Novel Oncolytic Virus VG161 in Hepatocellular Carcinoma Patients Refractory to Standard Systemic Therapies

Abstract For hepatocellular carcinoma (HCC) patients, treatment options are limited after failing second-line therapy. This phase I, multicenter trial evaluates the safety and antitumor efficacy of VG161 in patients with advanced liver cancer. The study included dose escalation using a ‘3 + 3’ design across five dose levels, followed by a dose expansion phase using Simon’s two-stage design. Forty-four patients received doses with no dose-limiting toxicity observed. Among the 40 HCC patients, 37 were evaluable. The objective response rate (ORR) was 18.92%, and the disease control rate (DCR) was 64.86%. The median progression-free survival (PFS) was 2.9 months, and overall survival (OS) was 12.4 months. Subgroup analysis showed that among 34 patients who had failed second-line treatment, the ORR was 17.65% and the DCR was 64.71%. The median PFS and OS for this group were 2.8 and 9.4 months, respectively. Patients with prior checkpoint inhibitor treatment (PreCPI) longer than 3 months had a median OS of 17.3 months, compared to 7.4 months for those with PreCPI ≤ 3 m (p = 0.04). Additionally, patients receiving systemic therapies after VG161 showed longer survival (p = 0.03). Multiple detection techniques revealed that VG161 reshapes the immune microenvironment of HCC, enhancing tumor sensitivity to systemic treatments. An efficacy prediction model based on differentially expressed genes was established, which successfully predicts prolonged OS in study patients (p < 0.001) but not in public database patients (p = 0.17). Anti-hepatitis B agents were confirmed to not affect the replication and efficacy of VG161. In summary, VG161 demonstrated comparable efficacy to second-line treatments in third-line patients, providing a new option for patients who have failed second-line therapy. It was well-tolerated and showed promising efficacy, extending survival in some subgroups and enhancing post-treatment systemic therapy efficacy, supporting its potential use in combination treatments. ClinicalTrials.gov registration: NCT04806464.