Abstract CT246: Open-label, single-arm, multicenter, phase 2 trial of garsorasib in KRAS G12C-mutated non-small-cell lung cancer

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Abstract Background: Garsorasib (D-1553), a potent KRAS G12C inhibitor, has previously demonstrated promising anti-tumor activity in KRAS G12C-mutated non-small-cell lung cancer (NSCLC) in a phase 1 study. Here we present the efficacy and safety of garsorasib in a pivotal phase 2 study. Methods: In this open-label, multicenter, single-arm phase 2 study, patients received garsorasib 600 mg twice daily in 21-day cycles. Eligible criteria included patients with locally advanced or metastatic NSCLC harboring KRAS G12C mutation, who had disease progression after prior anti-PD-(L)1 therapy and platinum-based chemotherapy or intolerance to the above regimens due to toxicity, and had measurable tumor lesions according to the RECIST, v1.1. The primary end point was objective response rate (ORR) evaluated by independent review committee (IRC) per RECIST v1.1. The secondary end points included duration of response (DOR), disease control rate (DCR), time to response (TTR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of November 17, 2023, 123 patients (108 [87.8%] male, median age 64 [range: 33-80], and 11.4%/88.6% ECOG PS 0/1) were enrolled and treated, with a median follow-up of 7.92 months (range, 0.7, 16.5) and a median duration of treatment of 6.24 months (range, 0.7, 15.9). At data cutoff date, 82 patients (66.7%) discontinued treatment, with disease progression (46 patients [37.4%]) being the most common reason. Among 123 patients, IRC confirmed-ORR was 49.6% (61/123, 95% CI, 40.5 to 58.8) and DCR was 88.6% (109/123, 95% CI, 81.6 to 93.6). The median TTR was 1.38 months (range, 1.12 to 5.55). The median DOR was 12.78 months (95% CI, 6.21 to NE). The median PFS was 7.56 months (95% CI, 5.55 to 9.69), and the median OS was not reached. A total of 117 (95.1%) patients reported treatment-related adverse events (TRAEs) with 61 (49.6%) patients experiencing grade 3 or higher events. The most commonly reported (≥25%) TRAEs (any grade) were increased AST, ALT and γ-GGT, anemia, increased blood bilirubin, and increased blood ALP. No new safety signals were identified, and most of the adverse events were well managed. No TRAE resulted in permanent discontinuation of garsorasib. Conclusions: Garsorasib has shown a high tumor response rate and long response duration in patients with KRAS G12C mutated NSCLC that have progressed after prior anti-PD-(L)1 therapy and platinum-based chemotherapy. Its safety profile was also shown to be well-tolerated and manageable. Garsorasib could be considered as a promising treatment option for KRAS G12C-mutant NSCLC patients with a high unmet medical need. Citation Format: Ziming Li, Xiaomin Dang, Dingzhi Huang, Shi Jin, Weiwei Li, Jianhua Shi, Xicheng Wang, Yiping Zhang, Zhengbo Song, Junping Zhang, Wu Zhuang, Xuewen Liu, Liyan Jiang, Xiangjiao Meng, Mingfang Zhao, Jianying Zhou, Liangming Zhang, Pingli Wang, Hui Luo, Junquan Yang, Shundong Cang, Xiang Wang, Jing Wang, Jiuwei Cui, Yan Yu, Zhihong Zhang, Junguo Lu, Weihua Yang, Gaofeng Li, Jifeng Feng, Dongqing Lv, Lin Wu, Yong Fang, Yan Wang, Yanqiu Zhao, Baoshan Cao, Wei Zhu, Zhixiang Zhuang, Qingshan Li, Mingxi Wang, Huan Zhou, Xiaorong Dong, Sheng Hu, Jian Fang, Yihong Zhang, Wenjia Wang, Ziyong Xiang, Zhe Shi, Ling Zhang, Shun Lu. Open-label, single-arm, multicenter, phase 2 trial of garsorasib in KRAS G12C-mutated non-small-cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT246.

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