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.

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 adverse event. Eight pts (25%) had treatment interruptions, and 2 (6.3%) discontinued treatment due to treatment emergent adverse events (TEAEs). No dose reduction occurred. The most common TRAEs were gastrointestinal events including diarrhea (71.9%), vomiting (71.9%) and nausea (62.5%); all were grade 1 or 2. Anti-tumor activities were observed starting from 100 mg QD. Among 22 pts who had at least one post-treatment tumor assessment, objective response rate (ORR) was 27.3% (6/22), and disease control rate (DCR) was 86.4% (19/22). Nine out of 13 pts with stable disease (SD) had tumor shrinkage. Among the 7 pts with PDAC, all exhibited tumor shrinkage with 3 partial response (PR) and 4 SD. Among the 9 pts with NSCLC, 3 achieved PR, 5 SD, and 1 progression disease (PD). GFH375 demonstrated good oral bioavailability with a T max of 2~4 h and a terminal half-life of 18.5-21.6 h. Conclusions: According to the preliminary data from ongoing FIH study, GFH375 monotherapy has demonstrated good tolerability and promising anti-tumor activities in pts with advanced solid tumor supporting further clinical development. Clinical trial information: NCT06500676 .