Farnesyl transferase inhibitor (FTI) darlifarnib (KO-2806) in combination with adagrasib in <i>KRAS</i> G12C mutated (mut) advanced solid tumors: Preliminary results from the FIT-001 phase 1 first-in-human trial.

Abstract

3078 Background: Clinical response to RAS inhibitors (RASi) is often limited by inherent/adaptive resistance mediated by persistent mTORC1 signaling. RHEB is a farnesylation-dependent protein required for mTORC1 activation. Darlifarnib, a potent next-generation FTI, selectively inhibits mTORC1 pathway activation and demonstrates synergistic antitumor activity in combination with the KRAS G12C inhibitor adagrasib (ada) in preclinical models, supporting potential to improve clinical activity in KRAS G12C mut tumors. Methods: FIT-001 (NCT06026410) is an ongoing, multicenter, open-label Ph1 dose escalation/expansion study of darlifarnib in advanced solid tumors. Darlifarnib 3, 5 or 8 mg QD D1–7, D15–21 + ada 400 mg BID in 28d cycles was evaluated in heavily pretreated pts with KRAS G12C mut NSCLC, PDAC or CRC. Primary objectives: safety/tolerability; key secondary objective: antitumor activity. Results: Dose escalation resulted in candidate darlifarnib doses of 3 and 5 mg. As of 15 Dec 2025, 30 pts (median age 61y; 63% male; 83% White; 93% baseline [BL] Karnofsky performance status 80–100%) received ≥1 darlifarnib 3 (n=15) or 5 mg (n=15) + ada dose. Primary tumor types: 30% NSCLC, 20% PDAC, 50% CRC. Pts were heavily pretreated: 43% had ≥3 prior systemic therapies; 40% had prior KRASi. Both darlifarnib 3 and 5 mg + ada were well tolerated; most common (≥30%) any-grade (Gr) treatment-emergent AEs (TEAEs): 63% diarrhea, 57% nausea, 50% anemia, 43% vomiting, 40% neutropenia, 40% thrombocytopenia. Most common (≥15%) Gr ≥3 TEAEs: 30% neutropenia, 17% anemia. 1 dose limiting toxicity occurred (anemia, darlifarnib 5 mg + ada). Most common treatment (trx) discontinuation reason was progressive disease (n=10). With a median follow-up of 23 wks, 13 pts remained on trx. Preliminary results from 25 response-evaluable pts (≥1 darlifarnib dose + post BL scan) included confirmed + unconfirmed responses. Antitumor activity was observed in all tumor types. Across darlifarnib 3 and 5 mg + ada dose levels, ORRs (95% CI) were 67% (22.3–95.7) for NSCLC, 60% (14.7–94.7) for PDAC, 14% (1.8–42.8) for CRC (Table); DCRs (CR+PR+SD): 83% (35.9–99.6) for NSCLC, 100% (47.8–100) for PDAC, 71% (41.9–91.6) for CRC. Updated data across all doses to be presented. Conclusions: Darlifarnib 3 and 5 mg + ada were well tolerated with encouraging antitumor activity in heavily pretreated KRAS G12C mut NSCLC, PDAC and CRC. These preliminary data support further investigation of darlifarnib + KRASi, such as ada, to address mTORC1-mediated resistance and potentially improve clinical outcomes for pts. Clinical trial information: NCT06026410 . n (%) Darli 3 mg + ada Darli 5 mg + ada Total NSCLC 3 3 6 ORR a 1 (33) 3 (100) 4 (67) DCR 2 (67) 3 (100) 5 (83) PDAC 2 3 5 ORR a 2 (100) 1 (33) b 3 (60) b DCR 2 (100) 3 (100) 5 (100) CRC 6 8 14 ORR a 0 2 (25) 2 (14) DCR 3 (50) 7 (88) 10 (71) a Confirmed+unconfirmed responses. b 1 uPR post datacut.