Olomorasib + Pembrolizumab Delivers 70% ORR and 80% 6-mo PFS in Front-Line KRAS-G12C NSCLC

Olomorasib (LY3537982), a next-generation covalent KRAS-G12C inhibitor, was combined with pembrolizumab (PD-1 checkpoint inhibitor) in the Phase 1/2 LOXO-RAS-20001 trial (NCT04956640). 43 previously untreated metastatic KRAS G12C NSCLC patients (any PD-L1 level) received olomorasib 50 mg or 100 mg BID plus pembrolizumab Q3W. About 13% of NSCLC cases are KRAS G12C mutants Investigator-assessed ORR reached 70% (1 CR, 23 PR, 4 unconfirmed PRs) with disease-control in 90%. Responses were enhanced in PD-L1 ≥50% tumors (ORR 82%, DCR 94%). After a median follow-up of 5.5 months, median DoR was not reached, and the 6-month PFS rate was 80%. Grade 3 ALT/AST elevations occurred in 26%/16% (olomorasib- and/or pembrolizumab-related) but led to permanent discontinuation in only 5% of patients overall. Other common TRAEs were diarrhea (28%), fatigue (16%) and grade 2/4 pneumonitis in two patients. By comparison, pembrolizumab monotherapy in high-PD-L1 disease demonstrates an ORR of 45% and mPFS of 10.3 months, while the first-generation combo adagrasib (an approved KRAS G12C inhibitor) + pembrolizumab has an ORR of 44% and mPFS of 11 months.