Divarasib (KRAS G12C inhibitor) + pembrolizumab drives 73% ORR and 19.3-mo PFS in 1L KRAS G12C+ NSCLC

Divarasib is an oral, next-generation covalent KRAS G12C inhibitor combined with pembrolizumab (PD-1) in the open-label Phase Ib/II Krascendo-170 dose-finding/expansion study (NCT05789082) in untreated advanced/metastatic KRAS G12C+ NSCLC (ECOG ≤1), reported by PD-L1 status. In the PD-L1 TC ≥1% cohort treated at divarasib 400 mg (cohort A1; n=59 enrolled; safety n=55), confirmed ORR was 73% (95% CI 60–84), no patient had PD as best response, median PFS was 19.3 months (95% CI 12.4–NE), and median DOR was not reached at the Oct 29, 2025 cutoff—well above typical 1L pembrolizumab + pemetrexed/platinum benchmarks (ORR ~48%, mPFS ~8.8 months) from KEYNOTE-189. TRAEs occurred in 98%, with 65% grade 3/4 and 0% grade 5; common toxicities included diarrhea (75%; grade 3/4 16%) and notably frequent transaminitis (ALT increase 49% with grade 3/4 20%; AST increase 47% with grade 3/4 18%), with 25% discontinuing due to TRAEs; in PD-L1 TC <1% (cohort A2; n=23), unconfirmed ORR was 70% with similarly high grade 3/4 TRAEs (65%) but short follow-up (median 3.4 months).