An open-label, single-arm, phase II clinical trial of RP1, an enhanced potency oncolytic herpes virus, combined with nivolumab in four solid tumor types: Initial results from the skin cancer cohorts.
Authors: Middleton Mark R. , Aroldi Francesca , Sacco Joseph , Milhem Mohammed M. , Curti Brendan D. , Vanderwalde Ari M. , Baum Scott , Samson Adel , Pavlick Anna C. , Chesney Jason Alan , Niu Jiaxin , Rhodes Terence Duane , Bowles Tawnya Lynn , Olsson-Brown Anna , Laux Douglas Earl , Bommareddy Praveen , Deterding Alex , Elassal Joseph , Coffin Robert S. , Harrington Kevin 
Published: May 2020

e22050 Background: RP1 is an oncolytic HSV that encodes a fusogenic GALV-GP R- protein and GM-CSF. RP1 demonstrated tolerable safety and tumor regression alone and with nivolumab (nivo) in ph 1 in patients (pts) with a number of tumor types. To further define the efficacy of the combination, ph2 cohorts of 30 pts with 4 tumor types were then opened. Initial data from the melanoma (mel) and the non-mel skin cancer (NMSC) cohorts will be presented. Methods: Unresectable stage IIIb-IV mel pts for whom anti-PD-1 was indicated or who were refractory to 1 prior standard therapy including anti-PD-1 or ipi/nivo were enrolled. NMSC pts were anti-PD1 naïve. Pts received up to 8 doses of RP1 (<=10 mL/visit based on tumor diameter) Q2W (first dose 106 PFU/mL then 107 PFU/mL). From the second RP1 dose pts also received nivo (240 mg IV Q2W for 4 mos then 480 mg IV Q4W up to 2 yrs in the absence toxicity or confirmed progressive disease (PD)). Imaging was done every 8 wks and response assessed by RECISTv1.1 (with confirmation required for PD). Results: As of Jan 22nd 2020, 30 mel pts and 9 NMSC pts had been enrolled with follow up between <1 and 7mo. Of the mel pts 21 were cutaneous, 5 were mucosal and 4 were ocular. Of the NMSC pts, 6 had squamous cell, 1 had basal cell, 1 had Merkel cell carcinomas and 1 had angiosarcoma. Recruitment of the mel cohort is complete, with recruitment into the NMSC cohort ongoing. Based on initial data in melanoma, a further cohort of 125 pts with anti-PD1 refractory cutaneous mel has been opened. Adverse events (AEs) in the ph2 cohorts have been consistent with those in ph1, with RP1 side effects of in general Grade 1/2 constitutional and related symptoms, self-limiting within 72hrs of RP1 injections, with no exacerbation of the side effects expected for nivo. With currently short follow up, multiple objective responses have been observed in treatment naïve mel, anti-PD1 refractory mel (including ipi/nivo refractory and mucosal), and NMSC. Of note 3 of the first 4 anti-PD1 refractory mel pts treated are responding to treatment, as are 5 of the first 6 CSCC pts, including 3 CR. Tumor biopsies routinely showed immune activation, including robust recruitment of CD8+ T cells and increased PD-L1 expression. Treatment remains ongoing in the majority of patients, and current data will be presented. Conclusions: RP1 and nivo has continued to be well tolerated, with promising signs of efficacy in patients with skin cancers, including with anti-PD1 refractory disease. These data support the further development of RP1 combined with anti-PD1 blockade. Clinical trial information: NCT03767348 .