darlifarnib + daraxonrasib

Darlifarnib + daraxonrasib is an investigational combination of two oral small-molecule drugs: darlifarnib (KO-2806), a farnesyltransferase inhibitor developed by Kura Oncology, and daraxonrasib (RMC-6236), an oral, noncovalent, multi-selective RAS(ON) tri-complex inhibitor developed by Revolution Medicines. The combination is designed to target KRAS-mutant cancers, specifically second-line-or-later KRAS-mutant pancreatic ductal adenocarcinoma (PDAC). Darlifarnib acts by inhibiting farnesylation of RHEB, thereby suppressing adaptive mTORC1 signaling, which is a key mechanism of resistance to RAS pathway inhibitors. Daraxonrasib acts as a molecular glue that binds cyclophilin A to form a complex that blocks the active, GTP-bound form of mutant and wild-type RAS (KRAS, NRAS, and HRAS). By combining these two agents, the regimen aims to overcome or delay resistance to RAS inhibition and deepen antitumor responses. A Phase 1a study evaluating the combination is planned to initiate in early 2027.