Updated Analysis From KEYNOTE-189: Adding Pembrolizumab to Pemetrexed/Platinum for Nonsquamous NSCLC

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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

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).


  • Longer-term follow-up showed maintained overall and progression-free survival benefits with pembrolizumab plus pemetrexed/platinum.
  • Updated median overall survival was 22.0 months in the pembrolizumab/combination group vs 10.7 months in the placebo/combination group.

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

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