Updated results from KEYNOTE-021 cohort G: A randomized, phase 2 study of pemetrexed and carboplatin (PC) with or without pembrolizumab (pembro) as first-line therapy for advanced nonsquamous NSCLC

Abstract

Background: Cohort G of the multicenter, open-label, phase 1/2 KEYNOTE-021 study evaluated the efficacy and safety of pembro + PC vs PC alone as first-line therapy for advanced nonsquamous NSCLC. At the primary analysis of cohort G (min. follow-up, 6 mo; median, 10.6mo), pembro significantly improved ORR (estimated treatment difference, 26%; P = 0.0016) and PFS (HR, 0.53; P= 0.010). The HR for OS was 0.90 (95% CI, 0.42-1.91). In a subsequent analysis with median follow-up of 14.5 mo, the HR for OS was 0.69 (95% CI, 0.36-1.31). Methods: 123 patients with stage IIIB/IV nonsquamous NSCLC, no prior systemic therapy, and no EGFR mutation or ALK translocation were randomized 1:1 (stratified by PD-L1 TPS -1% vs<1%) to receive 4 cycles of carboplatin AUC 5 + pemetrexed 500 mg/m2 Q3W with or without pembro 200 mg Q3W. Pembro treatment continued for up to 2 y; maintenance pemetrexed was permitted in both arms. Eligible patients in the PC arm with radiologic progression could cross over to pembro monotherapy. Response was assessed by blinded, independent central review per RECIST v1.1. All P values are nominal (one-sided P< 0.025). Results: At the time of data cutoff (May 31, 2017), median follow-up was 18.7 mo (range, 0.8-29.0 mo). ORR was 57% with pembro + PC and 32% with PC (estimated difference, 25%; 95% CI, 7%-41%; P= 0.0029). PFS was significantly improved with pembro + PC vs PC (HR, 0.54; 95% CI, 0.33-0.88; P = 0.0067) with median (95% CI) PFS of 19.0 (8.5-NR) mo vs 8.9 (95% CI, 6.2-11.8) mo. 40 of 53 (75%) patients in the PC arm who discontinued received subsequent anti-PD-1/anti-PD-L1 therapy (including 25 who received pembro in the on-study cross over). The HR for OS was 0.59 (95% CI, 0.34-1.05; P = 0.0344). Median (95% CI) OS was not reached (22.8-NR) mo for pembro + PC and 20.9 (14.9-NR) mo in the PC arm. 18-mo OS rate was 70% with pembro + PC and 56% with PC. Grade 3-5 treatment-related AEs occurred in 41% of patients in the pembro +PC arm vs 29% in the PC arm. Conclusions: The significant improvements in PFS and ORR with pembro+ PC vs PC first observed in the primary analysis have been maintained with longer follow-up (median 18.7 mo). The HR for OS continues to improve for pembro +PC vs PC (HR: 0.90 to 0.69 to 0.59).