Safety and efficacy of ifebemtinib combined with garsorasib in KRAS G12C mutant colorectal cancer from a randomized part of a phase Ib/II study.

Abstract

3591 Background: Studies (Yaeger R, et al.; Fakih, MG, et al.) have shown when RASi is combined with optimal therapeutic partner(s), clinical efficacy and benefit can be maximized. Ifebemtinib (ifebe) is a highly potent and selective oral inhibitor of focal adhesion kinase (FAK) that exhibits synergistic effect with RASi in both preclinical and clinical setting. Garsorasib (D-1553) is a novel KRAS G12Ci approved in China for treatment of KRAS G12C mutant NSCLC. We previously reported a promising objective response rate (ORR) of 44.4% in patients (pts) with KRAS G12C mutant CRC receiving ifebe + D-1553, with the durability of efficacy yet to be confirmed. Herein, we present the updated results with median follow-up of (14.4 months) from a randomized cohort of phase Ⅰb/Ⅱ study, comparing ifebe + D-1553 vs D-1553 alone in KRAS G12C mutant CRC, to elucidate the relative therapeutic contribution of ifebe and durability of response. Methods: Metastatic KRAS G12C mutant CRC pts with at least 1 prior line of systemic anticancer therapy were enrolled in a randomized part and randomized 1:1 to ifebe (100mg QD) + D-1553 (600mg BID) or D-1553 (600mg BID) alone. Results: As of January 4, 2026, 36 previously treated metastatic CRC pts were enrolled, with 18 pts in ifebe + D-1553 group and 18 pts in D-1553 group (≥3 prior lines of treatment: 33.3% vs 27.8%; liver metastasis: 55.6% vs 72.2%). The median treatment duration was 8.5 months vs 3.6 months and 4 pts (3 [16.7%] vs 1 [5.6%]) were still on treatment. The hazard ratio (HR) for progression free survival (PFS) and overall survival (OS) was 0.47 and 0.44, respectively, demonstrating the durability of efficacy in pts receiving ifebe + D-1553 (Table). The safety profiles of ifebe + D-1553 in CRC pts are comparable to each single agent. No ifebe or D-1553 related death or AEs leading to drug withdrawal were reported. Conclusions: The combination of ifebe and D-1553, a dual-oral regimen, exhibits favorable safety profiles and better efficacy in treating KRAS G12C mutant CRC, with mOS exceeding 16 months. Clinical findings from this randomized study have shown robustness of improvement in overall ORR, PFS, DOR and OS benefit with this combination regimen, indicating that adding ifebe to a RASi can further improve clinical outcome to CRC patients with RAS G12C mutation. Clinical trial information: NCT06166836 . Efficacy. ifebe + D-1553(N=18) D-1553(N=18) Objective response rate (ORR), % 44.4 (21.5, 69.2) 16.7 (3.6, 41.4) Disease control rate (DCR), % 100.0 (81.5, 100.0) 77.8 (52.4, 93.6) Median duration of response (mDoR), months 12.1 (1.41, NE) 6.8 (6.3, NE) Median PFS, months 8.4 (3.0, 11.9) 4.0 (2.0, 5.6) HR for PFS (95% CI) 0.47 (0.23, 0.98) Median OS, months 16.4 (13.1, NE) 7.8 (5.3, NE) HR for OS (95% CI) 0.44 (0.17, 1.15)