Efficacy and safety of IBI351 (GFH925) monotherapy in metastatic colorectal cancer harboring KRAS^G12C mutation: Preliminary results from a pooled analysis of two phase I studies.

3586 Background: IBI351 (GFH925) is an irreversibly covalent inhibitor of KRAS G12C and has demonstrated promising anti-tumor activity with acceptable safety in advanced solid tumors. Here, we report a pooled analysis of two phase I studies (NCT05005234, NCT05497336) evaluating the efficacy and safety of IBI351 (GFH925) monotherapy for metastatic colorectal cancer (CRC) harboring KRAS G12C mutation. Methods: Eligible metastatic CRC patients (pts) with KRAS G12C mutation were included. Pts received IBI351 (GFH925) orally at dose levels of 700mg once daily (QD), or 450/600/750mg twice daily (BID). The primary endpoint was objective response rate (ORR) assessed by investigator per RECIST v1.1. Data cutoff for the analyses was November 30, 2022 unless otherwise specified. Results: A total of 45 pts were enrolled (median age: 58.0 years; male: 57.8%; ECOG PS 1: 71.1%; pts with ≥2 prior lines of treatment: 66.7%), including 3, 4, 37, and 1 pts in 700mg QD, 450mg BID, 600mg BID, and 750mg BID cohorts, respectively. The median exposure to therapy was 84 days (range, 7-286), and 36 pts (80.0%) were still on treatment including one patient at 450mg BID with treatment exposure for 286 days. As of December 15, 2022, ORR was 47.5% (19/40, 95% CI: 31.5%-63.9%) and disease control rate (DCR) was 85.0% (95% CI: 70.2%-94.3%) for the efficacy-evaluable pts across all dose levels. The median duration of response (DOR) was not reached. For 32 efficacy-evaluable patients at 600mg BID, ORR and DCR were 43.8% (14/32) and 87.5%, respectively. Treatment-related adverse events (TRAEs) occurred in 40 (88.9%) pts, with the most common being anaemia, white blood cell count decreased, alanine aminotransferase increased, and pruritus. Grade ≥ 3 TRAEs occurred in 9 (20.0%) pts. No drug-related adverse events leading to treatment discontinuation or death occurred. Conclusions: IBI351 (GFH925) monotherapy demonstrated promising anti-tumor activity with manageable safety profile in metastatic CRC patients harboring KRAS G12C mutation. These two studies are still ongoing and longer follow-up will provide more solid evidence. Updated data will be presented at the meeting. Clinical trial information: NCT05005234 , NCT05497336 .