The addition of an investigational oncolytic virus to standard chemotherapy demonstrated significant survival improvements in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC), according to results from the phase 2b VIRAGE trial presented at the 2025 ESMO Congress.
The multicenter, open-label, randomized trial evaluated zabilugene almadenorepvec (VCN-01) combined with gemcitabine plus nab-paclitaxel (Abraxane) versus chemotherapy alone in 92 treatment-naive patients with metastatic disease. Results confirmed the trial met its primary endpoints of overall survival and safety, along with secondary endpoints including progression-free survival and response rates.
Substantial Survival Benefits in Subgroup Analysis
A preplanned subgroup analysis of patients who completed four cycles of treatment revealed particularly striking results. Among these patients, those receiving VCN-01 plus standard-of-care experienced a 56% reduction in risk of death compared to chemotherapy alone, with median overall survival reaching 14.8 months (95% CI, 10.6-NE) versus 11.6 months (95% CI, 8.6-12.8) in the control arm (HR, 0.44; 95% CI, 0.21-0.92; P = .046).
"Survival benefit was greater among patients who received two VCN-01 doses and with longer follow-up," explained lead investigator Rocio Garcia-Carbonero, MD, head of the GI and NET oncology unit at Hospital Universitario 12 de Octubre in Madrid, Spain. "These encouraging data support further evaluation of this combination in a larger, blinded, randomized trial with additional VCN-01 doses."
The subgroup analysis also demonstrated a 52% reduction in risk of disease progression or death, with median progression-free survival of 11.2 months (95% CI, 7.3-16.6) in the VCN-01 arm versus 7.4 months (95% CI, 5.7-8.4) with chemotherapy alone (HR, 0.48; 95% CI, 0.25-0.91; P = .017).
Broader Population Results
In the modified intent-to-treat population, median overall survival was 10.6 months (95% CI, 6.6-14.8) versus 8.6 months (95% CI, 6.9-11.6) in the VCN-01 and standard-of-care arms, respectively (HR, 0.69; 95% CI, 0.42-1.12; P = .196). The full analysis set yielded similar results with median overall survival of 10.8 months (95% CI, 7.4-15.8) versus 8.6 months (95% CI, 6.9-11.6) (HR, 0.5; 95% CI, 0.34-0.96; P = .055).
Duration of response showed marked improvement with VCN-01 treatment, reaching a median of 11.2 months (95% CI, 7.4-NE) compared to 5.4 months (95% CI, 2.06-6.8) in the control arm (HR, 0.22; 95% CI, 0.08-0.62; P = .0035).
Overall response rates were 39.6% in the VCN-01 arm, including one complete response and 18 partial responses, versus 31.3% in the chemotherapy-alone arm with no complete responses and 15 partial responses (P = .314). Disease control rates were 77.1% and 70.8% for the experimental and control arms, respectively.
Mechanism of Action and Bioactivity
VCN-01 is an oncolytic adenovirus engineered to replicate selectively in cancer cells with dysfunctional RB1 pathways. The virus expresses hyaluronidase (PH2), which degrades tumor stroma to enhance chemotherapy penetration and stimulate anticancer immune responses. The systemic treatment targets both primary tumors and metastases while avoiding liver toxicity.
Biological data confirmed sustained viral activity throughout treatment. "Sustained VCN-01 genome levels indicated persistent replication and confirmed the bioactivity of the second dose despite the presence of neutralizing antibodies," Garcia-Carbonero reported.
Safety Profile
The combination demonstrated a manageable safety profile with all 13 serious treatment-related adverse events resolving completely. The most common grade 3 or higher treatment-related adverse events were transaminase increase (15.1%), flu-like symptoms (13.2%), and drug-induced liver injury (3.8%).
Notably, adverse events decreased with the second VCN-01 dose, with only one patient experiencing grade 3 or higher toxicity (asthenia/fatigue) compared to 27 patients after the first dose. Two patient deaths from treatment-emergent adverse events occurred, but neither was attributed to VCN-01 or standard chemotherapy.
The VCN-01 arm showed higher rates of grade 3 or higher neutropenia (33.9% versus 14.6%), increased transaminase levels (20.8% versus 10.4%), and elevated GGT (7.5% versus 0%) compared to chemotherapy alone.
Trial Design and Patient Population
The VIRAGE trial randomized 92 patients 1:1 to receive either standard-of-care chemotherapy (125 mg/m² IV gemcitabine plus 1000 mg/m² IV nab-paclitaxel on days 1, 8, and 15 of 28-day cycles) or the same regimen plus two doses of IV VCN-01 (1×10¹³ viral particles) administered one week before cycles 1 and 4.
Eligible patients had histologically or cytologically confirmed newly diagnosed metastatic pancreatic ductal adenocarcinoma with no prior systemic therapy and ECOG performance status of 0 or 1. Stratification factors included geographical region (US versus EU) and ECOG status. Overall survival analysis was conducted after 57 deaths.
