A first-in-human phase I/II study of GFH375, a highly selective and potent oral KRAS G12D inhibitor in patients with KRAS G12D mutant advanced solid tumors.

作者：Xinghao Ai, Aiping Zhou, Lin Wu, Zhengbo Song, Zhi-Hua Li, Heshui Wu, Ying Yuan, Hong Zong, Lingjun Zhu, Haitao Zhao, Yuping Sun, Zuoxing Niu, Yu Wang, Haige Shen, Huaqiang Zhu, Chanli Zheng, Shuang Wang, Congqiao Zhao, Cui Zhao, Shun Lu · 发表于：Journal of Clinical Oncology · 年份：2025 · DOI：10.1200/jco.2025.43.16_suppl.3013 · 被引用次数：14 · 研究领域：Protein Kinase Regulation and GTPase Signaling、Cancer, Hypoxia, and Metabolism、bioluminescence and chemiluminescence research

3013 Background: Kirsten rat sarcoma (KRAS) G12D is one of the most prevalent RAS mutations in human cancers and suggests poor survival. GFH375 is an orally bioavailable, highly selective and potent KRAS G12D inhibitor targeting both “ON” (GTP-bound) and “OFF” (GDP-bound) states. Here we report the preliminary results of GFH375 in patients (pts) with advanced KRAS G12D mutant solid tumors. Methods: This is a Phase I/II study (NCT06500676) evaluating the safety, tolerability, pharmacokinetics and efficacy of GFH375 in pts with advanced solid tumors harboring KRAS G12D mutation. Pts with locally advanced or metastatic solid tumor failed to prior standard therapies are eligible for enrollment. Accelerated titration, plus Bayesian Optimal Interval (BOIN) and back filling design are employed in the phase I part with safety and tolerability as the primary objective, and pharmacokinetics and anti-tumor activity as the secondary objectives. Results: As of 03Jan2025, thirty-two pts were treated, including 11 pancreatic ductal adenocarcinoma (PDAC), 11 non-small cell lung cancer (NSCLC), 5 colorectal cancer (CRC) and 5 others (median age: 59.5 yrs; 62.5% female). No dose-limiting toxicities (DLTs) were observed at the tested dose levels of 100 mg, 200 mg, 400 mg, 600 mg, 750 mg, 900 mg once daily (QD) and 300 mg twice daily (BID). Eight pts (25%) experienced at least one G3/G4 treatment related adverse event (TRAE) and no G5 TRAEs. Five pts (15.6%) experienced at least one serious adve...