Daraxonrasib monotherapy as first-line (1L) treatment for patients with metastatic pancreatic adenocarcinoma (mPDAC)
Presenter: Eileen O’Reilly, MD Session: Late-Breaking Research: Clinical Research 3 Time: 4/21/2026 2:00:00 PM → 4/21/2026 5:00:00 PM
Authors
Eileen M. O’Reilly 1 , Brian Wolpin 2 , Shubham Pant 3 , Joel Randolph Hecht 4 , Jennifer Valerin 5 , Dae Won Kim 6 , Nilofer Azad 7 , Kyaw Aung 8 , Lin Tao 9 , Sumit Kar 9 , Hina Patel 9 , Rashmi Vora 9 , Aparna Hegde 9 , Alexander Spira 10 , Alexander Starodub 11 , Benjamin Herzberg 12 , Ignacio Garrido-Laguna 13 1 Memorial Sloan Kettering Cancer Center, New York, NY, 2 Dana-Farber Cancer Institute, Boston, MA, 3 MD Anderson Cancer Center, Houston, TX, 4 David Geffen School of Medicine at UCLA, Los Angeles, CA, 5 University of California Irvine, Orange, CA, 6 Moffitt Cancer Center, Tampa, FL, 7 Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 8 University of Texas Health Austin, Austin, TX, 9 Revolution Medicines, Redwood City, CA, 10 NEXT Oncology Virgina, Virgina Cancer Specialists Research Institute, Fairfax, VA, 11 The Christ Hospital, Cincinnati, OH, 12 Columbia University, New York, NY, 13 Huntsman Cancer Institute, Salt Lake City, UT
Abstract
Background: mPDAC is a challenging, RAS-driven disease with 5-y survival of ~3%. Standard 1L chemotherapy has substantial toxicity and limited benefit (ORR: 23-43%; PFS at 6 mo: 40%-50%; mOS: 8.5-11.7 months). Oncogenic RAS mutations occur in >90% of cases. Daraxonrasib is a potent, oral, RAS(ON) multi-selective inhibitor targeting GTP-bound mutant (incl. G12, G13, and Q61 mutations) and WT RAS. In a phase 1/2 study (NCT05379985), second-line daraxonrasib demonstrated manageable safety and encouraging early efficacy in pts with RAS-mutant mPDAC. Here, we present the safety and efficacy of daraxonrasib as 1L therapy for pts with RAS-mutant mPDAC (NCT05379985). Methods: Pts with RAS-mutant mPDAC received 1L daraxonrasib 300 mg QD and were evaluated for safety, tolerability, antitumor activity, and ctDNA response per treated and evaluable pts. Results: As of Dec 1, 2025 (median follow-up: 13.7 mo), 40 pts received daraxonrasib. All-grade TRAEs a (≥20%) were rash (88%), diarrhea (63%), stomatitis/mucositis (63%), nausea (53%), vomiting (50%), fatigue (35%), and paronychia (20%). Grade ≥3 TRAEs (≥10%) were rash, diarrhea, and stomatitis/mucositis (10% each). No Grade 4/5 TRAEs occurred. TRAEs led to dose modifications in 70% of pts and discontinuation in 1 (3%) pt. The mean relative dose intensity was 84%. Antitumor and ctDNA responses to daraxonrasib treatment are shown in the table. Conclusions: Daraxonrasib monotherapy in 1L mPDAC showed manageable safety, consistent with prior studies, and compelling preliminary efficacy supporting the initiation of a global 3-arm phase 3 study (RASolute 303) of daraxonrasib with or without chemotherapy in 1L mPDAC. Table Antitumor activity Treated pts Evaluable pts Efficacy measures n=38 b n=35 c ORR d , % (95% CI) 47% (31-64) 51% (34-69) Disease control rate (DCR), % (95% CI) 92% (79-98) 97% (85-100) PFS at 6 mo e % (95% CI) 71% (53-83) _ OS at 6 mo e , % (95% CI) 83% (67-92) _ ctDNA Response f _ n=28 f >50% RAS VAF g reduction, % _ 100% 100% RAS VAF g clearance, % _ 57% C, Cycle; D, Day; VAF, variant allele frequency. a TRAEs include any study drug-related treatment-emergent AE. b 2 pts were excluded from the efficacy analysis as they did not meet the definition of previously untreated mPDAC. 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). g VAF variant allele frequency reduction at C2D1/C3D1 from baseline (C1D1).
Disclosure
E. M. O’Reilly, Arcus ), Travel, Other, Consulting/DSMB. Genentech/Roche ). BioNTech ), Travel, Other, Consulting/DSMB. AstraZeneca ), Other, Consulting/DSMB. Elicio Therapeutics ). Digestive Care ). Agenus ), Other, Consulting/DSMB. Amgen ), Other, Consulting/DSMB. Revolution Medicines ), Other, Consulting/DSMB. Tango Therapeutics ). Ability Pharma; Alligator BioSciences; Pfizer; Ipsen; lkena; Merck; lmmuneering; Moma Therapeutics; Novartis; Astellas; BMS; Regeneron Other, Consulting/DSMB. American Association of Cancer Research (AACR) Other. American Society of Clinical Oncology (ASCO) Other. lmedex Other. Research To Practice Other. Stand Up To Cancer (SU2C) Other. NIH/NCI Other. Break Through Cancer Other. Cancer Center Support Grant/Core Grant P30 CA008748 Other. NCI/NIH P50 CA257881-01A1 Other. B. 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. 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. 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. J. Valerin, Astra Zeneca ), Other, Speaker Bureau. Dragonfly ). Revolution Medicine ). Pfizer ). Ikena ). Bioatla ). Incyte Other, Speaker bureau. Tempus Other, Consulting. D. Kim, Ipsen Other, Honorarium. 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 Other, Honoraria/Consulting. GlaxoSmithKline Other, Honoraria/Consulting. Astellas Other, Honoraria/Consulting. Eli Lilly Other, Honoraria/Consulting. Tempus Other, Honoraria/Consulting. K. Aung, None. L. Tao, Revolution Medicines Employment. S. Kar, Revolution Medicines Employment. H. Patel, Revolution Medicines Employment. R. Vora, Revolution Medicines Employment. A. Hegde, Revolution Medicines Employment, Stock, Stock Option. 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 Therapeutics ). NEXT Oncology Virginia g., Board of Directors, non-salaried role). A. Starodub, None. B. Herzberg, Amgen ), Other, Consulting. Repare ). Ideaya ), Other, Consulting. Astellas ), Other, Consulting. Revolution Medicines ), Other, Consulting. AstraZeneca ), Other, Consulting. Seagen ). Genentech ). Monte Rosa Therapeutics ). Eli Lilly ), Other, Consulting. Prelude ). DAVA Oncology Travel. Arvinas Travel. Boxer Capital Other, Consulting. Johnson and Johnson Other, Consulting. Guidepoint Other, Consulting. Onclive Other, Consulting. Ideology Health Other, Consulting. Curio Health Other, Consulting. Abbvie Other, Consulting. I. Garrido-Laguna, SOTIO; Abbvie; Revolution Medicines; Lilly; Quanta Therapeutics; Kestrel Therapeutics; Fortvita; EcoR1 Capital; Guidepoint Global; KeyQuest Health Other, Consulting. EcoRl; Guidepoint Inc; Novartis; Bayer; Bristol-Myers Squibb; Pfizer; Medimmune; Lilly; Incyte; GlaxoSmithKline; Tolero Pharmaceuticals; BridgeBio Pharma; Jacobio; Repare Therapeutics ). Sumitomo Dainippon Pharma Oncology; Revolution Medicines; Yingli Pharma; Quanta Therapeutics; 280 BIO; ABM Therapeutics; Tango; Kumquat Biosciences ).
Cited in
Control: 10234 · Presentation Id: 11375 · Meeting 21436