First-line durvalumab with arterial chemotherapy in major portal invaded hepatocellular carcinoma: The phase 2 DurHope study with biomolecular analyses.

Abstract

e16232 Background: Hepatocellular carcinoma (HCC) patients with Vp4 portal vein tumor thrombus (PVTT) have a poor prognosis and are underrepresented in global clinical trials. Previous FOHAIC-1 study indicated the favorable efficacy of arterial FOLFOX chemotherapy (fluorouracil, leucovorin, and oxaliplatin) in this population. Methods: The biomolecular exploratory, phase 2 DurHope study trial investigated durvalumab combined with arterial FOLFOX as first-line treatment in 30 pts with major PVTT (Vp4: n = 24, 80.0%; Vp3: n = 6, 20.0%). Arterial FOLFOX was given on day 1–3, plus durvalumab (1120 mg) intravenously on day 7 (± 2) of each 21-day cycle up to 8 cycles. Maintenance durvalumab (1500 mg) was administered every 28 days thereafter until disease progression, unacceptable toxicity, or death. Primary endpoint was 1-year OS rate. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR) per RECIST v1.1, and safety. Single-cell RNA sequencing (scRNA-seq) was performed on pre-treatment biopsies and peripheral blood mononuclear cells (PBMCs) collected at baseline and during treatment from responders (CR/PR) and nonresponders (SD/PD). Results: With a median follow-up of 21.6 months, the 1-year OS rate was 63.3%, median OS was 13.9 months (95% CI, 10.7–NR), and median PFS was 9.0 months (95% CI, 4.5–12.2). ORR was 53.3% (CR: 5/30 [16.7%]; PR: 11/30 [36.7%]), and median duration of response was 9.1 months (> 6 months: 11/16 [68.8%]; > 12 months: 4/16 [25%]). Grade ≥ 3 TRAEs occurred in 43.3% of patients, with no unexpected safety events beyond those of each agent. ScRNA-seq of biopsies revealed enrichment of chemotherapy resistance and immune escape signatures, and a subcluster of MECOM+ malignant cells associated with reduced clinical benefits in non-responders. In contrast, responders exhibited higher immune cell infiltration and stronger immune-malignant cell interaction. Dynamic scRNA-seq of serial PBMCs demonstrated expanded T cell subsets and increased expression of cytotoxicity-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. These genomic findings were further validated by in situ immunohistochemistry analysis and in vivo mouse models. Conclusions: Durvalumab plus arterial FOLFOX showed promising efficacy and manageable toxicities in advanced HCC with Vp4 PVTT. Biomolecular exploratory analyses revealed enhanced cellular immune responses triggered by treatment, along with novel molecular biomarkers that may help predict therapeutic response. Clinical trial information: NCT04945720 .