RASolve 301: A Phase 3 study of daraxonrasib (RMC-6236) vs. docetaxel in patients with previously treated RAS-mutant NSCLC
Presenter: Ferdinandos Skoulidis, MD;PhD Session: Phase II and Phase III Clinical Trials in Progress Time: 4/21/2026 9:00:00 AM → 4/21/2026 12:00:00 PM
Authors
Ferdinandos Skoulidis 1 , Kathryn C. Arbour 2 , Sanjay Popat 3 , Colin R. Lindsay 4 , Hidehito Hironouchi 5 , Gérard Zalcman 6 , Alessandra Curioni-Fontecedro 7 , Jarushka Naidoo 8 , Adrianus J. de Langen 9 , Lin Tao 10 , Erica Su 10 , Minoti Hiremath 10 , Achim Rittmeyer 11 , Melissa Johnson 12 1 The University of Texas MD Anderson Cancer Center, Houston, TX, 2 Memorial Sloan Kettering Cancer Center, New York, NY, 3 Royal Marsden Hospital-Sutton, Sutton, United Kingdom, 4 The Christie Hospital, Manchester, United Kingdom, 5 National Cancer Center Hospital, Tokyo, Japan, 6 Hôpital Bichat - Claude Bernard, Paris, France, 7 HFR Fribourg, Kantonsspital Fribourg, Villars-sur Glâne, Switzerland, 8 Beaumont Hospital, Dublin, Ireland, 9 Antoni van Leeuwenhoek, Amsterdam, Netherlands, 10 Revolution Medicines Inc, Redwood City, CA, 11 LKI Lungenfachklink Immenhausen, Immenhausen, Germany, 12 SCRI Oncology Partners, Nashville, TN
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).
Disclosure
F. Skoulidis, AstraZeneca; Amgen; Revolution Medicines; Novartis; BridgeBio; Beigene; BergenBio; Guardant Health; Calithera Biosciences; Tango Therapeutics; Hookipa Pharma; Novocure; MSD; Roche Other, Consulting. Amgen; Mirati Therapeutics; Revolution Medicines; Pfizer; Novartis; MSD Other, Researcher/Grant/Contract. BioNTech; Moderna Stock. ESMO; Japanese Lung Cancer Society; Medscape; Intellisphere; VSPO McGill Universite de Montreal; RV Mais Promocao Eventos; MJH Life Sciences; IDEOlogy Health; MI&T; PER; CURIO; DAVA Oncology Other, Honoraria. American Association for Cancer Research; International Association for the Study of Lung Cancer Other, Honoraria. K. C. Arbour, Revolution Medicines, Inc; Bristol Meyer Squibb; Lilly; Genentech; Verastem Other, Researcher/Grant/Contract (PAID TO INSTITUTE). Revolution Medicines, Inc Travel. Amgen; Novartis; Revolution Medicines; Lilly; Regeneron; AstraZeneca; G1 Therapeutics; Merck; Bristol Meyer Squibb Other, Advisory board participation. S. Popat, Anheart Therapeutics; Amgen; Arcus Biosciences; AstraZeneca; Bayer; BMS; Boehringer Ingelheim; Daiichi Sankyo; Ellipses; Erasca; Gilead; GSK; Guardant Health; IO Biotech; Janssen; Lilly; Merck KGaA; Other, Consulting fees. Mirati; MSD; Novocure; Novartis; Pfizer; Pharmamar; Pierre Fabre; Regeneron; Roche; Sanofi; Takeda; Turning Point Therapeutics Other, Consulting fees. Anheart Therapeutics; Amgen; Arcus Biosciences; AstraZeneca; Bayer; BMS; Boehringer Ingelheim; Daiichi Sankyo; Ellipses; Erasca; Gilead; GSK; Guardant Health; IO Biotech; Janssen; Lilly; Merck KGaA; Other, Advisory boards. Mirati; MSD; Novocure; Novartis; Pfizer; Pharmamar; Pierre Fabre; Regeneron; Roche; Sanofi; Takeda; Turning Point Therapeutics Other, Advisory boards. Amgen; AstraZeneca; Bayer; Gilead; Guardant Health; Janssen; Merck KGaA; Novocure; Pharmamar; Pfizer; Roche; Takeda Honoraria. Gilead Travel. British Thoracic Oncology Group; ALK Positive UK; Lung Cancer Europe; Ruth Strauss Foundation; ETOP-IBCSG Partners Foundation Board Other, Fiduciary Officer. C. R. Lindsay, Amgen Other, Researcher/Grant/Contract: Coordinating Principal Investigator, Institutional, No financial interest, Clinical Investigator for a phase III clinical trial Invited Speaker, Personal, Advisory role; Invited Speaker, Personal, Educational Presentation/Workshop. Qiagen Other, Advisory Board, Personal. Apollomics Other, Researcher/Grant/Contract: Local Principal Investigator, Institutional, No financial interest, Principal Investigator for a phase II clinical trial. Boehringer Ingelheim Travel, Other, Researcher/Grant/Contract: Coordinating Principal Investigator, Institutional, No financial interest, Clinical Investigator for a phase I-II clinical trial. Mirati Therapeutics Other, Researcher/Grant/Contract: Coordinating Principal Investigator, Institutional, No financial interest, Clinical Investigator for a phase III clinical trial. Revolution Medicines, Inc. Other, Researcher/Grant/Contract: Coordinating Principal Investigator, Institutional, No financial interest, Clinical Investigator for a phase I-II clinical trial; Research Grant, Institutional, Financial interest, Research funding which includes use of their medical products. Roche Other, Researcher/Grant/Contract: Coordinating Principal Investigator, Institutional, No financial interest, C Clinical Investigator for a phase II clinical trial. H. Hironouchi, AstraZeneca K.K. Other, Payment or honoraria, Researcher/Grant/Contract: Payment to institution. Chugai Pharmaceutical Co., Ltd. Other, Payment or honoraria, Researcher/Grant/Contract: Payment to institution. MSD K.K. Other, Payment or honoraria, Researcher/Grant/Contract: Payment to institution. Bristol Myers Squibb K.K. Other, Payment or honoraria, Researcher/Grant/Contract: Payment to institution. Daiichi Sankyo Other, Researcher/Grant/Contract: Payment to institution. AbbVie GK Other, Researcher/Grant/Contract: Payment to institution. Eli Lilly Japan K.K. Other, Payment or honoraria. ONO PHARMACEUTICAL CO., LTD. Other, Payment or honoraria. G. Zalcman, Roche; Lilly; Pfizer; Bristol Myers Squibb; AstraZeneca; Boehringer Ingelheim; MSD Oncology; Inventiva Pharma; Da Volterra Other, Honoraria. Roche; Boehringer Ingelheim; Pfizer; Bristol Myers Squibb; MSD Oncology; Inventiva Pharma; AstraZeneca; Da Volterra Other, Consulting/Advisory (payment to institution). Bristol Myers Squibb Other, Consulting/Advisory (personal). Roche; Pfizer; AstraZeneca; Bristol Myers Squibb; Takeda; Regeneron Other, Researcher/Grant/Contract (payment to institution). Roche; Lilly; Pfizer; Bristol Myers Squibb; Pfizer; AstraZeneca; AbbVie Travel. A. Curioni-Fontecedro, Amgen; AstraZeneca; Boehringer Ingelheim; Bristol Myers Squibb; Daichii Sankyo; Janssen; Medscape; Merck Sharp & Dohme; Roche/Genentech; Takeda Other, Consulting/Advisory. Amgen; AstraZeneca; Bristol Myers Squibb; Foundation Medicine; Medscape; Merck Sharp & Dohme; Roche/Genentech; Takeda Other, Speaker. Amgen; AstraZeneca; Boehringer Ingelheim; Bristol Myers Squibb; Merck Sharp & Dohme; Roche/Genentech Other, Researcher/Grant/Contract: Payment to institution. J. Naidoo, AstraZeneca; Bristol Myers Squibb; Roche/Genentech; Amgen; Arcus Biosciences; NGM Pharmaceuticals; Bayer; Regeneron; Takeda; Pfizer; Elevation Oncology; Abbvie; Kaleido Biosciences; Mirati; Other, Consulting. Daiichi Sankyo Other, Consulting. AstraZeneca; Bristol Myers Squibb; Roche/Genentech; Daiichi Sankyo Other, Honoraria. AstraZeneca; Bristol Myers Squibb; Roche/Genentech; Amgen; Arcus Biosciences; NGM Pharmaceuticals; Bayer; Regeneron; Takeda; Pfizer; Elevation Oncology; Abbvie; Kaleido Biosciences; Mirati; Other, Participation on a Data Safety Monitoring Board or Advisory Board. Daiichi Sankyo Other, Participation on a Data Safety Monitoring Board or Advisory Board. A. J. de Langen, AstraZeneca; BMS; Boehringer Ingelheim; Pfizer; Lilly; MSD Other, Advisor. AstraZeneca; BMS; Boehringer Ingelheim; MSD Other, Researcher/Grant/Contract. L. Tao, Revolution Medicines, Inc. Employment, Stock, Stock Option. E. Su, Revolution Medicines, Inc. Employment, Stock, Stock Option. M. Hiremath, Revolution Medicines, Inc. Employment, Stock, Stock Option. A. Rittmeyer, Abbvie; AstraZeneca; BMS; Boehringer Ingelheim; Daiichi Sankyo; Eli Lilly; Gilead; J&J; GSK; MSD; Novartis; Pfizer; Regeneron; Roche Other, Consultant. M. Johnson, Adaptimmune; Amgen; ArriVent BioPharma; AstraZeneca; Bayer; Black Diamond; BlossomHill Therapeutics; Boehringer Ingelheim; Boundless Bio; Bristol-Myers Squibb; Carisma Therapeutics Other, Researcher/Grant/Contract (PAID TO INSTITUTION) . Conjupro Biotherapeutics; Corvus Pharmaceuticals; D3 Bio; Daiichi Sankyo; Lilly; Erasca; Exelixis; Genentech/Roche; Genmab; Genocea Biosciences; Harpoon; Helsinn Healthcare SA; IDEAYA Biosciences Other, Researcher/Grant/Contract (PAID TO INSTITUTION) . IGM Biosciences; Immuneering Corporation; Immunitas Therapeutics; Immunocore; Incyte; Janssen; LockBody Therapeutics; Loxo Oncology; Merck; Merus; Mirati Therapeutics; Modex Therapeutics Other, Researcher/Grant/Contract (PAID TO INSTITUTION) . NeoImmune Tech; Neovia Oncology; NextPoint Therapeutics; Novartis; Nuvalent; OncoC4; Palleon Pharmaceutical; Pfizer; Pierre Fabre; PMV Pharmaceuticals; Prelude Therapeutics; Puma Biotechnology Other, Researcher/Grant/Contract (PAID TO INSTITUTION) . RasCal Therapeutics; Regeneron Pharmaceuticals; Revolution Medicines; Ribon Therapeutics; Shattuck Labs; Shanghai Junshi Biosciences; Silicon Therapeutics; Summit Therapeutics; Systimmune Other, Researcher/Grant/Contract (PAID TO INSTITUTION) . Taiho Oncology; TCR2 Therapeutics; Tempest Therapeutics; TheRas; Tizona Therapeutics; Vividion; Zymeworks; Mythic Therapeutics Other, Researcher/Grant/Contract (PAID TO INSTITUTION) . AbbVie; Amgen; AstraZeneca; BeOne Medicines; Biohaven Pharmaceuticals; BioNTech; Bristol-Myers Squibb; Daiichi Sankyo; Ellipses Pharma; Genentech / Roche; Gilead Sciences; GlaxoSmithKline; Janssen Other, Consulting paid to institution. Jazz Pharmaceuticals; Lilly; Merck; Nuvalent; Ottimo Pharma; Pfizer; Regeneron Pharmaceuticals; Revolution Medicines; Summit Therapeutics; Zai Laboratory Other, Consulting paid to institution.
Cited in
Control: 10387 · Presentation Id: 12235 · Meeting 21436