Key Clinical Summary: 

• Design/Population: This phase 1/2 study evaluated first-line daraxonrasib in 40 patients with RAS-mutant metastatic pancreatic ductal adenocarcinoma. The study assessed safety, efficacy, and ctDNA response.
• Key Outcomes: Daraxonrasib demonstrated manageable toxicity with no grade 4/5 treatment-related adverse events and encouraging early signals of antitumor activity. Dose modifications were common, but treatment discontinuation was infrequent.
• Clinical Relevance: Targeting active RAS represents a promising strategy in pancreatic cancer, a disease with limited therapeutic options. These results support further investigation of daraxonrasib in randomized phase 3 trials.

Results from a phase 1/2 study demonstrate that first-line daraxonrasib, a RAS(ON) multi-selective inhibitor, shows encouraging clinical efficacy and safety among patients with RAS-mutated metastatic pancreatic ductal adenocarcinoma.

These findings were presented by Eileen O’Reilly, MD, Memorial Sloan Kettering Cancer Center, New York, New York, at the 2026 American Association for Cancer Research (AACR) Annual Meeting in San Diego, California.

In this study, 38 patients received 300 mg of once daily daraxonrasib. The primary end point was safety. Key secondary end points included objective response rate (ORR), disease control rate, progression-free survival (PFS), overall survival (OS), and ctDNA response in evaluable patients (n = 35).

At a median follow-up of 13.7 months, the most frequently reported treatment-related adverse events of any grade occurring in ≥ 20% of patients included rash (88%), diarrhea (63%), stomatitis or mucositis (63%), vomiting (50%), fatigue (35%), and paronychia (20%). The most common grade ≥ 3 treatment-related adverse events occurring in ≥ 10% of patients were rash, diarrhea, and stomatitis or mucositis. No grade 4/5 treatment-related adverse events were reported. Dose modifications occurred in 70% of patients, with treatment discontinuation in one patient. The mean relative dose intensity was 84%.

In ctDNA evaluable patients, the ORR was 51% and the disease control rate was 97%. All patients achieved more than a 50% reduction in RAS VAF, with complete VAF clearance observed in 57% of patients. In the intention-to-treat population, the ORR was 47% and the disease control rate was 92%, with 6-month PFS and OS rates of 71% and 83%, respectively.

“Daraxonrasib monotherapy in [first-line metastatic pancreatic ductal adenocarcinoma] 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 [first-line metastatic pancreatic ductal adenocarcinoma].” 

Source:

O’Reilly E, Wolpin B, Pant S, et al. Daraxonrasib monotherapy as first-line (1L) treatment for patients with metastatic pancreatic adenocarcinoma (mPDAC). Presented at AACR Annual. April 17 - 22, 2026; San Diego, California. LB337.