Multicenter phase 1-2 trial of daraxonrasib in previously treated advanced RAS-mutated pancreatic ductal adenocarcinoma

Activating RAS mutations occur in more than 90% of pancreatic ductal adenocarcinoma (PDAC) tumors. Daraxonrasib (RMC-6236) is an oral RAS(ON) multiselective inhibitor that targets guanosine triphosphate-bound mutant and wild-type RAS. The phase 1-2 RMC-6236-001 trial, at 16 centers in the USA, evaluated daraxonrasib in patients with activating RAS mutations. Patients received 10 to 400 mg daraxonrasib once daily; 300 mg was selected as the phase 3 dose. The primary endpoint was safety; pharmacokinetics and antitumor activity were secondary endpoints. Results among 168 patients with previously treated RAS-mutated PDAC have now been published. Treatment-related adverse event were reported in 96%; grade 3 or higher in 30%. In a subgroup of 26 patients with RAS G12 mutations who received second-line daraxonrasib at a dose of 300 mg, objective response rate was 35% (95% CI 17-56), with median duration of response 8.2 months (3.8-NE). Among 38 patients with RAS G12, G13, or Q61 mutations, the ORR was 29% (95% CI 15-46) with median duration of response 8.2 months (3.8-8.8). The figure shows progression-free survival and overall survival. The authors conclude that daraxonrasib was associated with treatment-related adverse events of grade 3 or higher in one third of patients with previously treated RAS-mutated PDAC, and showed antitumor activity.