Somatic KRAS mutations are detected in approximately 15%-30% of lung adenocarcinomas, with regional variation, and are associated with poor prognosis. We explored the prevalence of KRAS mutations and their association with efficacy in participants (pts) with nonsquamous NSCLC enrolled in the KEYNOTE-042 study of pembrolizumab monotherapy vs platinum-based chemotherapy as first-line therapy for advanced PD-L1-positive (TPS ≥1%) NSCLC (NCT02220894).
KRAS mutational status and tumor mutational burden (TMB) were assessed by whole-exome sequencing (WES) in pts with who had available tumor and matched-normal tissue. This exploratory analysis included descriptive analyses of the correlation between KRAS mutational status and shifts in distributions of TMB and PD-L1 expression and the association of KRAS and KRAS G12C status with efficacy.
Of the 782 pts with nonsquamous histology, 301 (38%) were evaluable by WES and had matched tumor and normal DNA. KRAS mutations were identified in 69 (23%) pts, including 29 (10%) G12C carriers. Pts with vs without KRAS mutation tended to have higher PD-L1 TPS (median [IQR] 60% [10-95] vs 35% [10-80]) and TMB (median [IQR] 191 [129-288] vs 105 [56-226] mut/exome). Outcomes of pembrolizumab and of chemotherapy for pts with and without KRAS mutation and for KRAS G12C carriers are in the Table. Of note, CIs were wide given the modest frequency of KRAS mutation and low frequency of KRAS G12C.
Findings of this descriptive exploratory analysis suggest that pembrolizumab monotherapy should be considered as a standard first-line treatment option for PD-L1-positive advanced nonsquamous NSCLC regardless of KRAS mutational status. These findings also suggest that a pembrolizumab-containing regimen is a clinically relevant comparator for studies of KRAS -targeted therapy given as first-line treatment of NSCLC.
| With Any KRAS Mutation | With KRAS G12C Mutation | Without Any KRAS Mutation | ||||
| Pembro Mono-therapy (N = 30) | Chemo-therapy (N = 39) | Pembro Mono-therapy (N = 12) | Chemo-therapy (N = 17) | Pembro Mono-therapy (N = 127) | Chemo-therapy (N = 105) | |
| ORR, % (95% CI) | 56.7 (37.4-74.5) | 18.0 (7.5-33.5) | 66.7 (34.9-90.1) | 23.5 (6.8-49.9) | 29.1 (21.4-37.9) | 21.0 (13.6-30.0) |
| PFS, median, mo (95% CI) | 12 (8-NR) | 6 (4-9) | 15 (10-NR) | 6 (4-8) | 6 (4-7) | 6 (6-8) |
| PFS, HR (95% CI) | 0.51 (0.29-0.87) | 0.27 (0.10-0.71) | 1.00 (0.75-1.34) | |||
| OS, median, mo (95% CI) | 28 (23-NR) | 11 (7-25) | NR (23-NR) | 8 (5-NR) | 15 (12-24) | 12 (11-18) |
| OS, HR (95% CI) | 0.42 (0.22-0.81) | 0.28 (0.09-0.86) | 0.86 (0.63-1.18) | |||
KEYNOTE-042; NCT02220894
Joanne Tomassini and Melanie Leiby, both of Merck & Co., Inc., Kenilworth, NJ, for writing support.