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Treatment standards and emerging options for previously untreated advanced NSCLC

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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Dr West

Is immunotherapy the wrong choice for some lung cancer patients?

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Amidst all of the glowing reports about immunotherapy for lung and many other cancers, it would be understandable for patients and physicians to be tempted to rush toward prioritizing immunotherapy as the first treatment strategy to pursue. In fact, a highly publicized trial called KEYNOTE-024 was just presented at the ESMO meeting in Copenhagen and demonstrated a significant improvement in progression-free and overall survival over standard chemotherapy doublet treatment as the first line approach for patients with high level expression of the PD-L1 protein on their tumor (about 30% of patients).  But there is also converging evidence that some patients are consistently less likely to benefit from immunotherapy — specifically, those patients with an EGFR mutation and perhaps others with another “driver mutation” such as an ALK or ROS1 rearrangement.  This is an important issue to know, because I and some other lung cancer specialist colleagues see patients with one of these highly targetable lesions sometimes being mistakenly recommended immunotherapy over the optimal targeted therapy for their cancer, or patients deflect a recommendation for an EGFR or ALK inhibitor in favor of immunotherapy based largely or completely on the hype around the latest new idea in cancer treatment.

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Dr West

Death by “Pseudo-progression”: Knowing When to Cut Your Losses with Immunotherapy

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Among the many novel concepts in managing immunotherapy is the potential for “pseudo-progression”. This unusual phenomenon is when a patient’s scans of the areas of cancer actually appear worse on early imaging, potentially even with new lesions, after starting immunotherapy, but a patient’s scans later show shrinkage of the cancer.  These patients typically feel well, often with improvement in their cancer-related symptoms (fatigue, appetite, etc.) that don’t seem to be concordant with their worse-appearing scans.

Why might this happen? Some biopsies of lesions that have grown or appeared as new in such patients help explain that the growth is from infiltration of immune cells around tumor cells, preceding the time when those tumor cells are attacked and eradicated by the immune system.  In cases where new nodules appear that then resolve with later scans, it is felt that this situation represents immune cells infiltrating a “micro-nodule” of cancer that wasn’t visible until it was surrounded by immune cells that then enlarged it enough to become newly detectable on scans.

Pseudoprogression West JAMA Oncol 2015

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Dr West

It’s most likely the study population, not the drug choice, that leads to different outcomes for immunotherapy agents in lung cancer

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Yesterday, news that the Checkmate 026 trial that compared the PD1 checkpoint inhibitor Opdivo (nivolumab) to standard chemotherapy as first line treatment for advanced non-small cell lung cancer (NSCLC) failed to demonstrate an improvement in the primary endpoint of progression-free survival. This led to Bristol-Myers Squibb stock being spanked, with a 16% drop over the day, while the stock price for Merck , the makers of the remarkably similar agent Keytruda (pembrolizumab), jumped more than 10% on the same news, since Keytruda had been reported in a press release to beat standard chemotherapy in a similar trial, Keynote 024

This website isn’t focused on analyzing what investors should do, but it’s clear that these dramatic changes in stock price represent a major misinterpretation of the take-home conclusions from the press releases that have emerged thus far.  The fact that Keytruda beat chemo in a first line trial vs. chemotherapy but Opdivo failed to beat chemo in a first line trial doesn’t mean that these agents are meaningfully different and that Keytruda is superior (disclosure: I’ve been paid to serve on advisory boards for both Merck and BMS in the past and am not pulling for either).  To understand why Keytruda beat first line chemotherapy in Merck’s Keynote 024 trial but Opdivo didn’t beat first line chemo in BMS’s Checkmate 026 trial, I refer you to one of the major points I made back in mid-June, when I offered my commentary about the positive results with Keytruda (bold included when originally written on 6/16/16):

Keynote 24 warning

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Dr West

Should Alecensa (Alectinib) be the new first line ALK inhibitor for ALK-positive NSCLC?

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Probably the most immediate potentially practice-changing presentation from ASCO was the Japanese J-ALEX study in the subset of about 4-5% of patients with non-small cell lung cancer (NSCLC) who have the molecular driver known as an anaplastic lymphoma kinase (ALK) rearrangement, which we now routinely test for from the tumor tissue of patients with a non-squamous metastatic NSCLC.   The current historical standard of care as first line treatment is Xalkori (crizotinib), which is an ALK inhibitor that happened to be readily available when the ALK rearrangement was first being studied in NSCLC about 5-7 years ago. Though it was granted an accelerated FDA approval back in 2011 based on early very promising activity and has since been confirmed to be superior to chemotherapy as first line treatment in ALK-positive patients, it is a less active ALK inhibitor than many other “second-generation” ALK inhibitors such as Zykadia (ceritinib) and Alecensa (alectinib), both now FDA-approved for patients who have developed progression after Xalkori or who are not able to tolerate it, as well as other agents still in development, including brigatinib (likely to become approved soon), and a few others further behind in development but also very active against ALK-positive NSCLC.

A question that logically follows is whether it is better to give one of these more active second generation ALK inhibitors as first line therapy, where they are likely to be more active for longer than if given for “acquired resistance” after Xalkori, or whether it’s better to start with Xalkori and have other powerful ALK inhibitors left for later.  Should we use our best drug up front or only the most effective drug required to do the job for now, saving something in the tank as we think more about advanced lung cancer as a distance race than a sprint? How much do we prioritize control now vs. options later?

There are several trials that have been initiated that all test a second generation ALK inhibitor vs. Xalkori.  Two of the first to be completed compare Alecensa to Xalkori, a large, global trial known as ALEX, and a smaller trial done in Japan only, known as J-ALEX, which reported early and remarkably interesting results at ASCO 2016.

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