GFH375 in Patients with Previously Treated Non-Small Cell Lung Cancer and KRASG12D Mutations: A First-in-Human Study

KRAS ^G12D mutations occur in approximately 2–4% of patients with non-small cell lung cancer (NSCLC). GFH375, a compound that targets both “ON” (GTP-bound) and “OFF” (GDP-bound) states of the KRAS ^G12D proteins, was evaluated in a phase 1/2 study among patients with advanced solid tumors harboring KRAS ^G12D mutations. The objectives were to evaluate safety and tolerability, characterize pharmacokinetics, and evaluate preliminary efficacy. A total of 86 patients with KRAS ^G12D -mutant advanced solid tumors, including 28 with advanced NSCLC, were treated with the single agent GFH375 administered orally once or twice daily. Overall, GFH375 was well tolerated and had a manageable safety profile. Treatment-related adverse events occurred in 97.7% of the patients: 37.2% experienced grade ≥3 adverse events, and 1 patient (1.2%) experienced a grade 5 adverse event. Encouraging antitumor activity was demonstrated in patients with previously treated NSCLC, with objective response rates of 57.7% (90% CI: 39.8–74.2) at all dose levels and 68.8% (90% CI: 45.2–86.8) at 600 mg once daily; the 6-month progression-free survival rates were 60.4% (90% CI: 46.2–78.8) and 77.4% (90% CI: 60.6–98.9), respectively. Co-occurring alterations were analyzed with circulating tumor DNA (ctDNA) collected at baseline and at the end of treatment. The study is ongoing (ClinicalTrials.gov identifier: NCT06500676).