Oral KRAS G12D inhibitor GFH375 for previously treated advanced solid tumors with KRAS^G12D mutations: a phase 1 trial

Kirsten rat sarcoma viral oncogene homolog (KRAS)^G12D is the most prevalent RAS mutation in solid tumors, associated with poor prognosis, and occurs mainly in pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC) and non-small cell lung cancer (NSCLC). Here we evaluated GFH375, a compound that targets both 'ON' (GTP-bound) and 'OFF' (GDP-bound) states of KRAS^G12D proteins, in a phase 1 dose-escalation trial in patients with advanced solid tumors harboring the KRAS^G12D mutation. The primary endpoints were safety/tolerability, the maximum tolerated dose and recommended phase 2 dose. The secondary endpoints included pharmacokinetics, objective response rate (ORR), duration of response, disease control rate, time to response, progression-free survival (PFS) and overall survival (OS). A total of 74 heavily treated patients with KRAS^G12D-mutant advanced solid tumors were administered orally with GFH375 once or twice daily, including 43 patients with PDAC, 16 with NSCLC and 10 with CRC. Overall, GFH375 was well tolerated and no dose-limiting toxicity was observed among the 22 patients in the dose-escalation part; the maximum tolerated dose was not reached. The recommended phase 2 dose of GFH375 was declared as 600 mg once daily. One (1.4%) grade 5 treatment-related adverse event was reported as septic shock. Grade ≥3 treatment-related adverse events occurred in 36.5% (27/74) of the patients and were more prevalent in patients previously treated with immune checkpoint inhibitors. In patients with PDAC, the confirmed ORR was 35.1% (13/37), with a median duration of response of 5.6 months; the median PFS and median OS were 5.5 months and 9.9 months, respectively. In patients with NSCLC, the confirmed ORR was 35.7% (5/14); the median PFS and median OS were 5.5 months and 13.4 months, respectively. This trial demonstrated the manageable safety/tolerability and encouraging antitumor activity of GFH375 monotherapy. The phase 2 portion of this trial with expansion cohorts for NSCLC, PDAC, CRC and other solid tumors is ongoing. ClinicalTrials.gov identifier: NCT06500676 .