Darlifarnib (KO-2806) FTI (RHEB/mTORC1) + adagrasib drives 67% ORR in KRAS G12C NSCLC (Ph1 FIT-001)

Darlifarnib (KO-2806) is a next-generation farnesyl transferase inhibitor designed to block farnesylation-dependent RHEB signaling and dampen mTORC1 activity (a proposed resistance node to KRAS G12C inhibition); in FIT-001 (Phase 1, open-label dose escalation/expansion; NCT06026410), KO-2806 3 or 5 mg QD (D1–7, D15–21) was combined with adagrasib 400 mg BID in 28-day cycles in heavily pretreated KRAS G12C–mut advanced NSCLC/PDAC/CRC (n=30; 43% with ≥3 prior lines; 40% prior KRASi). As of the December 15, 2025 cut, among 25 response-evaluable patients (confirmed+unconfirmed), ORR/DCR were NSCLC 67%/83% (4/6 responses; including 100% at 5 mg [3/3]), PDAC 60%/100% (3/5), and CRC 14%/71% (2/14); in context, adagrasib-based benchmarks are ~43% ORR in previously treated KRAS G12C NSCLC (monotherapy) and ~19% ORR in KRAS G12C mCRC with adagrasib alone (while CRC responses rise to 34% with adagrasib+cetuximab), so the NSCLC and PDAC signals look directionally above expected whereas CRC remains within/near known ranges for KRAS G12C inhibitor approaches. Safety looked manageable for a combo in a frail, multi-line population: common any-grade TEAEs included diarrhea (63%), nausea (57%), anemia (50%), vomiting (43%), neutropenia (40%), thrombocytopenia (40%); grade ≥3 TEAEs were led by neutropenia (30%) and anemia (17%), with 1 DLT (anemia) at 5 mg and discontinuations mainly from progression (n=10).