Abstract LB407: Daraxonrasib plus chemotherapy (CT) as first-line (1L) treatment for patients (Pts) with metastatic pancreatic adenocarcinoma (mPDAC)

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 TRAEsa (≥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 TRAEsa (≥10%) were anemia (33%), neutrophil count decreased (20%), fatigue (18%), rash (15%), diarrhea (15%), and stomatitis/mucositis (10%). No Gr 5 TRAEsa 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. Citation Format: Brian M. Wolpin, Benjamin L. Musher, Gulam A. Manji, Wungki Park, Alexander Spira, Nilofer Azad, Vaia Florou, Tiago Biachi De Castria, Mark H. O'Hara, Erkut Borazanci, Aparna Parikh, John Strickler, Joel Randolph Hecht, Shubham Pant, Shiraj Sen, E. Gabriela Chiorean, W. Clay Gustafson, Hina Patel, Vidya Seshadri, Yan Zheng, Davendra Sohal. Daraxonrasib plus chemotherapy (CT) as first-line (1L) treatment for patients (Pts) with metastatic pancreatic adenocarcinoma (mPDAC) 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 (8Suppl): Abstract nr LB407.