Zoldonrasib (RMC-9805) RAS(ON) KRAS G12D inhibitor drives 52% ORR and 11.1-mo PFS in pretreated NSCLC

Zoldonrasib (RMC-9805) is an oral, covalent, KRAS G12D-selective “RAS(ON)” tri-complex inhibitor that targets the active (GTP-bound) state; updated monotherapy data come from an ongoing Phase 1/1b dose-escalation study (NCT06040541) with 1200mg QD selected as the NSCLC RP2D. Safety at 1200mg QD (N=40; median 2 prior lines) was mostly low-grade GI toxicity—nausea 43%, vomiting 33%, diarrhea 30%, rash 18%—with Grade 3 TRAEs in 13% (no Grade 4/5), and dose interruption/reduction/discontinuation rates of 15%/3%/5% (mean relative dose intensity 94%). In an efficacy-enriched subset (N=27) previously treated with platinum chemotherapy and an immune checkpoint inhibitor (and docetaxel-naïve), confirmed ORR was 52% (95% CI: 32–71), DCR 93%, mPFS 11.1 months (95% CI: 5.3–NE), 12-month OS 73%, and mOS not reached—numerically far above common post–platinum/ICI benchmarks like docetaxel±ramucirumab (REVEL: ORR ~23% with ramucirumab+docetaxel; mPFS 4.5 months; mOS 10.5 months), albeit in a small, selected Phase 1 subset.