First-Line Combination of Pembrolizumab + Platinum/Pemetrexed Chemotherapy Improves Nonsquamous NSCLC Survival

For patients newly diagnosed with metastatic non-small cell lung cancer (NSCLC) without sensitizing EGFR or ALK mutations, the standard of care has historically been chemotherapy. Due to survival benefit and a favorable toxicity profile, immunotherapy with the PD-1 inhibitor pembrolizumab offers an attractive alternative to first-line chemotherapy, but only for patients with PD-L1 expression >50%. Based on efficacy results from a randomized phase II trial (KEYNOTE-021 cohort G), the combination of carboplatin/pemetrexed with pembrolizumab recently gained accelerated US Food & Drug Administration (FDA) approval in this setting for nonsquamous NSCLC regardless of PD-L1 expression. However, despite this approval many physicians are reluctant to routinely use this combination and results from the confirmatory double-blind randomized phase III KEYNOTE-189 trial of this combination have been eagerly expected. These results were recently presented at the American Association for Cancer Research (AACR) Annual Meeting and simultaneously published in the New England Journal of Medicine.

Patients involved in this study (N = 616) received pemetrexed and platinum-based chemotherapy plus either 200 mg pembrolizumab or placebo (every 3 weeks for 4 cycles), followed by pembrolizumab or a placebo for up to 35 cycles and pemetrexed maintenance. Crossover to pembrolizumab monotherapy was allowed for patients in the placebo group who had verifiable disease progression. Overall survival (OS) and progression-free survival (PFS) were the co-primary endpoints.

At a median of 10.5 months follow-up, pembrolizumab plus chemotherapy resulted in significant improvements in both PFS and OS compared to chemotherapy alone. The estimated 12-month OS rate was 69.2% with the pembrolizumab combination, compared to 49.4% for chemotherapy alone (HR 0.49, P<.001). The median OS was not yet reached in the pembrolizumab combination group, and was 11.4 months in the placebo combination group. The OS benefit with pembrolizumab was consistent across all prespecified patient subgroups, including PD-L1 expression (PD-L1 <1%: HR 0.59). The addition of pembrolizumab resulted in a 3.9-month improvement in PFS (8.8 months vs 4.9 months; HR 0.52, P<.001). Overall response rate (ORR) was 47.6% in patients receiving the pembrolizumab combination versus 18.9% in patients receiving the placebo combination (P<.001).

The frequency and severity of adverse events (AEs) were similar in the two treatment groups. Grade 3 or higher AEs occurred in 67.2% and 65.8% of patients in the pembrolizumab and placebo groups, respectively. Immune-mediated AEs occurred in 22.7% of patients treated with pembrolizumab plus chemotherapy and 11.9% of patients receiving chemotherapy alone.  Pemetrexed and platinum did not appear to exacerbate pembrolizumab-associated toxicity, with the exception of acute kidney injury (5.2% vs 0.5%) and nephritis (1.7% vs 0%). Rates of discontinuation of all trial drugs because of AEs were 13.8% for pembrolizumab-based therapy versus 7.9% for chemotherapy. The frequency of death because of immune-mediated pneumonitis was consistent as previously reported with pembrolizumab monotherapy in NSCLC.

The investigators concluded that the addition of pembrolizumab to first-line chemotherapy significantly improves OS, PFS, and ORR with minimal additional toxicity, and this combination should be considered a new standard of care for first-line treatment of metastatic nonsquamous NSCLC without sensitizing EGFR and ALK mutations regardless of PD-L1 expression.
N Engl J Med. 2018 April 16. [Epub ahead of print].


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