An updated analysis from the phase III KEYNOTE-189 trial, reported by Shirish Gadgeel, MB, BS, and colleagues in the Journal of Clinical Oncology, indicated that the addition of pembrolizumab to pemetrexed/platinum chemotherapy continues to be associated with progression-free and overall survival benefit in patients with previously untreated metastatic nonsquamous non–small cell lung cancer (NSCLC).

Shirish Gadgeel, MB, BS

The primary analysis from the study showed that first-line pembrolizumab plus pemetrexed/platinum significantly improved overall survival and progression-free survival compared with placebo plus pemetrexed/platinum in patients with metastatic nonsquamous NSCLC, irrespective of tumor programmed cell death ligand 1 (PD-L1) expression.

Study Details

In the trial, 616 patents were randomly assigned 2:1 to receive pemetrexed and platinum plus pembrolizumab (n = 410) or placebo (n = 206) every 3 weeks for 4 cycles, followed by pemetrexed maintenance plus pembrolizumab or placebo for up to a total of 35 cycles. Eligible patients in the placebo combination group could cross over to pembrolizumab monotherapy upon disease progression. 

Updated Efficacy Results

After median follow-up of 23.1 months (in September 2018), updated median overall survival was 22.0 months in the pembrolizumab/combination group vs 10.7 months in the placebo/combination group (hazard ratio [HR] = 0.56, 95% confidence interval [CI] = 0.45–0.70) and updated median progression-free survival was 9.0 vs 4.9 months (HR = 0.48, 95% CI = 0.40–0.58). Median progression-free survival 2 (time from randomization to either objective tumor progression on next-line treatment or death from any cause—whichever occurred first) was 17.0 months vs 9.0 months (HR = 0.49, 95% CI = 0.40–0.59).

Overall survival and progression-free survival benefit was observed for the pembrolizumab/combination group vs the placebo/combination group irrespective of PD-L1 expression status; for example, hazard ratios for overall survival were 0.62 (95% CI = 0.42-–0.92) among patients with tumor proportion score (TPS) of 1% to 49%, 0.59 (95% CI = 0.39–0.88) among those with TPS ≥ 50%, and 0.52 (95% CI = 0.36–0.74) among those with TPS < 1%.

Overall and progression-free survival benefit was also observed for the pembrolizumab/combination group among patients with or without liver and brain metastases; for example, hazard ratios for overall survival were 0.62 (95% CI = 0.39–0.98) among those with and 0.58 (95% CI = 0.45–0.74) among those without liver metastases, and 0.41 (95% CI = 0.24–0.67) in those with and 0.59 (95% CI = 0.46–0.75) in those without brain metastases.

Overall, grade ≥ 3 adverse events were observed in 71.9% of the pembrolizumab/combination group vs 66.8% of the placebo/combination group.

The investigators concluded, “First-line pembrolizumab plus pemetrexed/platinum continued to demonstrate substantially improved [overall survival and progression-free survival] in metastatic nonsquamous NSCLC, regardless of PD-L1 expression or liver/brain metastases, with manageable safety and tolerability.”

Dr. Gadgeel, of the Division of Hematology/Oncology, University of Michigan, Ann Arbor, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Merck Sharp & Dohme, a subsidiary of Merck & Co. For full disclosures of the study authors, visit ascopubs.org.