e15104 Background: Later-line (3L+) treatment for PDAC remains a high unmet need, with historically poor outcomes with chemotherapy (ORR, 3%-6%; mPFS, 2 mo; mOS, 5 mo). Oncogenic RAS mutations occur in > 90% of pts with mPDAC. Daraxonrasib is a potent, oral, RAS(ON) multi-selective, tri-complex inhibitor that targets active GTP-bound RAS, including variants with mutations at codons G12, G13, and Q61, as well as wild-type RAS. Previously reported phase 1/2 data for daraxonrasib (NCT05379985) demonstrated manageable safety and encouraging efficacy in previously treated RAS mutant PDAC (2L+). We now present safety and efficacy outcomes from this study in pts with RAS mutations treated in the 3L+ setting. Methods: Pts with 3L+ RAS-mutant PDAC received daraxonrasib 300 mg QD. The primary objective was safety and tolerability; the secondary objective was efficacy. Results: As of Dec 1, 2025, 46 pts received daraxonrasib 300 mg; median follow-up was 22.6 months (range, 15.1-27.8). The majority of pts enrolled had ECOG PS of 1 (63%); the median number of prior systemic therapies in the metastatic setting was 2 (range, 2-5). Treatment-related adverse events (TRAEs) occurring in ≥15% of all pts were rash (87%), diarrhea (50%), stomatitis/mucositis (48%), nausea (41%), vomiting (35%), dry skin (22%), paronychia (22%), and fatigue (15%); the most common (≥5%) grade ≥3 TRAEs were rash (9%), stomatitis/mucositis (7%), and anemia (7%). Grade 4 platelet count decrease and lymphocyte count decrease were reported in 1 pt each. No grade 5 TRAEs occurred. No pts discontinued treatment due to TRAEs. The mean relative dose intensity was 88%. Efficacy outcomes of daraxonrasib are shown in the table. Conclusions: Daraxonrasib 300 mg QD in 3L+ PDAC demonstrated a manageable safety profile consistent with earlier-line experience. A majority of pts achieved disease control supported by encouraging survival. Clinical trial information: NCT05379985 . Efficacy measures in 3L+ a PDAC All RAS mutant (n=46) ORR (95% CI), % b 20 (9-34) Disease control rate (95% CI), % c 85 (71-94) PFS d , median (95% CI), mo d 4.3 (4.0-7.8) OS d , median (95% CI), mo d 9.0 (6.4-11.1) a Defined as treatment in pts who had received ≥2 prior lines of therapy in the metastatic setting, including pts who had received prior therapy in the neoadjuvant or adjuvant setting whose disease had progressed within 6 mo. b Includes confirmed complete response (CR) and partial response (PR). c Includes confirmed CR, confirmed PR, and stable disease. d Estimate based on Kaplan-Meier method.
Garrido-Laguna et al. (2026) studied this question.