Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer

We previously reported encouraging efficacy in a Phase 1/2 clinical trial evaluating daraxonrasib monotherapy at clinically active dose levels in patients with previously treated, RAS mutant metastatic pancreatic adenocarcinoma (PDAC), providing the basis for confirmatory evaluation in the randomized Phase 3 RASolute 302 clinical trial .

Here, we report mechanisms of acquired resistance to daraxonrasib monotherapy observed through targeted sequencing of over 800 genes in paired pre- and end of treatment ctDNA samples from 44 patients in the Phase 1/2 clinical trial. Treatment-emergent genomic alterations in the RAS signaling pathway were observed in more than half (26/44; 59%) of these patients including, most notably, mutant KRAS amplifications in one third (16/44; 36%), as well as alterations in receptor tyrosine kinase (RTK) (4/44, 9%), MAPK (11/44, 25%) and PI3K (4/44, 9%) pathways.