Daraxonrasib plus chemotherapy (CT) as first-line (1L) treatment for patients (Pts) with metastatic pancreatic adenocarcinoma (mPDAC)
Presenter: Brian Wolpin, MD;MPH Session: Minisymposium: Late-Breaking Research Time: 4/21/2026 4:05:00 PM → 4/21/2026 4:20:00 PM
Authors
B. M. Wolpin 1 , B. L. Musher 2 , G. A. Manji 3 , W. Park 4 , A. Spira 5 , N. Azad 6 , V. Florou 7 , T. Biachi De Castria 8 , M. H. O’Hara 9 , E. Borazanci 10 , A. Parikh 11 , J. Strickler 12 , J. R. Hecht 13 , S. Pant 14 , S. Sen 15 , E. Chiorean 16 , W. Gustafson 17 , H. Patel 17 , V. Seshadri 17 , Y. Zheng 17 , D. Sohal 18 ; 1 Dana-Farber Cancer Institute, Boston, MA, 2 Baylor College of Medicine, Houston, TX, 3 Columbia University Medical Center, New York, NY, 4 Memorial Sloan Kettering Cancer Center, New York, NY, 5 NEXT Oncology Virgina, Virgina Cancer Specialists Research Institute, Fairfax, VA, 6 Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 7 Huntsman Cancer Institute, Salt Lake City, UT, 8 Moffitt Cancer Center, Tampa, FL, 9 Hospital of the University of Pennsylvania, Philadelphia, PA, 10 HonorHealth Research Institute, Scottsdale, AZ, 11 Harvard Medical School, Boston, MA, 12 Duke Cancer Center, Durham, NC, 13 David Geffen School of Medicine at UCLA, Los Angeles, CA, 14 MD Anderson Cancer Center, Houston, TX, 15 Texas Oncology, Dallas, TX, 16 University of Washington, Fred Hutchinson Cancer Center, Seattle, WA, 17 Revolution Medicines, Redwood City, CA, 18 University of Cincinnati Cancer Center, Cincinnati, OH
Abstract
Background: mPDAC is a challenging RAS-driven disease. Standard 1L CT has limited benefit (ORR: 23%-43%; PFS at 6 mo: 40%-50%; mOS: 8.5-11.7 mo). Oncogenic RAS mutations occur in >90% of PDAC. Daraxonrasib is a potent, oral, RAS(ON) multi-selective inhibitor targeting GTP-bound mutant (incl. G12, G13, and Q61 mutations) and WT RAS. A phase 1/2 study (NCT05379985) of second-line mPDAC pts showed daraxonrasib had manageable safety and early efficacy. In preclinical PDAC models, daraxonrasib + CT improved the depth and durability of response. In this study (NCT06445062), 1L pts received daraxonrasib + gemcitabine/nab-paclitaxel (GnP) in a regimen designed to sustain suppression of RAS signaling by maintaining sufficient dose intensity of daraxonrasib and safely leverage the antitumor activity of CT. Methods: Pts with 1L RAS-mutant mPDAC were treated with daraxonrasib (200 mg QD) + GnP (D1, D15). Safety, tolerability, PK, antitumor activity, and ctDNA response were evaluated. Results: As of Dec 1, 2025, 40 pts with mPDAC received daraxonrasib + GnP (mFU 9.7 mo). The safety profile of the combination was consistent with known toxicities of each component. All-Gr TRAEs a (≥30%) were rash (90%), diarrhea (75%), fatigue (70%), nausea (68%), vomiting (55%), anemia (50%), stomatitis/mucositis (45%), edema peripheral (43%), neutrophil count decreased (43%), platelet count decreased (38%), peripheral sensory neuropathy (38%), alopecia (33%) and AST increased (30%). Gr ≥3 TRAEs a (≥10%) were anemia (33%), neutrophil count decreased (20%), fatigue (18%), rash (15%), diarrhea (15%), and stomatitis/mucositis (10%). No Gr 5 TRAEs a occurred. Mean dose intensity was 82% for daraxonrasib and 80% for GnP. Preliminary efficacy is in the table. Conclusions: Daraxonrasib + GnP showed manageable safety and compelling preliminary efficacy supporting initiation of a global 3-arm phase 3 study (RASolute 303) of daraxonrasib vs daraxonrasib + GnP vs GnP in 1L mPDAC. Table Antitumor activity Treated pts Evaluable pts Efficacy measures n=40 b n=39 c ORR d , % (95% CI) 58% (41%-73%) 59% (42%-74%) DCR, % (95% CI) 90% (76%-97%) 92% (79%-98%) PFS at 6 mo e , % (95% CI) 84% (68%-93%) - ctDNA Response f - n=28 f >50% RAS VAF reduction, % - 96% 100% RAS VAF clearance, % - 61% VAF, variant allele frequency. a TRAEs include any study drug-related treatment-emergent AE. b Pts with ≥18 weeks of follow-up. c Pts with measurable disease at baseline and either had ≥ 1 post-baseline tumor assessment or had clinical progression or death prior to such assessment. d Includes confirmed complete responses (CR) and partial responses (PR). e Estimate based on Kaplan-Meier method. f Patients who had ctDNA sequenced at baseline (C1D1) and at least one on-tx (C2D1 or C3D1).
Disclosure
B. M. Wolpin, Amgen ). AstraZeneca ). Eli Lilly ). Harbinger Health ), Other, Advisory boards/consulting. Novartis ). Revolution Medicines ), Other, Advisory boards/consulting. Agenus Other, Advisory boards/consulting. BeiGene Other, Advisory boards/consulting. BMS/Mirati Other, Advisory boards/consulting. Cancer Panels Other, Advisory boards/consulting. Diaceutics Other, Advisory boards/consulting. EcoR1 Capital Other, Advisory boards/consulting. GRAIL Other, Advisory boards/consulting. lmmuneering Other, Advisory boards/consulting. Ipsen Other, Advisory boards/consulting. Takeda Other, Advisory boards/consulting. Tango Therapeutics Other, Advisory boards/consulting. Third Rock Ventures Other, Advisory boards/consulting. B. L. Musher, Merus Other, Advisory board. G. A. Manji, Genentech/Roche ). Merck ). Plexxikon ). Regeneron ). BioLineRx ), Other, Consulting fees. Arcus Bioscience Other, Consulting fees. Ipsen Other, Consulting fees. Pfizer Other, Advisor. Revolution Medicine Other, Advisor. CEND Pharm Other, Advisor. EnGeneIC Inc. Other, Consultant. W. Park, Break Through Cancer ). Parker Institute for Cancer lmmunotherapy ). The Society of MSK ). Merck ). Astellas ), Other, Consulting. Lepu Biopharma ). Amgen ), Travel. Revolution Medicines ), Other, Consulting. EXACT Therapeutics Other, Consulting. lnnovent Biologics Other, Consulting. Regeneron Pharmaceuticlas Other, Consulting. KeyQuest Other, Consulting. TD Cowen Other, Consulting. Alphasights Other, Consulting. American Physician Institute; Curio; Integrity; Physicians’ Education Resource; Aptitude Health Other, CME honoraria. DAVA Oncology Travel. NIH/NCI SPORE Pancreas (P50 CA257881-01A1); Paul Calabresi Career Development Award for Clinical Oncology (K12 CA184746), Cancer Center Support Grant/Core Grant (P30 CA008748) ). A. Spira, CytomX Therapeutics; AstraZeneca/MedImmune; Merck; Takeda; Amgen; Janssen Oncology; Novartis; Bristol-Myers Squibb; Bayer; Prelude Therapeutics; Abbvie; Astellas Pharma; Lilly Other, Honoraria. Incyte; Amgen; Novartis; Mirati Therapeutics; Gritstone Oncology; Jazz Pharmaceuticals; Takeda; Janssen Research & Development; Mersana; Gritstone Bio; Daiichi Sankyo; Astra Zeneca; Regeneron; Lilly Independent Contractor. Black Diamond Therapeutics; Sanofi; ArriVent Biopharma; Synthekine; GSK; Crisp Therapeutics; Revolution Medicines; AstraZeneca/MedImmune; Merck; Bristol-Myers Squibb; Blueprint Medicines Independent Contractor. LAM Therapeutics; Roche; AstraZeneca; Boehringer Ingelheim; Astellas Pharma; MedImmune; Novartis; Incyte; Abbvie; Ignyta; Takeda; Macrogenics; CytomX Therapeutics; Astex Pharmaceuticals ). Bristol-Myers Squibb; Loxo; Gritstone; Plexxikon; Amgen; Daiichi Sankyo; ADCT; Janssen Oncology; Rubius; Synthekine; Mersana; Blueprint Medicines; Regeneron; Alkermes; Revolution Medicines; Medikine ). Synthekine; Black Diamond Therapeutics; BluPrint Oncology; Nalo Therapeutics; Scorpion Therapeutics; ArriVent Biopharma; Prelude Therapeutics; Lilly; Lepu Biopharma; Tango Therapy ). NEXT Oncology Virginia g., Board of Directors, non-salaried role). N. Azad, Johns Hopkins University Employment. Haystack Oncology/Quest Stock, Stock Option. Cage Pharma Stock, Stock Option. Irazu Stock, Stock Option. AstraZeneca ), Other, Honoraria/Consulting. Revolution Medicine ), Other, Honoraria/Consulting. Beigene Other, Honoraria/Consulting. Atlas ). Mirati/BMS ). Inctye ), Other, Honoraria/Consulting. Taiho ). Syndax ). Bayer ). Pfizer/Seagen ). Compass ). Agenus; GlaxoSmithKline; Astellas; Eli Lilly; Tempus; Incyte Other, Honoraria/Consulting. V. Florou, Deciphera Other, Consulting. SpringWork Therapeutics Other, Consulting. Aadi Other, Consulting. Ipsen Other, Consulting. Merus Other, Consulting. T. Biachi De Castria, Encapsulate Stock, Stock Option, Other, Speaker’s bureau, consulting or advisory role. Astellas ). Ipsen ), Travel. Moderna Travel, Other, Speaker’s bureau, consulting or advisory role. AstraZeneca Travel, Other, Speaker’s bureau, consulting or advisory role. Bayer Other, Speaker’s bureau, consulting or advisory role. Takeda Other, Speaker’s bureau, consulting or advisory role. BMS Other, Speaker’s bureau, consulting or advisory role. M. H. O’Hara, Revolution Medicines ). GenMab ). BMS ). Verismo ). Verastem ). Elicio ). Geistlich ). Merck ). Arcus ). Incyte ). Akamis ). Astra Zeneca ). E. Borazanci, Revolution Medicines Independent Contractor, Stock, Stock Option. Immuneering Independent Contractor. VCN Independent Contractor. Fortress Independent Contractor. ARCUS Independent Contractor. A. Parikh, C2i Genomics; Khora; OneCell; XGenomes; Cadex; Parithera Stock, Stock Option. Zola; CVS; Phesi; 3T Biosciences; Do More Diagnostics; Summit Therapeutics; Pfizer; Regeneron; GSK; Foundation Medicine; Careset; Value Analytics Labs; Naterara; Adroya; Astra Zeneca; Scare; Hookipa Other, Advisor/consultant. Xilio; Mirati; PMV Pharmaceuticlas; Eli Lilly; BMS ), Other, Advisor/consultant. Guardant; Abbvie; Seagen; Takeda; Kahr; Sirtex; Merck; Amgen; Delicate; Exact; Caris; Incyte; Pheon; Neogenomics; J & J; Boehringer Ingelheim; Novartis; Third Rock Ventures; MPM Capital Other, Advisor/consultant. Science For America Other, Advisor/consultant. Reversing Early Recurrence Other, Chief Scientist. Up to Date Other, Fees. Karkinos Healthcare Travel. Erasca; Genentech; Daiichi Sankyo; Syndax; Revolution Medicines; Parthenon ). J. Strickler, Abbvie Independent Contractor, ), Travel. Alterome; Astellas; Astra Zeneca; Boehringer Ingelheim; BMS; Cytovation; Exelixis; Full-Life Technologies; GE Healthcare; Incyte; Ipsen; Johnson and Johnson; Jazz Pharmaceuticals; Merck; Natera Independent Contractor. Amgen; Bayer; BeOne; Daiichi-Sankyo; Eli Lilly; GSK; Leap; Pfizer; Quanta Therapeutics; Roche/Genentech; Regeneron; Revolution Medicines Independent Contractor, ). Pheon Therapeutics; Sanofi; Taiho; Takeda; Tempus; Xilio Therapeutics Independent Contractor. Apollo Therapeutics; Novartis ). Triumvira Immunologics Stock, Stock Option. J. R. Hecht, A2 Bio ), Travel. Affini-T ). Agenus ). AstraZeneca ). Bold ). Camurus ). Crinetics ). Exelixis ), Other, Consulting. Gilead ), Other, Consulting. GSK ). Gritstone ). IGM ). Janssen ). Mirati; NGM; Pfizer; Regeneron; Tizona ). Triumvira; Actym Stock, Stock Option. NCCN Colorectal Committee g., Board of Directors, non-salaried role). Revolution Medicines ), Other, Consulting. Scripps; Research To Practice; MLJ Other, Honoraria. Astellas; BeiGene; Novartis; Hexagon; Corcept; Deciphera; BMS; Parabilis; Taiho; Urogen Other, Consulting. Xilio ), Other, Consulting. S. Pant, Ipsen; Novartis; Daiichi Sankyo; Janssen; Jazz Pharmaceuticals; AstraZeneca; Boehringer Ingelheim; USWorldmeds; Alligator Bioscience; Revolution Medicines; Arcus; BMS; Merck; Pfizer; Immuneering Other, Consulting or advisory Role. EMD Serono Other, Consulting or advisory Role. Incyte; CG Pharmaceuticals; Bristol-Myers Squibb; Boehringer Ingelheim; Janssen; Arcus; Elicio; Pfizer; ImmunoMET; Immuneering; Amal Therapeutics; Jazz Therapeutics; Revolution medicines; AstraZeneca ). Oncomed LLC, Telperian Stock, Stock Option. S. Sen, Next Oncology Employment, g., Board of Directors, non-salaried role). Incendia Therapeutics, Inc.; IconOVir; Georgiamune, Inc.; Pyxis Oncology Inc.; Boehringer Ingelheim Pharmaceutical, Inc.; Centessa Pharmaceuticals (UK) Limited; BeiGene; Tubulis GmbH ). Astellas Pharma Global Development Inc.; Pasithea Therapeutics Corp.; D2M Biotherapeutics Inc.; Nuvation Bio Inc.; Dicerna Pharmaceutical Inc. a Novo Nordisk company; Iambic Therapeutics Inc. ). Biohaven Pharmaceutical Inc; Revolution Medicines Inc.; Nested Therapeutics Inc.; MediLink Therapeutics (Suzhou) Co., Ltd.; Aprea Therapeutics Inc.; Boundless Bio, Inc. ). Innovent Biologics (Suzhou) Co., Ltd/Fortiva Biologics Inc.; Auricula Biosciences Inc; Immunome Inc; Innate Pharma SA; Bayer HealthCare Pharmaceuticals Inc.; Vividion Therapeutics ). Vividion Therapeutics; Tagworks Pharmaceuticals BV; Tango Therapeutics; Janssen Research & Development, LLC; Fortvita Biologics (USA), Inc.; Conjupro Biotherapeutics; Erasca Inc.; Daiichi Sankyo Inc ). Daiichi Sankyo Inc; Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc.; ArriVent BioPharma, Inc . ). E. Chiorean, Affini-T ). BioAtla ). Lonza ). BMS ), Other, Participation on a Data Safety Monitoring Board or Advisory Board. Sapience ). Erasca ). Roche ). Genentech ). Revolution Medicines ). Sanofi ). Gilead ). Novartis ). Fibrogen ). Clovis ). AADi ), Other, Participation on a Data Safety Monitoring Board or Advisory Board. Biosplice ). Merck ). Boehringer-Ingelheim ). Astellas; Purple Biotech; Pfizer; Merus; Regeneron; Fortvita; GlaxoSmithKline; Ipsen; BPGBio; Takeda; Pegascy; Verastem Other, Participation on a Data Safety Monitoring Board or Advisory Board. W. Gustafson, Revolution Medicines Employment. H. Patel, Revolution Medicines Employment. V. Seshadri, Revolution Medicines Employment. Y. Zheng, Revolution Medicines Employment. D. Sohal, Astra Zeneca ), Other, Consulting/Honoraria (ended Jan 2024), speakers bureau. Incyte Other, Speakers bureau. Replimune Other, Consulting/Honoraria (ended Jan 2024). Cancer Commons Other, Consulting/Honoraria (ended Jun 2023). Totus Medicines ), Other, Consulting/Honoraria (ended Jul 2023). Aadi Other, Consulting/Honoraria (ended Jun 2023). Elevar Other, Consulting/Honoraria (ended Jun 2024). Regeneron ), Other, Consulting/Honoraria (ended Jun 2024). Revolution Medicines ), Other, Consulting/Honoraria (ended Jan 2024). Ability Pharma ), Other, Consulting/Honoraria. Amgen; Astellas; Bexion; Bristol-Myers Squibb; Carisma; Genentech; Hengrui; Lilly; Medilink; Merck; Mirati; NextCure; Pfizer; Roche; Takeda; Tempus; Tizona; Triumvira ).
Cited in
Control: 11041 · Presentation Id: 12321 · Meeting 21436