GRACE :: Lung Cancer

KEYNOTE-021g

Dr West

Why I Don’t Favor an Front-Loaded Approach for Most Advanced NSCLC Patients

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To many, the recent FDA approval of a combination of chemotherapy and concurrent immunotherapy for the vast majority of patients with advanced (metastatic) non-squamous non-small cell lung cancer (NSCLC) probably seems like a great idea. This approval was based on the more favorable results for the combination of the IV immunotherapy agent Keytruda (pembrolizumab) every 3 weeks along with first line carboplatin and Alimta (pemetrexed) as a the chemo backbone, compared to the same chemotherapy alone, in a relatively small randomized trial of 123 patients, called KEYNOTE-021g. The “g” part refers to this actually being just one portion of a much larger trial comparing chemo to the same chemo with Keytruda. The other arms haven’t panned out as favorably.

Importantly, when we talk about the arm of patients getting chemo combined with immunotherapy, we aren’t talking about improving survival. Instead, we’re talking about prolonging the time before patients showed significant progression of their cancer on scans, which leads us to switch to a new treatment. This “progression-free survival”, or PFS, was the primary goal of the trial, though the gold standard of what we should really want from our treatments is improvement in how long patients live. There’s a bit of a favorable trend for that, but that’s all. There was also a significant improvement in the fraction of patients who show major shrinkage of their cancer when Keytruda is added to chemotherapy.

Still, even if survival isn’t improved, the results seem promising enough, so what’s not to like? Continue reading


Dr West

Imprecision Medicine: Why Keytruda (Pembrolizumab) + Chemo for PD-L1+ NSCLC isn’t Ready for Prime Time

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Let me start by saying that I’m a fan of the immune checkpoint inhibitor Keytruda (pembrolizumab) and consider it the new standard of care as a single agent (monotherapy) first line treatment for the subset of about 28-30% of patients with advanced NSCLC, either squamous or non-squamous, whose cancers have high level expression of PD-L1, defined as 50% or more cancer cells staining on the companion test for Keytruda (an antibody called 22c3).  It can lead to some terrific and long-lasting responses, but it works well only in a minority of patients; in fact, even in the cherry-picked population of patients with cancers that show high PD-L1 expression, the response rate is a little less than 50%, and it’s below 20% in patients with low or no PD-L1 expression. Merck just announced that the FDA has accepted a “supplemental Biologics License Application” (sBLA) that would broaden the FDA approval for Keytruda in NSCLC to all non-squamous NSCLC patients without an EGFR mutation or ALK rearrangement and without regard to PD-L1 expression, giving Keytruda in combination with chemotherapy (carboplatin and Alimta (pemetrexed)).  I think the evidence we have with this combination is encouraging and worthy of further study, but it shouldn’t be enough to lead to broad use as requested in the FDA filing. I think it’s a premature money grab that isn’t necessarily better for patients and is definitely bad for broad society. Let me explain why.

The evidence behind this strategy is from a cohort of patients (cohort G) from a larger study, KEYNOTE-021) of patients randomized to various chemo combinations with or without Keytruda. This particular trial did not have a threshold requirement for PD-L1 and enrolled 123 patients with a good performance status and advanced NSCLC to receive either carboplatin/Alimta alone or the same chemo with Keytruda at a fixed dose of 200 mg IV every 3 weeks. Patients who hadn’t progressed after 4 cycles would continue to receive maintenance Alimta (for the chemo only arm) or Alimta/Keytruda (for the chemo/immunotherapy arm) until progression or prohibitive side effects.

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