Olomorasib (KRAS G12C inhibitor) + pembrolizumab drives 58–67% ORR in 1L KRAS G12C NSCLC with PD-L1 0–49%

Olomorasib (LY3537982) is an oral KRAS G12C inhibitor combined here with pembrolizumab (anti–PD-1) as a potential chemotherapy-sparing 1L regimen for KRAS G12C–mutant advanced NSCLC with PD-L1 0–49%. In dose-optimization cohorts of LOXO-RAS-20001 (NCT04956640) and SUNRAY-01 (NCT06119581), efficacy-evaluable patients with PD-L1 <1% had ORR 58.3% (7/12) including 8.3% CR and DCR 91.7%, while PD-L1 1–49% had ORR 66.7% (12/18) including 5.6% CR and DCR 88.9% (brain metastases at baseline 23% and 17%, respectively). Safety across all treated patients (PD-L1 0–100%, n=85; data cut 6 June 2025) showed common any-grade TRAEs of diarrhea (31%) and ALT/AST increases (26%/24%); 12% permanently discontinued study treatment due to TRAEs—worth weighing against pembrolizumab + platinum doublet chemotherapy (SOC for PD-L1 <50%), where ORR is typically ~48% in KEYNOTE-189 (nonsquamous) and ~58% in KEYNOTE-407 (squamous), albeit with different toxicity profiles driven by cytotoxics.