Abstract CT215: RASolve 301: A Phase 3 study of daraxonrasib (RMC-6236) vs. docetaxel in patients with previously treated RAS-mutant NSCLC

Abstract Background: Previously treated non-small cell lung cancer (NSCLC) patients represent a significant unmet medical need. After patients have received platinum-based chemotherapy and/or immune checkpoint inhibitors, docetaxel monotherapy is often the mainstay of treatment, with reported objective response rates (ORRs) of 9.2%-14.7%, median progression-free survival (mPFS) of 3.0-4.5 months, and median overall survival (mOS) of 9.1-11.8 months across multiple studies. RAS mutations occur in ∼30% of NSCLC cases, with non-G12C variants making up 60%. The majority of these are G12X mutations (e.g., G12D, G12V, etc.), for which no approved targeted therapies are available.In an ongoing Phase 1 monotherapy trial (NCT05379985), 120-220 mg daily daraxonrasib (RMC-6236), an oral, RAS(ON) multi-selective, tri-complex inhibitor of GTP-bound mutant and wild-type RAS, showed manageable safety and preliminary efficacy in patients with NSCLC. As of a September 30, 2024 data cutoff (N=73), Grade ≥3 treatment-related adverse events (TRAEs) reported in ≥2 patients included rash (n=5, 7%), vomiting (n=2, 3%), and anemia (n=2, 3%), with no Grade 4 or Grade 5 TRAEs. In 40 patients with RAS G12X-mutant NSCLC previously treated with one or two lines of therapy (including immunotherapy and platinum-based chemotherapy), daraxonrasib at 120-220 mg resulted in a confirmed ORR of 38%, median duration of response (DOR) of 15.1 months (95% CI: 11.1, Not Estimable [NE]), mPFS of 9.8 months (95% CI: 6, 12.3), and a mOS of 17.7 months (95% CI: 13.7, NE). These preliminary data provide strong rationale for the continued development of daraxonrasib in patients with previously treated, locally advanced or metastatic, RAS-mutant NSCLC. Methods: RASolve 301 is a global, multicenter, open-label, randomized Phase 3 study (NCT06881784) designed to evaluate efficacy and safety of daraxonrasib vs. docetaxel in patients with previously treated, locally advanced or metastatic, RAS-mutant NSCLC. Patients are randomized 1:1 to receive either docetaxel or daraxonrasib. Key eligibility criteria: pathologically confirmed NSCLC, age ≥18 years, ECOG performance status of 0 or 1, prior treatment with an anti-PD(L)-1 agent and platinum-based chemotherapy, and a documented RAS mutation based on local testing. Eligible RAS mutations are defined as nonsynonymous mutations in KRAS/NRAS/HRAS at codons 12, 13, or 61 (G12, G13, or Q61). Key exclusion criteria include untreated central nervous system metastases, prior RAS-directed therapy, or presence of an actionable driver mutation for which there is an approved targeted therapy. Dual primary endpoints are PFS and OS in patients with RAS G12X mutations excluding G12C (G12X-C). Key secondary endpoints include PFS and OS in patients with all RAS mutations, and ORR per RECIST v1.1. The study will enroll ∼420 patients globally, including from sites in the USA (including Puerto Rico). Citation Format: Ferdinandos Skoulidis, Kathryn C. Arbour, Sanjay Popat, Colin R. Lindsay, Hidehito Hironouchi, Gérard Zalcman, Alessandra Curioni-Fontecedro, Jarushka Naidoo, Adrianus J. de Langen, Lin Tao, Erica Su, Minoti Hiremath, Achim Rittmeyer, Melissa Johnson. RASolve 301: A Phase 3 study of daraxonrasib (RMC-6236) vs. docetaxel in patients with previously treated RAS-mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT215.