive regimen. On the other hand, it would be a less toxic regimen, and we’d avoid the hair loss and the neuropathy we typically see with taxanes. For squamous disease, until we see the formal unveiling of both the IMpower131 and KEYNOTE-407 data, a carboplatin combination with either gemcitabine or a taxane is the standard. I choose nab-paclitaxel. I think it’s better tolerated. It’s easier to give. We have survival data in the elderly that look quite promising.

But now we have heard, at least through press release, of positive findings in both PFS and OS for the combination of nab-paclitaxel/carboplatin with pembrolizumab once more, analogous to the KEYNOTE-189 trial, compared with chemotherapy alone. I suspect, once those data are unveiled, that we will have another new standard of care for the squamous population. So, it’s a heady time. I’ve never seen so many changes in how we practice based on a single set of meetings.

Hossein Borghaei, DO: In my clinical practice, we’ve been checking PD-L1 expression for a long time at the time of initial diagnosis. We obviously conducted thorough molecular testing on all our patients, and patients are offered treatment that are specific to their tumor. I think KEYNOTE-189 clearly establishes a new standard of care for us, in the context of patients with either less than 1% or 1% to 49% expression. I think the greater than 50% expressing patient population can get pembrolizumab as a single agent. If I don’t have a clinical trial for my patients, I would offer them the triple combination.

The carboplatin/paclitaxel/bevacizumab and atezolizumab combination, the IMpower150 combination, is also a valid option for some patients. But Taxol (paclitaxel) comes with some side effects like neuropathy and hair loss that some of the patients are not happy with. Unless there is a need for my patients with nonsquamous histology, I would prefer to stay with the carboplatin/pemetrexed-based regimens.

Regarding the CheckMate-227 trial, in full disclosure, we’ve spent a lot of our resources on the combination of ipilimumab plus nivolumab because I really believe that combination to be an active and valid combination to be investigated. We treated a lot of patients on clinical trials with that, and we were happy with the results that we were seeing from our patients for the most part. But the combination is not an FDA-approved regimen, so it is difficult from outside of a clinical trial to say that I’m offering that to my patients at this point. Moreover, I think overall survival data are important, and since the study is still ongoing, we don’t have those data. Once that becomes available, I think it gives us a different perspective as to whether an I-O/I-O combination can in fact improve overall survival in the specific patient population that we’re investigating.

Transcript Edited for Clarity 
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Transcript: 

Corey J. Langer, MD: Grappling with this tsunami of data has become quite difficult. I don’t think I’ve attended an ASCO meeting where we’ve seen so many positive phase III trials, really back to back. First at AACR and now ASCO, we’re witnessing 5, 6, even 7 strongly positive phase III trials. Oncogenic drivers are still the initial determinant in the nonsquamous population. If an individual has an EGFR mutation, they get a TKI. Osimertinib, based on the FLAURA data, has displaced the first-generation drugs erlotinib and gefitinib. If they have an ALK translocation, they get a TKI, specifically alectinib, which looks significantly better than crizotinib. In fact, the PFS data have been updated at ASCO 2018, and it’s 3-fold better. We’re seeing a PFS of roughly 35 months versus 11 to 12 months in the control group: unprecedented findings.

For those with ROS1 mutations, crizotinib is the standard. For BRAF mutations, it’s combination dabrafenib and trametinib. But that’s probably about 20% of our patients; for the much larger population that does not have readily identifiable oncogenic drivers, PD-L1 becomes our new standard of testing. If the patient has PD-L1 expression of 50% or higher, we have the choice of either pembrolizumab or combination pembrolizumab and chemotherapy, pemetrexed/carboplatin. If it’s less than 50%, the combination has benefit, and that includes the 0% group. For those individuals who are eligible for angiogenesis inhibition or who are no longer sensitive to TKIs—they have an oncogenic driver, but they’ve exhausted their benefits from TKIs, and that may happen 1, 2, or 3 years into their treatment—we have now the emergence of a new combination that has generated survival advantage. It hasn’t been formally FDA approved, but I suspect, based on the results generated at ASCO 2018, that paclitaxel/carboplatin/bevacizumab plus atezolizumab will be a new standard.

My question is whether we can slot in pemetrexed in exchange for paclitaxel in that setting. I’m not really sure of that. It would be an extraordinarily expensive regimen. On the other hand, it would be a less toxic regimen, and we’d avoid the hair loss and the neuropathy we typically see with taxanes. For squamous disease, until we see the formal unveiling of both the IMpower131 and KEYNOTE-407 data, a carboplatin combination with either gemcitabine or a taxane is the standard. I choose nab-paclitaxel. I think it’s better tolerated. It’s easier to give. We have survival data in the elderly that look quite promising.

But now we have heard, at least through press release, of positive findings in both PFS and OS for the combination of nab-paclitaxel/carboplatin with pembrolizumab once more, analogous to the KEYNOTE-189 trial, compared with chemotherapy alone. I suspect, once those data are unveiled, that we will have another new standard of care for the squamous population. So, it’s a heady time. I’ve never seen so many changes in how we practice based on a single set of meetings.

Hossein Borghaei, DO: In my clinical practice, we’ve been checking PD-L1 expression for a long time at the time of initial diagnosis. We obviously conducted thorough molecular testing on all our patients, and patients are offered treatment that are specific to their tumor. I think KEYNOTE-189 clearly establishes a new standard of care for us, in the context of patients with either less than 1% or 1% to 49% expression. I think the greater than 50% expressing patient population can get pembrolizumab as a single agent. If I don’t have a clinical trial for my patients, I would offer them the triple combination.

The carboplatin/paclitaxel/bevacizumab and atezolizumab combination, the IMpower150 combination, is also a valid option for some patients. But Taxol (paclitaxel) comes with some side effects like neuropathy and hair loss that some of the patients are not happy with. Unless there is a need for my patients with nonsquamous histology, I would prefer to stay with the carboplatin/pemetrexed-based regimens.

Regarding the CheckMate-227 trial, in full disclosure, we’ve spent a lot of our resources on the combination of ipilimumab plus nivolumab because I really believe that combination to be an active and valid combination to be investigated. We treated a lot of patients on clinical trials with that, and we were happy with the results that we were seeing from our patients for the most part. But the combination is not an FDA-approved regimen, so it is difficult from outside of a clinical trial to say that I’m offering that to my patients at this point. Moreover, I think overall survival data are important, and since the study is still ongoing, we don’t have those data. Once that becomes available, I think it gives us a different perspective as to whether an I-O/I-O combination can in fact improve overall survival in the specific patient population that we’re investigating.

Transcript Edited for Clarity 
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