Background While PD-1/PD-L1 antagonists have improved the prognosis for many patients with melanoma, the majority fail therapy. PVSRIPO is a novel immunotherapy consisting of a non-neurovirulent rhinovirus:poliovirus chimera that activates innate immunity to facilitate a targeted anti-tumor immune response. Preclinical data show that PVSRIPO plus anti-PD-1 therapy leads to a greater anti-tumor response than either agent alone, warranting clinical investigation.

Methods An open-label phase I trial of intratumoral PVSRIPO in patients with unresectable melanoma (AJCC version 7 stage IIIB, IIIC, or IV) was performed. Eligible patients failed at least prior anti-PD-1 and BRAF/MEK (if BRAF mutant) therapy. The primary objective was to characterize the safety and tolerability of PVSRIPO. 12 patients in 4 cohorts received a total of 1, 2 (into 2 different lesions) or 3 (same lesion 3x or 3 different lesions) injections of PVSRIPO monotherapy, 21 days apart.

Results PVSRIPO injections were well tolerated with no SAEs or DLTs reported; all TEAEs were grade (G) 1 or 2 (grade 1 pruritus most common at 58%), with all but 2 PVSRIPO-related TEAEs localized to the injected or adjacent lesions ( n=1 G1 hot flash, n=1 G1 fatigue). Despite the limited number of PVSRIPO treatments relative to the overall lesion burden (67% patients >5 lesions), 4 of 12 patients (33%) achieved an objective response per irRC, including 4/6 (66%) who received 3 injections (maximum administered). Pathologic complete response (ie, no viable tumor detected in injected and non-injected lesions biopsied) was observed in 2 of 4 (50%) patients with in-transit disease. PVSRIPO response relative to time since prior anti-PD-1 exposure is summarized in table 1. Following study completion/PVSRIPO therapy, 10/12 patients (83%) again received immune checkpoint inhibitor (ICI)-based therapy and 6/12 patients (50%) remained progression free at the data cutoff.

Conclusions Intratumoral PVSRIPO was well tolerated. When taken together with preclinical data, the anti-tumor responses observed relative to prior or subsequent ICI therapy suggests that PVSRIPO, either alone or in combination with anti-PD-1, may be an effective treatment in anti-PD-1 refractory melanoma. An amendment exploring higher PVSRIPO dose levels is ongoing and a phase 2 study with and without anti-PD-1 in the refractory population is initiating.

Ethics Approval This study (NCT03712358) was approved by WIRB; ID 20181772.