6MO - Safety and clinical activity of daraxonrasib (RMC-6236) in RAS mutant non-small cell lung cancer (NSCLC)

Background

Patients with previously treated NSCLC have a high unmet medical need, with a median reported overall survival (OS) of

Methods

Patients with advanced RASmut tumors were enrolled and dose optimization was performed at 120–300 mg. In NSCLC, 300 mg was not considered for further development due to a less favorable tolerability profile and reduced dose intensity; 200 mg daily is the proposed dose for NSCLC. Safety is reported for relevant doses (120–220 mg, N=73). Clinical activity is reported in patients treated at 120–220 mg with RAS G12X mutant NSCLC receiving 1 or 2 prior lines of therapy, including prior immunotherapy and platinum chemotherapy, and have not received docetaxel previously (N=40).

Results

Patients evaluated for safety received a median of 2 prior therapies; 81% had ECOG=1. Any grade (G), treatment-related adverse events (TRAEs) in ≥20% of patients were rash (90%), diarrhea (63%), nausea (49%), vomiting (40%), and stomatitis (34%). Rash (7%) was the only G3 TRAE in ≥5% patients; no G4 or 5 TRAEs were observed. TRAEs led to dose modifications in 41% of patients and to dose discontinuations in 4% of patients. The mean relative dose intensity was 88%. Preliminary data suggest that prophylaxis reduced incidence of G3 TR rash (9% without prophylaxis, N=58; 0% with prophylaxis, N=15). Clinical activity is shown by confirmed ORR=38%, median duration of response=15.5 months (m) (11.1, NE), median PFS=9.8 m (95% CI:6–12.3), and median OS=17.7 m (95% CI:13.7-NE).

Conclusions

Daraxonrasib (120–220 mg daily) demonstrated encouraging and durable clinical activity in patients with NSCLC with a manageable safety and tolerability profile and favorable dose intensity. These data support the initiation of a randomized phase III study (RASolve 301) of daraxonrasib versus docetaxel in patients with previously treated, locally advanced or metastatic RASmut NSCLC.

Clinical trial identification

NCT05379985.

Legal entity responsible for the study

Revolution Medicines, Inc.

Funding

Revolution Medicines, Inc.

Disclosure

D.S. Hong: Financial Interests, Institutional, Research Grant: AbbVie, Adaptimmune, Adlai-Nortye, Amgen, Astellas, AstraZeneca, Bayer, Biomea, Bristol Myers Squibb, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Endeavor, Erasca, F. Hoffmann-LaRoche, Fate Therapeutics, Genentech, Genmab, Immunogenesis, Infinity, Inhib; Financial Interests, Institutional, Other, Travel, accommodations and expenses: AACR, ASCO, CLCC, Bayer, Genmab, Northwestern, SITC, Telperian, UNC; Financial Interests, Institutional, Advisory Role: 280Bio, AbbVie, Acuta, Adaptimmune, Alkermes, Alpha Insights, Amgen, Affini-T, Astellas, Aumbiosciences, Axiom, Baxter, Bayer, Boxer Capital, Blackstone, BridgeBio, CARSgen, CLCC, COG, COR2ed, Cowen, Ecor1, EDDC, Erasca, Exelixis, Fate Therapeutics, F. Hof; Financial Interests, Personal, Ownership Interest: CrossBridge Bio (Advisor), Molecular Match (Advisor), OncoResponse (Founder, Advisor), Telperian (Founder, Advisor). J. Luo: Financial Interests, Institutional, Research Grant: Amgen, Black Diamond, Genentech, Kronos, Novartis, Revolution Medicines; Non-Financial Interests, Personal, Invited Speaker: Cancer GRACE, Communication Cancer Education, Inc; Financial Interests, Personal, Invited Speaker: MedScape, Physicians’ Education Resource, Targeted Oncology, VI Oncology, Blueprint Medicines, Daiichi Sankyo, Genentech; Financial Interests, Personal, Other, Patent: MSKCC. S.I. Ou: Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: JNJ/Janssen, Elevation Oncology, AnHeart Therapeutics, BMS, Daiichi Sankyo; Financial Interests, Personal, Ownership Interest: MBrace Therapeutics, BlossomHill Therapeutics; Financial Interests, Personal, Stocks/Shares: Nuvalent; Financial Interests, Institutional, Invited Speaker: Pfizer, Mirati, JNJ/Janssen, Merus, Revolution Medicine. M.L. Johnson: Financial Interests, Institutional, Other, Consulting: AbbVie, Amgen, Arcus Biosciences, Arrivent, AstraZeneca, Daiichi Sankyo, Genentech/Roche, GSK, Gritstone Oncology, Immunocore, Janssen, Jazz Pharmaceuticals, Merck, Mirati Therapeutics, Novartis, Pyramid Biosciences, Alentis Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, D3 Bio Limitied, Fate Therapeutics, Gilead Sciences, Hookipa Biotech, Lilly, Normunity, Novocure, Pfizer, Revolution Medicines, Sanofi-Aventis, SeaGen, Synthekine, Takeda Pharmaceuticals, Biohaven Pharmaceuticals, ModeX Therapeutics, Regeneron Pharmaceuticals, Zai Laboratory; Financial Interests, Institutional, Invited Speaker: AbbVie, Adaptimmune, Amgen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, BeiGene, BerGenBio, BioAtla, Black Diamond, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Carisma Therapeutics, City of Hope National Medical Center, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Lilly, Elicio Therapeutics, EMD Serono, EQRx, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GSK, Gritstone Oncology, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchinson MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunitas Therapeutics, Immunocore, Incyte, Janssen, Kartos Therapeutics, Loxo Oncology, Memorial Sloan-Kettering, Merck, Merus, Mirati Therapeutics, Mythic Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Therapeutics, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Syndax Pharmaceuticals, Takeda Pharmaceuticals, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, Vyriad, Y-mAbs Therapeutics, ArriVent BioPharma, Bayer, LockBody Therapeutics, Taiho Oncology, Conjupro, Immuneering Corporation, Impact Therapeutics, NextPoint Therapeutics, OncoC4, Summit Therapeutics, Systimmune, TheRas, Vividion. A. Spira: Financial Interests, Personal, Other, Consulting or Advisory Role: Incyte, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Array Biopharma, Blueprint Medicines, Regeneron, Lilly, Black Diamond Therapeutics, Sanofi; Financial Interests, Personal, Other, Consulting or Advisory Role/Honoraria: Amgen, Novartis, Takeda, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, Janssen Oncology, Bayer; Financial Interests, Institutional, Officer, CEO: NEXT Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Institutional, Invited Speaker: LAM Therapeutics, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines, Kezar, Revolution Med, Regeneron, Loxo, Alkermes, Medikine, Black Diamond Therapeutics, Nalo Therapeutics, Scorpion Therapeutics, Arrivent Biopharma, GV20 Therapeutics. I. Garrido-Laguna: Non-Financial Interests, Personal, Advisory Role: S0TIO, Kanaph, Jazz, OnXer, AbbVie; Financial Interests, Personal, Funding: EcoR1, Guidepoint, Novarits; Financial Interests, Institutional, Funding: Bayer, Bristol Myers Squibb, Pfizer, MedImmune, Lilly, Incyte, GSK, Tolero Pharmaceuticals, BridgeBio Pharma, Jacobio, Repare, Sumitorno Dainippon Pharma Oncology, Revolution Medicines, Yingli Pharma, Quanta Therapeutics, 280 BIO, ABM Therapeutics, Tango. J.W. Goldman: Financial Interests, Personal, Advisory Role: AstraZeneca, AbbVie, Genentech, Regeneron, Jazz Pharmaceuticals, Gritstone Bio, Gilead Sciences, Daiichi Sankyo/AstraZeneca, Summit Biomedical. Research Funding: Lilly (Inst), Genentech/Roche (Inst), Bristol Myers Squibb (Inst), AstraZeneca/MedImmune (In. B. Herzberg: Financial Interests, Institutional, Research Grant: Amgen, Repare, Ideaya, Astellas, Revolution Medicines, AstraZeneca, Seagen, Monte Rosa Therapeutics, Eli Lilly, Genentech; Financial Interests, Institutional, Other, Salary support: NIH UM1 NIH P30 Stand Up 2 Cancer; Financial Interests, Personal, Other, Consulting: Amgen, Boxer Capital, Eli Lilly, Johnson and Johnson, Astellas; Financial Interests, Personal, Invited Speaker: MJH Health, ASCO, Eisai; Financial Interests, Personal, Other, Support for attending meetings: Dava Oncology; Financial Interests, Personal, Invited Speaker, Support to attend meeting: ASCLC Education Award. A. Saltos: Financial Interests, Institutional, Funding, Funding to institution, provision of study materials, medical writing.: Revolution Medicines; Financial Interests, Institutional, Funding: Genentec, Janssen, Turning Point Therapeutics, Novartis, Memgen, Mersana, BioAtla, AstraZeneca, Daiichi Sanko, NGM Biopharmaceuticals; Non-Financial Interests, Personal and Institutional, Invited Speaker: MJH Life Sciences; Non-Financial Interests, Personal, Sponsor/Funding, support for attending meetings: Dava Oncology; Non-Financial Interests, Personal, Advisory Board: Pfizer, Janssen, Daiichi Sankyo, Boehering Ingelheim, Zymeworks. P. Mitra: Financial Interests, Personal, Full or part-time Employment: Revolution Medicines. A. Hegde: Financial Interests, Personal, Full or part-time Employment: Revolution Medicines. R. Vora: Financial Interests, Personal, Full or part-time Employment: Revolution Medicines. M. Hiremath: Financial Interests, Personal, Invited Speaker: Revolution Medicines. K.C. Arbour: Financial Interests, Personal, Advisory Board: G1 Therapeutics, Novartis, Sanofi-Genzyme, Revolution Medicines, Lilly, AstraZeneca, Regeneron, Merck, Amgen; Financial Interests, Institutional, Invited Speaker: Revolution Medicines, Mirati, Genentech, Lilly, Bristol Myers Squibb; Financial Interests, Personal and Institutional, Invited Speaker: Lilly. All other authors have declared no conflicts of interest.