Pemetrexed Plus Platinum With or Without Pembrolizumab in Patients With Previously Untreated Metastatic Nonsquamous NSCLC: Protocol-Specified Final Analysis From KEYNOTE-189

Abstract Background In the phase 3 KEYNOTE-189 study (NCT02578680), pembrolizumab plus pemetrexed and platinum-based chemotherapy (pemetrexed-platinum) significantly improved overall survival (OS) and progression-free survival (PFS) in patients with previously untreated metastatic nonsquamous NSCLC versus placebo plus pemetrexed-platinum. We report updated efficacy outcomes from the protocol-specified final analysis, including outcomes in patients who crossed over to pembrolizumab from pemetrexed-platinum and in patients who completed 35 cycles (approximately 2 years) of pembrolizumab. Patients and Methods Eligible patients were randomized 2:1 to pembrolizumab 200 mg (n=410) or placebo (n=206) every 3 weeks (for up to 35 cycles, approximately 2 years) plus 4 cycles of pemetrexed (500 mg/m2) and investigators' choice of cisplatin (75 mg/m2) or carboplatin (AUC 5 mg/ml/min) every 3 weeks, followed by pemetrexed until progression. Patients assigned to placebo plus pemetrexed-platinum could crossover to pembrolizumab upon progression if eligibility criteria were met. The primary endpoints were OS and PFS. Results After median follow-up of 31.0 months, pembrolizumab plus pemetrexed-platinum continued to improve OS (hazard ratio [HR], 0.56; 95% CI, 0.46‒0.69), and PFS (HR, 0.49; 95% CI, 0.41‒0.59) over placebo plus pemetrexed-platinum regardless of PD-L1 expression. ORR (48.3% versus 19.9%) and time to second/subsequent tumor progression on next-line treatment (PFS2; HR, 0.50; 95% CI, 0.41‒0.61) were improved in patients who received pembrolizumab plus pemetrexed-platinum. 84 patients (40.8%) from the placebo plus pemetrexed-platinum group crossed over to pembrolizumab on-study. Grade 3‒5 adverse events occurred in 72.1% of patients receiving pembrolizumab plus pemetrexed-platinum and 66.8% of patients receiving placebo plus pemetrexed-platinum. 56 patients completed 35 cycles (approximately 2 years) of pembrolizumab; ORR was 85.7% and 53 (94.6%) were alive at data cutoff. Conclusion Pembrolizumab plus pemetrexed-platinum continued to show improved efficacy outcomes compared with placebo plus pemetrexed-platinum, with manageable toxicity. These findings support first-line pembrolizumab plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous NSCLC.