Abstract
Zabilugene almadenorepvec (VCN-01) is a hyaluronidase-expressing oncolytic adenovirus with a favorable safety profile and encouraging antitumor activity in patients with pancreatic ductal adenocarcinoma. This randomized phase 2b trial evaluated the efficacy and safety of two doses of intravenous VCN-01 with gemcitabine and nab-paclitaxel (GnP) versus GnP alone as first-line therapy in metastatic pancreatic ductal adenocarcinoma. The primary endpoints were overall survival (OS) in the intent-to-treat and full analysis set (FAS) populations, and safety and tolerability in the safety population. In the intent-to-treat population (VCN-01 + GnP, n = 53; GnP, n = 48), median OS in the VCN-01 + GnP versus GnP group was 10.6 versus 8.6 months (hazard ratio (HR) = 0.69 (95% confidence interval (CI) 0.42-1.12), P = 0.196) and progression-free survival was 5.6 versus 4.6 months (HR = 0.63 (95% CI 0.4-1.00), P = 0.046). In the FAS population (n = 48 per group), median OS was 10.8 months in the VCN-01 + GnP group versus 8.6 months in the GnP group (HR = 0.57 (95% CI 0.34-0.96), P = 0.055) and progression-free survival was 7.0 versus 4.6 months (HR = 0.55 (95% CI, 0.34-0.88), P = 0.011). The primary efficacy endpoint of OS was met in the FAS population. Duration of response was 11.2 versus 5.4 months (HR = 0.22 (95% CI 0.08-0.63), P = 0.004). No statistically significant differences were observed in overall response rate, disease control rate or carbohydrate antigen 19-9 levels between treatment groups. In addition, survival rates in the VCN-01 + GnP group versus the GnP group were 35.5% versus 12.8% at 15 months, and 31.1% versus 8.5% at 18 months. Patients receiving two VCN-01 doses 14 weeks apart showed greater survival benefit, with sustained circulating viral genomes indicating ongoing viral replication and preserved second-dose bioactivity despite persistent neutralizing antibodies. More frequent VCN-01-related events included pyrexia, flu-like symptoms, elevation in liver enzymes and decreases in platelet counts, with serious events occurring in 22.6% of patients. Milder toxicity was observed after the second administration. Two fatal events occurred, one in each treatment group; neither was considered related to study treatment. These results further support VCN-01 combined with GnP as a first-line therapy for metastatic pancreatic ductal adenocarcinoma and warrant evaluation in a blinded phase 3 trial. ClinicalTrials.gov identifier: NCT05673811 .