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: VCN-01 is a hyaluronidase-expressing oncolytic adenovirus that increases immune checkpoint antibody tumor uptake in mice. VCN-01 was evaluated with durvalumab in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) patients refractory to anti-PD-(L)1. 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 (1500 mg/q4w) 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, eight in Arm II LD, and six 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. Anti-tumor responses were observed, with Arm II HD displaying the longest OS of 17.3 months (8.1-NE), although not statistically significant. Eleven patients (61.1%) 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 2 dose (RP2D) was 1.0E13 vp, on the sequential schedule. Encouraging survival was observed in patients after progressing on anti-PD-(L)1 agents. Data supports 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.