Daraxonrasib in Previously Treated Advanced RAS-Mutated Pancreatic Cancer

N Engl J Med. 2026 May 7;394(18):1790-1802. doi: 10.1056/NEJMoa2505783.

Abstract

Background: Current therapies for patients with pancreatic ductal adenocarcinoma (PDAC) provide modest benefit. Activating RAS mutations occur in more than 90% of PDAC tumors. Daraxonrasib (RMC-6236) is an oral RAS(ON) multiselective inhibitor that targets guanosine triphosphate-bound mutant and wild-type RAS.

Methods: In this phase 1-2 study, we evaluated daraxonrasib in patients with advanced solid tumors with activating RAS mutations. Patients received 10 to 400 mg of daraxonrasib orally once daily; 300 mg was selected as the phase 3 dose. The primary end point was safety. Pharmacokinetics and antitumor activity were secondary end points. This report focuses on the 168 study patients with previously treated RAS-mutated PDAC.

Results: Among the 168 patients with PDAC who received daraxonrasib at a dose of 300 mg or less, treatment-related adverse events of any grade were reported in 96%; such events of grade 3 or higher were reported in 30%. Treatment-related adverse events that occurred in at least 10% of the patients included rash, diarrhea, nausea, stomatitis or mucositis, vomiting, and fatigue. In a subgroup of 26 patients with RAS G12 mutations who were treated with second-line daraxonrasib at a dose of 300 mg, an objective response to therapy was reported in 35% (95% confidence interval [CI], 17 to 56). The median duration of response was 8.2 months (95% CI, 3.8 to not evaluable), with median values of 8.5 months for progression-free survival and 13.1 months for overall survival. Among the 38 patients with RAS G12, G13, or Q61 mutations, 29% (95% CI, 15 to 46) had an objective response. The median duration of response was 8.2 months (95% CI, 3.8 to 8.8), with median values of 8.1 months for progression-free survival and 15.6 months for overall survival.

Conclusions: Daraxonrasib was associated with treatment-related adverse events of grade 3 or higher in one third of patients with previously treated RAS-mutated PDAC; antitumor activity was also reported. (Funded by Revolution Medicines; RMC-6236-001 ClinicalTrials.gov number, NCT05379985.).

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Clinical Trial, Phase II

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents* / administration & dosage
  • Antineoplastic Agents* / adverse effects
  • Carcinoma, Pancreatic Ductal* / drug therapy
  • Carcinoma, Pancreatic Ductal* / genetics
  • Carcinoma, Pancreatic Ductal* / mortality
  • Female
  • Genes, ras / genetics
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Pancreatic Neoplasms* / drug therapy
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / mortality
  • Piperazines* / administration & dosage
  • Piperazines* / adverse effects
  • Progression-Free Survival
  • Time Factors
  • ras Proteins* / antagonists & inhibitors
  • ras Proteins* / genetics

Substances

  • Antineoplastic Agents
  • daraxonrasib
  • Piperazines
  • ras Proteins

Associated data

  • ClinicalTrials.gov/NCT05379985