MK-1084 (KRAS G12C inhibitor) + pembrolizumab drives 74% ORR and 25-month PFS in first-line metastatic NSCLC

MK-1084 is an oral, next-gen covalent inhibitor that locks KRAS G12C in its inactive GDP form. In the phase 1 KANDLELIT-001 trial (NCT05067283), 21 previously treated NSCLC showed a 38% ORR and mPFS of 8 months with MK-1084 monotherapy. Thirty-four untreated PD-L1 ≥ 1% patients given MK-1084 + pembrolizumab in the dose escalation arm achieved a 74% ORR, 91% disease-control, and a median PFS of 25 months; a triplet with first-line MK-1084, pembrolizumab, and chemotherapy in 22 patients posted a 41% ORR. In the doublet expansion (2.5 month follow-up) and triplet arms (4.1 month follow-up), mPFS was not reached. Grade ≥ 3 drug-related AEs were 9% (monotherapy), 33% (doublet), and 58% (triplet); transaminase rises were the main lab signal, and there was one treatment-related death. ctDNA showed a >90% drop in KRAS G12C variant allele fraction by week 6, confirming target engagement.