Kirsten rat sarcoma viral oncogene homolog (KRAS) G12D is reported as the most prevalent RAS mutation across solid tumors and is associated with poor prognosis. It occurs most commonly in pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC) and non‑small‑cell lung cancer (NSCLC). GFH375 is an orally administered small molecule that the authors describe as capable of binding both the active (GTP‑bound, ‘ON’) and inactive (GDP‑bound, ‘OFF’) conformations of KRAS G12D protein. This first‑in‑human phase 1 study evaluated GFH375 in patients with advanced solid tumors that harbor the KRAS G12D mutation.
This phase 1, dose‑escalation trial enrolled patients with advanced, previously treated solid tumors carrying the KRAS G12D mutation. The primary objectives were safety and tolerability, determination of the maximum tolerated dose (MTD) and recommendation of the phase 2 dose (RP2D). Secondary objectives included pharmacokinetics and antitumor activity measures: objective response rate (ORR), duration of response, disease control rate, time to response, progression‑free survival (PFS) and overall survival (OS). The trial is registered as ClinicalTrials.gov identifier NCT06500676.
A total of 74 heavily pretreated patients received oral GFH375 administered once or twice daily. Tumor histologies included 43 patients with PDAC, 16 with NSCLC and 10 with CRC; other solid tumors were also represented. The dose‑escalation portion included 22 patients. Dose schedules and individual cohort dosing details are reported in the full article; the summary reports the eventual recommended phase 2 dose as 600 mg once daily.
In the 22 patients evaluated during dose escalation there were no dose‑limiting toxicities (DLTs) observed and the MTD was not reached. The trial team declared the RP2D of GFH375 to be 600 mg once daily.
Overall, GFH375 was described as well tolerated in this heavily pretreated population. A single treatment‑related grade 5 adverse event (septic shock) was reported. Grade ≥3 treatment‑related adverse events occurred in 36.5% (27 of 74) of patients. The report notes that higher rates of grade ≥3 treatment‑related events were observed among patients who had previously received immune checkpoint inhibitors. Detailed adverse event tables and attribution are provided in the full manuscript.
Antitumor activity was observed across tumor types. In the PDAC cohort, the confirmed ORR was 35.1% (13 of 37 evaluable patients). The median duration of response in PDAC was 5.6 months. Median PFS and median OS in the PDAC group were reported as 5.5 months and 9.9 months, respectively.
In the NSCLC cohort the confirmed ORR was 35.7% (5 of 14 evaluable patients). Median PFS and OS for NSCLC were both reported: PFS 5.5 months and OS 13.4 months.
The manuscript includes efficacy summaries and waterfall/Swimmer plots for PDAC, NSCLC and other tumor types (figures are provided in the article). The CRC cohort and other tumor groups are included in the trial; specific confirmed response rates and survival outcomes for CRC beyond cohort counts are summarized in the full text and figures.
Pharmacokinetic analyses were predefined secondary endpoints. The article reports that pharmacokinetic data were collected; specific concentration‑time parameters and exposure–response details are available in the full manuscript. Circulating tumor DNA (ctDNA) analyses and co‑occurring genomic alterations at baseline were assessed and are presented in figure form to illustrate relationships between baseline co‑mutations and clinical response. The public summary indicates these biomarker data were analyzed but does not provide exhaustive lists of co‑mutations or subgroup biomarker outcomes in the preview.
The authors report that the phase 2 portion of the trial is ongoing, with expansion cohorts planned for NSCLC, PDAC, CRC and other solid tumors. Data availability is constrained by intellectual‑property and confidentiality obligations: individual deidentified participant data may become available after completion of the first‑in‑human trial and finalization of the clinical study report. Requests must be directed to the corresponding author and require review and a signed data access agreement with the sponsor.
The molecular structure of GFH375 is referenced and linked to a patent filing (WO2024061370) with supplementary material available alongside the published article. Figures in the article include patient disposition, antitumor activity plots for PDAC/NSCLC/other tumors, and ctDNA co‑alteration heat maps.
Summary
In this phase 1 study of orally administered GFH375 in patients with KRAS G12D–mutant advanced solid tumors, the agent reached an RP2D of 600 mg once daily after a dose‑escalation phase with no observed DLTs and without reaching an MTD. Safety was described as manageable in a heavily pretreated population, with 36.5% of patients experiencing grade ≥3 treatment‑related adverse events and one treatment‑related death reported. The trial showed encouraging antitumor activity in PDAC and NSCLC cohorts (confirmed ORRs of 35.1% and 35.7%, respectively), and phase 2 expansion cohorts are underway. For further numeric detail, cohort‑level safety tables, and full pharmacokinetic and biomarker results, refer to the complete article and supplementary materials.