Phase I Trial of Intravenous VCN-01 Oncolytic Adenovirus and Durvalumab in Patients with Head and Neck Metastatic Squamous Cell Carcinoma Refractory to Immunotherapy.

PURPOSE: Zabilugene almadenorepvec (VCN-01) is a hyaluronidase-expressing oncolytic adenovirus that increases immune checkpoint antibody tumor uptake in mice. VCN-01 was evaluated with durvalumab in patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) refractory to anti-programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1).

PATIENTS AND

METHODS

Patients received intravenous VCN-01 [3.3E12 viral particles (vp), low dose (LD) or 1.0E13 vp, high dose (HD)] plus durvalumab (1,500 mg/every 4 weeks) concomitantly (VCN-01 + durvalumab on day 1; arm I) or sequentially (VCN-01 on day -14 + durvalumab on day 1; arm II). Six patients were enrolled in arm I LD, 8 in arm II LD, and 6 in arm II HD.

RESULTS

Two dose-limiting toxicities occurred in arm I LD, one in arm II LD, and none in arm II HD. Antitumor responses were observed, with arm II HD displaying the longest overall survival (OS) of 17.3 months (8.1-not estimable [NE]), although not statistically significant. Eleven (61.1%) patients were alive >12 months. VCN-01 was detected in blood and tumors, and hyaluronidase expression was confirmed. Changes in tumor immune markers were identified, including increased PD-L1 expression correlating with OS. Transcriptomic and radiomic analyses showed changes in the extracellular matrix and increased tumor perfusion.

CONCLUSIONS

Sequential VCN-01 plus durvalumab was better tolerated than concomitant treatment. The recommended VCN-01 phase II dose was 1.0E13 vp on the sequential schedule. Encouraging survival was observed in patients after progressing on anti-PD-(L)1 agents. Data support VCN-01 replication associated with increased PD-1, PD-L1, and CD8 tumor expression. Sequential systemic delivery of VCN-01 and anti-PD-L1 therapy may represent an improved treatment for HNSCC.