Daraxonrasib Shows Clinical Promise in Patients With RAS-mutated Pancreatic Ductal Adenocarcinoma

Clinical Summary: 

• Design/Population:  A phase 1/2 study evaluated daraxonrasib in 168 previously treated patients with previously treated RAS-mutated pancreatic ductal adenocarcinoma.
• Key Outcomes: Daraxonrasib demonstrated objective responses, with durable responses and median progression-free and overall survival exceeding historical expectations in this setting, alongside a manageable safety profile.
• Clinical Relevance: Targeting RAS(ON) signaling with a multiselective inhibitor may represent a promising therapeutic strategy in pancreatic ductal adenocarcinoma, where effective targeted options remain limited.

Results from a phase 1/2 study demonstrated that the daraxonrasib showed clinical promise among previously treated patients with RAS-mutated pancreatic ductal adenocarcinoma. 

“Activating RAS mutations occur in more than 90% of [pancreatic] tumors,” stated Brian Wolpin, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, and coauthors. “Daraxonrasib (RMC-6236) is an oral RAS(ON) multiselective inhibitor that targets guanosine triphosphate–bound mutant and wild-type RAS.”

In this study, 168 patients received once daily daraxonrasib at doses ranging from 10 mg to 400 mg, with 300 mg selected as the phase 3 dose. The primary end point was safety. Key secondary end points included pharmacokinetics, objective response rate (ORR), duration of response, progression-free survival (PFS), and overall survival (OS). 

At analysis, any-grade treatment-related adverse events were reported in 96% of patients, with grade ≥3 events occurring in 30% of patients. The most common treatment-related adverse events occurring in ≥10% of patients included rash, diarrhea, nausea, stomatitis or mucositis, vomiting, and fatigue.

In a subgroup of patients with RAS G12 mutations treated in the second line setting at the 300 mg dose (n = 26), the ORR was 35%. The median duration of response was 8.2 months, with a median PFS of 8.5 months, and a median OS of 13.1 months.

In a subgroup of patients with RAS G12, G13, or Q61 mutations (n = 38), the ORR was 29%. The median duration of response was 8.2 months, with a median PFS of 8.1 months, and a median OS of 15.6 months.

“Daraxonrasib was associated with treatment-related adverse events of [grade ≥3] in one third of patients with previously treated RAS-mutated [pancreatic ductal adenocarcinoma],” concluded Dr Wolpin et al. “Antitumor activity was also reported.” 

Source: 

Wolpin BM, Park W, Garrido-Laguna I, et al. Daraxonrasib in previously treated advanced RAS-mutated pancreatic cancer. N Engl J Med. Published online: May 6, 2026. doi:10.1056/NEJMoa2505783