Efficacy and Safety of Daraxonrasib (RMC-6236) in Previously Treated Metastatic RAS-Mutated Pancreatic Ductal Adenocarcinoma: A Systematic Review.

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is associated with a poor prognosis, and RAS gene mutations are present in more than 90% of cases. For this reason, direct RAS inhibition is a promising, but thus far difficult to achieve, therapeutic strategy. Daraxonrasib (RMC-6236) is a first-in-class, oral, non-covalent, multiselective inhibitor of the active form of RAS. It forms an intracellular trimeric complex with cyclophilin A, blocking both mutant and wild-type variants of the KRAS, NRAS, and HRAS genes. The aim of this systematic review was to evaluate the efficacy and safety of daraxonrasib in previously treated patients with RAS-mutated PDAC.

Methods

This review was conducted in accordance with the PRISMA 2020 guidelines. A systematic search was conducted in PubMed, Web of Science, and ClinicalTrials.gov for studies published between January 2020 and July 2026. Two studies met the inclusion criteria and were analyzed: the Phase 1-2 RMC-6236-001 (n = 168) and the Phase 3 RASolute 302 trial (n = 500), involving a total of 668 patients. The risk of bias was assessed using the Cochrane RoB 2.0 tool for the randomized trial and the Methodological Index for Non-Randomized Studies (MINORS) tool.

Results

In the RASolute 302 trial, daraxonrasib out performed investigator-selected chemotherapy in a population of patients with the RAS G12 mutation, improving median overall survival (13.2 vs. 6.6 months; HR 0.40), progression-free survival (7.3 vs. 3.5 months; HR 0.45), and objective response rate (33.2% vs. 11.8%; all p < 0.001), and also delayed the onset of pain and deterioration in quality of life. These results were consistent with the earlier RMC-6236-001 study (objective response rate [ORR] 35%, median overall survival [OS] 13.1 months in patients with RAS G12 mutation treated in the second-line setting). Daraxonrasib exhibited a predictable toxicity profile, consisting mainly of Grade 1-2 dermatologic and gastrointestinal symptoms, with lower rates of hematologic toxicity and treatment discontinuation than with chemotherapy.

Conclusions

Daraxonrasib demonstrates clinically relevant and statistically significant efficacy with an acceptable safety profile in previously treated patients with metastatic RAS G12-mutated PDAC, the population for which the strongest randomized evidence is currently available. These findings support its potential as a promising new treatment option in this setting. Further studies are needed regarding rare RAS gene variants and forms of the disease with wild-type RAS.