COMMENTARY

KEYNOTE-189 and CheckMate-227: Practice-Changing Results, but How Should We Prioritize Them?

H. Jack West, MD

Disclosures

April 24, 2018

We already knew from the press releases that the showdown at the American Association for Cancer Research (AACR) meeting was going to be a big day for lung cancer, and the fact that it was at AACR made it all the more remarkable. Of course, AACR is not a showcase for big clinical data, but the positive data have rolled in too rapidly for the results to wait until the American Society of Clinical Oncology (ASCO) meeting in early June. Though AACR is typically known for preclinical and very early clinical fare, novel and practice-changing results for advanced non-small cell lung cancer (NSCLC) were featured at a plenary session that beckoned me back to my first AACR meeting in decades, and for less than 24 hours in maddeningly arctic mid-April Chicago weather at that. But that session alone was worth the trip.

KEYNOTE-189

The first presentation was by Leena Gandhi, MD, PhD, director of thoracic medical oncology at NYU Langone in New York City, and covered the KEYNOTE-189 trial comparing first-line cisplatin or carboplatin with pemetrexed and pembrolizumab versus the same chemotherapy backbone alone, with potential crossover to pembrolizumab after progression on chemotherapy. The trial included 616 patients with advanced nonsquamous NSCLC without an EGFR mutation or ALK rearrangement and was also published concurrently in the New England Journal of Medicine (NEJM).[1]

We had already learned from a press release[2] that the trial was positive for an overall survival (OS) benefit. Questions remained, however, including just how positive the results were, and whether the benefits from a chemo/immunotherapy combination are driven primarily or exclusively by the subset of patients with high PD-L1 (tumor proportion score >50%), who today would be eligible and strong candidates for pembrolizumab monotherapy. I was also eager to learn what proportion of patients assigned to first-line carboplatin/pemetrexed alone crossed over to receive pembrolizumab.

It was a crushing win for a chemo/immunotherapy regimen.

We learned that the chemo/immunotherapy combination didn't just beat chemotherapy alone; it was a crushing win for a chemo/immunotherapy regimen (with carboplatin) that had already been approved by the US Food and Drug Administration (FDA) in May 2017,[3] based on promising but still limited results from the randomized phase 2 KEYNOTE-021g trial.[4] KEYNOTE-021g had a very similar design (using carboplatin alone rather than cisplatin or carboplatin) but with only 123 patients.

Specifically, the hazard ratio (HR) for death was 0.49 (P < .001), translating to an approximately 50% improvement in OS, and with a 1-year survival of 69.2% versus 49.4%. Of note, the benefit of pembrolizumab extended across all PD-L1 levels, even including the approximately 30% of patients with tumors showing < 1% PD-L1 expression. However, the OS differences were most pronounced in favor of chemo/immunotherapy for the patients in the high PD-L1 expression cohort (HR 0.42), lowest in those with tumor PD-L1 expression <1% (HR 0.59), and intermediate for the group with 1%-49% PD-L1 expression (HR 0.55). The chemo/immunotherapy arm was also associated with a significant improvement in progression-free survival (PFS; median PFS 8.8 vs 4.9 months; HR 0.52; P < .001) and a superior response rate (RR; 47.6% vs 18.9%; P < .001). The rates of overall and more serious toxicities were very similar, without unexpected findings except perhaps for a rate of grade 3-5 nephritis of 1.5%, which was higher than had been expected based on earlier studies of pembrolizumab monotherapy.

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