Durvalumab plus HAIC-FOLFOX followed by maintenance durvalumab for hepatocellular carcinoma with major portal invasion: phase 2 DurHope study.

Hepatocellular carcinoma (HCC) patients with Vp4 portal vein tumor thrombus (PVTT) have a poor prognosis and are underrepresented in global clinical trials. We conducted a single-arm phase 2 study (DurHope) enrolling 30 patients with Vp3/4 PVTT receiving durvalumab plus hepatic arterial infusion therapy (HAIC) of FOLFOX regimen (fluorouracil, leucovorin, and oxaliplatin) as first-line treatment. Primary endpoint was 1-year overall survival (OS) rate, and secondary endpoints included progression-free survival, objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1, and safety. The pre-specified study endpoints were achieved, the 1-year OS rate was 63.3%, with a median OS of 13.9 months (95% CI, 10.7-not reached [NR]) at the final analysis. In exploratory, post hoc biomolecular analyses, tumor single-nucleus RNA sequencing revealed chemotherapy resistance and immune escape signatures in nonresponders, including a MECOM+ malignant subcluster. Responders showed increased immune infiltration and stronger immune-tumor interactions. Peripheral blood dynamic single-cell RNA sequencing demonstrated expanded T-cell subsets and increased expression of cytotoxic-related genes after treatment, which was more pronounced in responders. This was accompanied by decreased nonclassical monocyte frequency and attenuated anti-inflammatory phenotype in responders. Findings were validated by immunohistochemistry and in vivo models. These data suggested the promising efficacy and generally tolerable toxicity of Durvalumab plus HAIC-FOLFOX in patients with Vp4 PVTT and provided candidate biomarkers. ClinicalTrials.gov number: NCT04945720.