VB-111 (ofranergene obadenovec) in combination with nivolumab in patients with microsatellite stable colorectal liver metastases: a single center, single arm, phase II trial.

ABSTRACT

BACKGROUND: Microsatellite stable colorectal liver metastases (MSS CLM) maintain an immunosuppressive tumor microenvironment (TME). Historically, immune-based approaches have been ineffective. VB-111 (ofranergene obadenovec) is a genetically-modified adenoviral vector targeting the TME; its unique dual mechanism induces an immune response and disrupts neovascularization. Checkpoint inhibition may synergize the immune response induced by viral-mediated anti-angiogenic gene therapy. We aimed to examine the safety and antitumor activity of VB-111 and nivolumab in patients with refractory MSS CLM and to characterize immunological treatment-response. METHODS: This was a phase II study of adult patients with histologically-confirmed MSS CLM who progressed on prior therapy. A priming dose of VB-111 1×1013 viral particles was given intravenously 2 weeks prior to starting biweekly nivolumab 240 mg and continued every 6 weeks. The combination continued until disease progression or unacceptable toxicity. The primary objectives were overall response rate and safety/tolerability. Secondary objectives included median overall survival and progression-free survival. Correlative studies were performed on paired tumor biopsies and blood. RESULTS: Between August 2020 and December 2021, 14 patients were enrolled with median age 50.5 years (40-75), and 14% were women. Median follow-up was 5.5 months. Of the 10 evaluable patients, the combination of VB-111 and nivolumab failed to demonstrate radiographic responses; at best, 2 patients had stable disease. Median overall survival was 5.5 months (95% CI 2.3 to 10.8), and median progression-free survival was 1.8 months (95% CI 1.4 to 1.9). The most common grade 3-4 treatment-related adverse events were fever/chills, influenza-like symptoms, and lymphopenia. No treatment-related deaths were reported. Qualitative analysis of immunohistochemical staining of paired tumor biopsies did not demonstrate significant immune infiltration after treatment, except for one patient who had exceptional survival (26.0 months). Immune analysis of peripheral blood mononuclear cells showed an increase of PD-1highKi67highCD8+ T cells and HLA-DRhigh T cells after VB-111 priming dose. Plasma cytokines interleukin-10 and tumor necrosis factor-α increased after treatment with both drugs. CONCLUSION: In patients with MSS CLM, VB-111 and nivolumab did not improve overall response rate or survival but were tolerated with minimal toxicities. While challenging to distinguish between antiviral or antitumor, correlative studies demonstrated an immune response with activation and proliferation of CD8+ T cells systemically that was poorly sustained. TRIAL REGISTRATION NUMBER NCT04166383.