Phase I study of IBI351 (GFH925) monotherapy in patients with advanced solid tumors: Updated results of the phase I study

Abstract Background: IBI351 (GFH925) is an irreversibly covalent inhibitor of KRASG12C. Data from prior data cutoffs (primary: Feb, 2022; initial update: July, 2022) showed that IBI351 (GFH925) was well-tolerated and demonstrated promising efficacy in patients (pts) with advanced solid tumors harboring KRAS p.G12C mutation. Here, we update results of this phase I study evaluating IBI351 (GFH925) in pts with advanced solid tumors again. Methods: Pts with locally advanced, recurrent or metastatic solid tumors with KRASG12C mutation for whom standard therapy had failed were enrolled. Phase I dose escalation had an accelerated titration design for dose level 250mg once daily (QD) and a Bayesian optimal interval (BOIN) design with 450-900mg QD and 450-750mg twice daily (BID). The primary endpoints were safety and tolerability. The secondary endpoints were pharmacokinetics (PK), anti-tumor activity of IBI351 (GFH925) monotherapy per RECIST v1.1, and overall survival. Results: As of November 30th, 2022, 74 pts (1 at 250mg QD, 3 at 450mg QD, 9 at 700mg QD, 5 at 900mg QD, 21 at 450mg BID, 31 at 600mg BID and 4 at 750mg BID; 62 men, 12 women; median age: 64 yrs, range: 42-76 yrs) were enrolled, among whom 67 pts had non-small cell lung cancer (NSCLC). Among 67 NSCLC pts, 44.8% pts received ≥2 prior lines of treatment (tx), 38.8% pts had brain metastases; adenocarcinoma was the most common histology (n=66, 98.5%). All 74 pts were included for safety analysis. No dose-limiting toxicity (DLT) were observed in any dose cohorts. The overall safety profile was consistent with the latest previous report, with no new safety signals identified. As of December 15th, 2022, among 67 response-evaluable NSCLC pts across all dose levels, the ORR (by investigator assessment) was 58.2% (95% CI, 45.5-70.2), and the confirmed ORR was 44.8% (95% CI, 32.6-57.4); the disease control rate (DCR) was 92.5% (95% CI, 83.4-97.5). At the 600mg BID dose level (RP2D), the ORR was 63.3% (95% CI, 43.9-80.1), and the confirmed ORR was 50.0% (95% CI, 31.3-68.7), the DCR was 96.7% (95% CI, 82.8-99.9). With a median progression-free survival (PFS) follow-up of 5.5 months (95% CI, 5.3-6.8) for NSCLC pts at the 600mg BID dose level, 21 (70%) pts were continuing treatments, and the median duration of response (DoR) and PFS were not reached. Thirteen out of 15 confirmed responders were still in response. Conclusion: IBI351 (GFH925) was well-tolerated across all doses explored in patients with advanced solid tumors harboring KRAS p.G12C mutation. The data also demonstrated promising efficacy and durable response of IBI351 (GFH925) in previously treated advanced NSCLC. Clinical trial information: NCT05005234. Citation Format: Qing Zhou, Nong Yang, Jun Zhao, Mingfang Zhao, Yan Yu, Ying Yuan, Huijuan Wang, Xingya Li, Xiaorong Dong, Longhua Sun, Tongmei Zhang, Dingzhi Huang, Qian Chu, Jingjing Huang, Sujie Zhang, Mengna Huang, Yuping Shen, Yi-Long Wu. Phase I study of IBI351 (GFH925) monotherapy in patients with advanced solid tumors: Updated results of the phase I study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT030.