Preliminary efficacy of GFH375 in patients with advanced cholangiocarcinoma or colorectal cancer harboring KRAS G12D mutation.

Abstract

3008 Background: Kirsten rat sarcoma (KRAS) G12D is the most prevalent RAS mutation in human cancers, accounting for 10.6-19.2% and 5.8-10.8% of cases in colorectal cancer (CRC) and cholangiocarcinoma (CCA), respectively. Currently, the later-line therapies for metastatic CCA and CRC remain very limited. The KRAS G12D mutation is associated with poor prognosis and confers resistance to conventional chemotherapy. GFH375, a potent, selective, orally bioavailable KRAS G12D inhibitor, has demonstrated antitumor efficacy in pancreatic cancer and non-small cell lung cancer. Here we report the preliminary efficacy results of GFH375 in patients (pts) with advanced KRAS G12D mutant CCA and CRC. 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 mutations. Pts with locally advanced or metastatic CCA and CRC who had failed prior therapies were also enrolled. Tumor assessments were performed every 6 weeks during the first 48 weeks, and every 12 weeks thereafter. All efficacy endpoints, including objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) were evaluated according to RECIST v1.1. Circulating tumor DNA (ctDNA) samples were collected at baseline and at the end of treatment for exploratory analyses. Results: As of 31 Oct 2025, twenty CCA and 41 CRC pts were treated with GFH375 once daily (400, 600 or 750 mg). Among the CCA pts (median age: 59.5 yrs; 80.0% male), 17 (85.0%) had metastatic disease at baseline, and the median prior lines of therapy were 2 (range: 1-6). ORR was 35.0% (7/20), and DCR was 95.0% (19/20). Nine out of 12 pts with stable disease (SD) had tumor shrinkage. Median PFS was 6.3 months, and median overall survival (OS) was not reached. Among those CRC pts (median age: 56 yrs; 61.0% male), all had metastatic disease at baseline, and the median prior lines of therapy were 3 (range: 1-6). Among 35 pts who had at least one post-treatment tumor assessment, ORR was 11.4% (4/35), and DCR was 77.1% (27/35). Median PFS was 4.1 months and median OS was not reached. Baseline ctDNA results were available in 19 CCA pts and 36 CRC pts. KRAS G12D mutations were detected in 14 (73.7%) CCA pts and 31 (86.1%) CRC pts. The common co-mutated genes (≥15%) in CCA were TP53, BCL2L11 and APC, while in CRC were TP53, APC, RUNX1, SMAD4 and PIK3CA. The safety profile in the 61 pts was similar to that of the whole population as previously reported. The most common treatment-related adverse events (TRAEs) (≥30%) included diarrhea, nausea, vomiting, aspartate aminotransferase increased, anemia and decreased appetite. Conclusions: GFH375 monotherapy has demonstrated promising antitumor activities in heavily treated pts with CCA and CRC. GFH375 monotherapy in CCA and in combination with other anti-tumor therapies for CRC is under development. Clinical trial information: NCT06500676 .