FTI Darlifarnib + Cabozantinib Shows 33–50% ORR in Pretreated ccRCC

Darlifarnib (KO-2806) is an investigational farnesyl transferase inhibitor that blocks RHEB farnesylation to selectively suppress mTORC1, here combined with cabozantinib in the Phase 1a/b FIT-001 trial (NCT06026410). Among 72 RCC patients (58 ccRCC; 53% with ≥2 prior lines and 38% previously treated with cabozantinib), 22 cabozantinib-naive ccRCC patients receiving darlifarnib 5 or 8 mg plus cabozantinib 60 mg had ORRs of 50% and 33%, DCRs of 80% and 100%, and median PFS of 11.2 months and not estimable, respectively; 6/19 response-evaluable patients previously exposed to cabozantinib responded, including 3 whose immediate prior therapy was cabozantinib. Grade ≥3 neutropenia occurred in 36%, while darlifarnib-related adverse events led to dose interruption in 58%, reduction in 18%, and discontinuation in 3%. For context, cabozantinib alone recently produced a 40.2% ORR and 10.7-month median PFS in post–PD-(L)1 ccRCC, while belzutifan + lenvatinib reached 52.6% and 14.8 months.