Nature Medicine September 30, 2026

Intravenous hyaluronidase-expressing oncolytic adenovirus with chemotherapy in metastatic pancreatic cancer: a randomized phase 2b trial

Rocio Garcia-Carbonero, Roberto Pazo Cid, Teresa Macarulla, et al.

Bottom Line

In a randomized phase 2b trial, the addition of the hyaluronidase-expressing oncolytic adenovirus VCN-01 to first-line gemcitabine and nab-paclitaxel improved progression-free survival and duration of response, showing a favorable overall survival trend in patients with metastatic pancreatic ductal adenocarcinoma.

Key Findings

1. In the intent-to-treat (ITT) population, median overall survival was 10.6 months for VCN-01 plus gemcitabine/nab-paclitaxel (GnP) versus 8.6 months for GnP alone (HR = 0.69; 95% CI 0.42-1.12; P = 0.196).

2. In the full analysis set (FAS; n=48 per group), the primary efficacy endpoint of overall survival was met, reaching 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).

3. Progression-free survival in the FAS population was significantly prolonged at 7.0 months for the VCN-01 combination compared to 4.6 months for GnP alone (HR = 0.55; 95% CI 0.34-0.88; P = 0.011).

4. The combination more than doubled the duration of response, achieving 11.2 months versus 5.4 months with chemotherapy alone (HR = 0.22; 95% CI 0.08-0.63; P = 0.004).

5. Long-term survival rates were markedly improved with the VCN-01 regimen: 35.5% versus 12.8% at 15 months, and 31.1% versus 8.5% at 18 months.

6. No statistically significant differences were observed between the treatment arms regarding overall response rate, disease control rate, or CA19-9 biomarker levels.

7. VCN-01 was associated with pyrexia, flu-like symptoms, liver enzyme elevations, and platelet decreases, with serious adverse events reported in 22.6% of patients.

Study Design

Design

Phase 2b RCT

Open-Label

Sample

101

Patients

Duration

18 mo

Median

Setting

Multicenter

Population Patients with treatment-naive metastatic pancreatic ductal adenocarcinoma

Intervention Intravenous VCN-01 (zabilugene almadenorepvec) administered with gemcitabine and nab-paclitaxel (GnP)

Comparator Gemcitabine and nab-paclitaxel (GnP) alone

Outcome Overall survival (OS) in the intent-to-treat and full analysis set populations, and safety/tolerability

Study Limitations

• The relatively small sample size of this phase 2b trial (N=101 in the ITT population) limited the statistical power to achieve significance for overall survival in the unselected intent-to-treat cohort.

• The open-label design of the study may introduce reporting bias for subjective safety metrics and investigator-assessed progression-free survival.

• There was a notable rate of serious adverse events (22.6%), which requires careful patient monitoring and toxicity management in broader clinical application.

• Despite survival advantages, the addition of VCN-01 did not significantly improve early anatomical response metrics, such as overall response rate or disease control rate.

Clinical Significance

The dense desmoplastic stroma characteristic of pancreatic cancer acts as a severe barrier to conventional chemotherapeutics. By employing a locally replicating adenovirus that produces hyaluronidase, this regimen effectively remodels the tumor microenvironment, substantially prolonging the duration of response and progression-free survival. The promising survival benchmarks observed—particularly the extended tails on the survival curve at 15 and 18 months—provide a strong rationale for advancing VCN-01 to blinded phase 3 evaluation as a potential new cornerstone in first-line metastatic pancreatic cancer treatment.

Historical Context

Metastatic pancreatic ductal adenocarcinoma (PDAC) has historically had a dismal prognosis with very limited treatment advances over the past decade. A major driver of chemoresistance is the robust, hyaluronan-rich fibrotic stroma that generates high interstitial pressures, suffocating vascular perfusion and blocking drug delivery. Previous attempts to systemically degrade hyaluronan using pegvorhyaluronidase alfa (PEGPH20) in the HALO-109-301 trial unfortunately failed to improve survival and caused systemic toxicities. Zabilugene almadenorepvec (VCN-01) represents a novel paradigm: employing an oncolytic adenovirus that restricts hyaluronidase production to the site of viral replication within the tumor. This phase 2b trial (VIRAGE) sought to determine if localized, viral-mediated stromal degradation could safely enhance the efficacy of standard gemcitabine and nab-paclitaxel.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Why is the tumor microenvironment in pancreatic ductal adenocarcinoma particularly resistant to standard systemic therapies, and how does the addition of a hyaluronidase-expressing oncolytic virus theoretically overcome this barrier?

Key Response

PDAC is characterized by an intense desmoplastic stroma rich in hyaluronic acid, which increases interstitial fluid pressure and collapses tumor vasculature, thereby preventing chemotherapy penetration. The oncolytic adenovirus VCN-01 expresses hyaluronidase to degrade this stroma, facilitating better delivery of gemcitabine and nab-paclitaxel into the tumor bed while simultaneously causing direct viral oncolysis.

Resident

Given the use of gemcitabine and nab-paclitaxel as the backbone in this trial, which patient populations with newly diagnosed metastatic pancreatic cancer are best suited for this regimen compared to FOLFIRINOX, and how might the addition of VCN-01 alter this selection?

Key Response

FOLFIRINOX is typically reserved for younger patients with excellent performance status (ECOG 0-1) due to its toxicity profile, while Gemcitabine/Nab-Paclitaxel is often utilized for patients who are slightly older or have an ECOG of 1-2. If VCN-01 significantly improves the efficacy of the Gem/Nab-Paclitaxel regimen without adding severe systemic toxicity, it could challenge FOLFIRINOX as the preferred first-line regimen even in highly fit patients.

Fellow

Oncolytic adenoviruses delivered intravenously face rapid clearance by neutralizing antibodies and hepatic sequestration. How might the timing of VCN-01 administration relative to cytotoxic chemotherapy influence both viral tumor tropism and the subsequent anti-tumor immune response?

Key Response

Chemotherapy can induce transient lymphodepletion, potentially mitigating the early clearance of the virus by neutralizing antibodies if sequenced correctly. Furthermore, virus-induced lysis and stroma degradation can unmask neoantigens, synergizing with chemotherapy-induced immunogenic cell death, but precise sequencing is critical to avoid chemotherapy blunting the initial viral replication phase.

Attending

Previous phase 3 trials in pancreatic cancer evaluating systemic stromal modifiers (like pegvorhyaluronidase alfa) failed to show overall survival benefits despite early PFS signals, largely due to systemic toxicity. What unique mechanistic features of VCN-01 provide optimism that this overall survival trend will hold without mirroring past failures?

Key Response

Past failures with systemic PEGPH20 were partly due to non-specific systemic toxicity, such as severe thromboembolic events, and lack of tumor specificity. VCN-01 is an oncolytic virus that selectively replicates within tumor cells with defective RB pathways, providing localized, tumor-specific hyaluronidase expression and concurrent viral-mediated oncolysis, which theoretically avoids the systemic toxicity of widespread stromal degradation.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The trial relies on clinical endpoints like PFS and OS, but how should future translational studies mechanistically validate the in vivo efficacy of VCN-01 in human subjects, specifically regarding stromal remodeling and viral replication kinetics?

Key Response

To definitively prove the mechanism of action, studies must incorporate paired pre- and post-treatment core biopsies to quantify hyaluronic acid degradation via histochemistry, assess CD8+ T-cell infiltration, and measure viral DNA/RNA via ddPCR or single-cell RNA-seq within the tumor versus adjacent normal tissue, thereby validating the pharmacodynamic action of the localized hyaluronidase payload.

Journal Editor

In assessing the validity of a randomized phase 2b trial involving an intravenous oncolytic virus, how does the potential lack of effective blinding (due to expected viral-mediated adverse events like pyrexia) bias the investigator-assessed progression-free survival, and how should this be mitigated?

Key Response

Viral therapies often cause distinct adverse events such as flu-like symptoms and infusion reactions that can easily unblind both the patient and the treating investigator. If the primary endpoint of PFS is investigator-assessed, this unblinding introduces significant assessment bias. A rigorous review would demand Blinded Independent Central Review (BICR) of all imaging to ensure the PFS benefit is methodologically robust.

Guideline Committee

Currently, NCCN guidelines recommend gemcitabine plus nab-paclitaxel as a Category 1 option for first-line metastatic PDAC. If a phase 3 trial confirms the PFS and OS benefits of adding VCN-01, what specific criteria regarding biomarker selection (e.g., baseline hyaluronic acid levels) would be required to grant this triplet a Category 1 recommendation over existing standard regimens?

Key Response

Guidelines demand clear indications of which specific patient populations benefit from a new therapy. Because VCN-01 targets hyaluronic acid, the committee would need to evaluate whether the benefit is restricted to patients with high-hyaluronan tumors. If so, a validated companion diagnostic for HA expression would be required for the Category 1 recommendation, ensuring the regimen is used safely and cost-effectively compared to unselected FOLFIRINOX or standard Gem/Nab-Paclitaxel.

Clinical Landscape

Noteworthy Related Trials

2011

PRODIGE 4/ACCORD 11 Trial

n = 342 · NEJM

Tested

FOLFIRINOX regimen

Population

Patients with metastatic pancreatic cancer

Comparator

Gemcitabine alone

Endpoint

Overall survival

Key result: FOLFIRINOX significantly improved median overall survival to 11.1 months compared to 6.8 months with gemcitabine alone.

2013

MPACT Trial

n = 861 · NEJM

Tested

Nab-paclitaxel plus Gemcitabine

Population

Patients with metastatic pancreatic cancer

Comparator

Gemcitabine alone

Endpoint

Overall survival

Key result: The combination of nab-paclitaxel and gemcitabine significantly improved median overall survival compared to gemcitabine alone (8.5 vs 6.7 months).

2019

HALO 109-301 Trial

n = 492 · J Clin Oncol

Tested

PEGPH20 (pegvorhyaluronidase alfa) plus Nab-paclitaxel and Gemcitabine

Population

Patients with hyaluronan-high metastatic pancreatic cancer

Comparator

Placebo plus Nab-paclitaxel and Gemcitabine

Endpoint

Overall survival

Key result: The addition of systemic PEGPH20 to standard chemotherapy failed to improve overall survival, leading to the halt of its clinical development.

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