Safety and efficacy of ifebemtinib (IN10018) combined with garsorasib (D-1553) in KRAS G12C mutant solid tumors from a phase Ib/II study: Results from single-arm of non-small-cell lung cancer (NSCLC) and randomized part of colorectal cancer (CRC).

Abstract

8629 Background: RAS inhibitors (RASi) need to be combined with optimal partner(s) to maximize their efficacy. Ifebemtinib (ifebe) is a highly potent and selective oral inhibitor of focal adhesion kinase (FAK) demonstrating synergies with RASi both preclinically and clinically. D-1553 is a novel KRAS G12Ci approved in China for KRAS G12C mutant NSCLC. We previously reported a promising ORR of 90.3% in KRAS G12C mutant NSCLC receiving ifebe + D-1553 with pending durability of efficacy. Here we are updating the follow-up (FU) results in NSCLC and also reporting preliminary results of ifebe + D-1553 vs D-1553 in KRAS G12C mutant CRC from a randomized part to decipher the relative contribution of ifebe. Methods: Locally advanced or metastatic KRAS G12C mutant NSCLC patients (pts) without any prior systemic anticancer therapy were enrolled in a single arm and received ifebe (100mg QD) + D-1553 (600mg BID). 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 22-Jan-25, 33 front-line NSCLC pts (81.8% stage IV) were enrolled and received ifebe + D-1553, and 36 previously-treated metastatic CRC pts were enrolled and randomized 1:1 to receive ifebe + D-1553 or D-1553 alone. In NSCLC with a median FU of 13.8 months (range: 1.1, 20.9), 12-month PFS rate is 67.9%, and Kaplan-Meier curve of PFS flattens as treatment continues, predicting durable efficacy. The mDOR, mPFS and mOS are not reached by the cut-off date. In the randomized part of CRC, all 36 pts are radiologically evaluable. The ORR is 33.3% (95%CI: 13.3, 59.0) vs 16.7% (95%CI: 3.6, 41.4) and DCR is 100.0% (95%CI: 81.5, 100.0) vs 77.8% (95%CI: 52.4, 93.6) in ifebe + D-1553 vs D-1553 alone, respectively. The mDOR, mPFS and mOS has not matured yet. The safety profiles of ifebe + D-1553 in both NSCLC and CRC pts are comparable to each single agent. No ifebe- or D-1553-related death or AEs leading to drug withdrawal were reported. The incidence of SAEs and ≥Grd.3 AEs are listed in Table 1. Conclusions: Combination of ifebe and D-1553, as a dual-oral regimen, is safe and highly efficacious against KRAS G12C mutant NSCLC with ORR over 90% and durable efficacy. Preliminary results from the randomized part of CRC demonstrated ORR doubling with the combo, validating the add-on benefits of ifebe. Our data suggest that ifebe could be an ideal partner of RASi. Clinical trial information: NCT06166836 ; NCT05379946 . Incidence of SAEs and ≥Grd.3 AEs. NSCLC CRC Ifebe + D-1553N=33 n(%) Ifebe + D-1553 N=18 n(%) D-1553 N=18 n(%) Pts with SAE 8 (24.2) 2 (11.1) 4 (22.2) ifebe-related 5 (15.2) 2 (11.1) - D-1553-related 5 (15.2) 2 (11.1) 1 (5.6) Pts with ≥ Grd. 3 AE 11 (33.3) 4 (22.2) 4 (22.2) ifebe-related 7 (21.2) 4 (22.2) - D-1553-related 7 (21.2) 4 (22.2) 2 (11.1)