In a phase I/II trial (RMC-6236-001) reported in The New England Journal of Medicine, Wolpin et al identified the safety profile of daraxonrasib and showed activity of the agent in patients with previously treated advanced RAS-mutated pancreatic ductal adenocarcinoma (PDAC).
Daraxonrasib (RMC-6236) is an oral RAS(ON) multiselective inhibitor targeting guanosine triphosphate–bound mutant and wild-type RAS.
Study Details and Key Findings
In the U.S. multicenter study, 168 patients enrolled between June 2022 and June 2025 received daraxonrasib at 10 to 400 mg once daily, with 300 mg once daily being selected as the phase III dose.
Among 168 patients receiving daraxonrasib at 300 mg once daily or less, treatment-related adverse events of any grade were reported in 96%, most commonly rash (88%), diarrhea (46%), nausea (42%), and stomatitis/mucositis (40%). Treatment-related grade 3 or higher adverse events occurred in 30%, with the most common including rash (7%), stomatitis/mucositis (4%), and diarrhea (3%). Treatment-related adverse events led to discontinuation of treatment in one patient.
Among 26 patients with RAS G12 mutations who received daraxonrasib at 300 mg daily as second-line therapy, objective response was observed in 9 (35%, 95% confidence interval [CI] = 17%–56%), with complete response in 1; the median duration of response was 8.2 months (95% CI = 3.8 months to not evaluable). Median progression-free survival was 8.5 months and median overall survival was 13.1 months.
Among 38 patients with RAS G12, G13, or Q61 mutations receiving daraxonrasib at 300 mg daily as second-line therapy, objective response was observed in 11 (29%, 95% CI = 15%–46%), including complete response in 1; median duration of response was 8.2 months (95% CI = 3.8–8.8 months). Median progression-free survival was 8.1 months and median overall survival was 15.6 months.
The investigators concluded: “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.”
Brian M. Wolpin, MD, MPH, of Hale Family Center for Pancreatic Cancer Research, Dana-Farber Cancer Institute, Boston, and David S. Hong, MD, of Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston, are the corresponding authors for the New England Journal of Medicine article.
DISCLOSURE: The study was funded by Revolution Medicines. For full disclosures of the study authors, visit nejm.com.
