GFH375 Plus Cetuximab vs Investigator's Choice of Treatment in KRAS G12D-Mutant Refractory Metastatic Colorectal Cancer

This is a Phase III trial. All enrolled subjects are patients with metastatic colorectal cancer (mCRC) harboring KRAS G12D mutations who have previously received systemic therapy. The study aims to evaluate and compare the efficacy of GFH375 in combination with cetuximab versus the investigator's choice of treatment in participants with KRAS G12D mutant refractory metastatic colorectal cancer (mCRC).

Inclusion Criteria: * Willing to participate in the study and provide written informed consent * Age ≥18 years at the time of signing informed consent; no sex restriction * Histologically or cytologically confirmed colorectal cancer (CRC) * KRAS G12D mutation confirmed by the central laboratory * Disease progression or intolerance during or after prior systemic anticancer therapy * At least one measurable lesion * Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0-1 * Investigator-assessed life expectancy ≥12 weeks * Adequate function of major organs * In the investigator's judgment, the participant is able to communicate effectively, adhere to the scheduled follow-up visits, and comply with the protocol requirements Exclusion Criteria: * Other malignancy that has progressed or required treatment within 3 years prior to randomization * Known presence of other actionable/targetable driver gene alterations * Leptomeningeal metastases, spinal cord compression, or active/symptomatic brain metastases * Pleural effusion, ascites, or pericardial effusion requiring repeated puncture/drainage (≥2 times/month) or causing significant symptoms within 28 days prior to randomization * Clinically significant severe cardiovascular disease * Stroke, transient ischemic attack (TIA), or other severe cerebrovascular disease within 6 months prior to randomization * High-risk factors for bleeding or perforation * Concurrent interstitial lung disease, radiation pneumonitis, or immune-mediated pneumonitis that is clinically significant and requires treatment * Major acute or chronic infectious disease * Other poorly controlled systemic disease * Prior targeted therapy against KRAS or RAS * History of organ transplantation or planned organ transplantation * Receipt of a live attenuated vaccine within 28 days prior to randomization, or planned vaccination with a live attenuated vaccine during the trial drug treatment period * Pregnant or lactating women * Any other condition that, in the investigator's judgment, makes the participant unsuitable for study participation