Multicenter phase 1 trial of GFH375 for previously treated advanced solid tumors with KRAS-G12D mutations

KRAS-G12D is the most prevalent RAS mutation in solid tumors and is associated with poor prognosis. The mutation occurs mainly in pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC). GFH375 is a compound that targets both GTP-bound and GDP-bound states of KRAS-G12D proteins. A multicenter phase 1 dose-escalation trial in China evaluated GFH375 for advanced solid tumors harboring the KRAS-G12D mutation. Primary endpoints were safety/tolerability, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D). A total of 74 heavily pretreated patients were administered oral GFH375 once or twice daily, including 43 PDAC patients, 16 NSCLC patients, and 10 CRC patients. Overall, GFH375 was well tolerated, and no dose-limiting toxicity was observed among the 22 patients in the dose-escalation part, the MTD was not reached, and 600 mg once daily was chosen as RP2D. One (1.4%) grade 5 treatment related adverse event occurred (septic shock). Grade ≥ 3 TRAEs occurred in 36.5% of patients. Among PDAC patients, the confirmed objective response rate was 35.1%, with a median duration of response of 5.6 months, median progression-free survival 5.5 months, and median overall survival 9.9 months. Among NSCLC patients, the confirmed ORR was 35.7%, with median PFS 5.5 months and median OS 13.4 months. The authors conclude that this trial demonstrated manageable safety/tolerability and encouraging antitumor activity of GFH375 monotherapy.