Background Intratumoral administration of V937, a bioselected genetically unmodified Coxsackievirus A21, has shown antitumor activity both as a monotherapy and in combination with the anti–PD-1 antibody pembrolizumab.^1–3 V937 induces lytic tumor cell infection and upregulation of members of immune checkpoint pathways.² We present the results from the phase 1b MITCI study that evaluated V937 plus ipilimumab for advanced melanoma.

Methods Eligible patients had unresectable or metastatic stage IIIB/C or IV melanoma amenable to intratumoral injection. Patients received intratumoral V937 3×108 TCID50 on days 1, 3, 5, 8, and 22, then Q3W for 14 more injections plus intravenous ipilimumab 3 mg/kg Q3W administered 4 times starting on day 22. Imaging was done Q6W beginning at day 106; response was assessed per immune-related response criteria (irRC). The primary endpoints were safety and ORR in the overall population and in patients whose disease progressed on prior anti–PD-1 therapy.

Results 50 patients were enrolled and received ≥1 dose of study treatment. At data cutoff (February 21, 2020), all had discontinued the study and study therapy. Median (range) age was 64.5 (28–88) years. Fourteen patients (28%) had stage III disease. Forty patients (80%) had received prior systemic treatment, 33 of whom had received anti–PD-1 therapy. The median number of cycles of ipilimumab was 4 (range, 1–4), and the number of intratumoral injections of V937 was 9 (range, 5–19). Among the 94% of patients who had ≥1 treatment-related AE, 14% had grade 3/4 treatment-related AEs, none of which were considered related to V937. The most common grade 3/4 treatment-related AEs were dehydration, diarrhea, and hepatotoxicity (4% each). No grade 5 treatment-related AEs occurred. The most common treatment-related AEs were pruritus (50%), fatigue (44%), diarrhea (32%), and nausea (22%). Efficacy outcomes for the overall population and by prior anti-PD-1 therapy use are presented in table 1. Tumor regression was observed in injected and noninjected lesions.

Conclusions V937 plus ipilimumab was safe and the toxicities were manageable and consistent with that anticipated for the individual treatment components. ORR was robust and significantly higher than anticipated with ipilimumab monotherapy, including in patients who had received prior anti–PD-1 therapy. Most responses were durable (≥26 weeks), and responses seen in noninjected metastases provided evidence of probable systemic immune activation. The combination of V937 plus ipilimumab warrants further investigation in a larger trial in patients with advanced melanoma.

Acknowledgements Medical writing assistance was provided by Kathleen Estes, PhD, of ICON plc (North Wales, PA, USA), funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Trial Registration NCT02307149

References

1. Pandha H, Harrington K, Ralph C, Melcher A, Gupta S, Akerley W, et al. Abstract CT115: phase 1b KEYNOTE 200 (STORM study): a study of an intravenously delivered oncolytic virus, coxsackievirus A21 in combination with pembrolizumab in advanced cancer patients. Cancer Res 2017;77(13 suppl):CT115.

2. Andtbacka RHI, Curti BD, Kaufman H, Nemunaitis JJ, Daniels GA, Hallmeyer S, et al. Dynamics of tumor response in advanced melanoma patients treated with coxsackievirus A21. J Clin Oncol 2016;34(15 suppl):9553.

3. Silk AW, Kaufman H, Gabrail N, Mehnert J, Bryan J, Norrell J, et al. Phase 1b study of intratumoral coxsackievirus A21 (CVA21) and systemic pembrolizumab in advanced melanoma patients: interim results of the CAPRA clinical trial. Cancer Res 2017;77(13 suppl):CT026.

Ethics Approval An independent institutional review board or ethics committee approved the protocol at each study site, and the trial was conducted in compliance with Good Clinical Practice guidelines and the Declaration of Helsinki. All patients provided informed consent.