Daraxonrasib (RMC-6236) RAS(ON) tri-complex inhibitor moves to Phase 3 vs docetaxel in RAS-mutant NSCLC

Daraxonrasib is an oral, RAS(ON) multi-selective tri-complex inhibitor designed to bind GTP-bound mutant and wild-type RAS, and is being advanced into RASolve 301, a global, open-label, randomized Phase 3 trial comparing daraxonrasib vs docetaxel in previously treated locally advanced/metastatic RAS-mutant NSCLC (NCT06881784; planned n≈420; post–anti–PD-(L)1 and platinum; ECOG 0–1). Dual primary endpoints are PFS and OS in KRAS/NRAS/HRAS G12X excluding G12C (G12X-C); key secondary endpoints include PFS/OS in all RAS mutations and ORR (RECIST v1.1). The rationale is Phase 1 monotherapy data (data cutoff Sep 30, 2024) in RAS G12X NSCLC treated 2L/3L (n=40 efficacy-evaluable) showing confirmed ORR 38%, median DOR 15.1 months, mPFS 9.8 months, and mOS 17.7 months—numerically above typical docetaxel benchmarks in this setting (ORR ~9.2%–14.7%, mPFS ~3.0–4.5 months, mOS ~9.1–11.8 months); Grade ≥3 TRAEs included rash 7%, vomiting 3%, and anemia 3%, with no Grade 4/5 TRAEs reported in that cutoff dataset (N=73 safety set). Take Home: If Phase 3 reproduces anything close to ~38% ORR with ~10-month mPFS in the post–chemo/IO population—where docetaxel is still a low-response, short-PFS default—daraxonrasib could become the first broadly applicable targeted option for the large non-G12C RAS-mutant NSCLC segment (but the open-label design and small Phase 1 efficacy-evaluable set make “regression to the mean” a real risk).