Safety and Efficacy of RP1 + Nivolumab in Patients with Non-Melanoma Skin Cancer of the Head and Neck: Results From IGNYTE Phase 1/2 Multi-Cohort Clinical Trial

Abstract

<h3>Purpose/Objective(s)</h3> RP1 is an enhanced potency oncolytic HSV-1 which expresses a fusogenic glycoprotein (GALV-GP R-) and granulocyte macrophage colony stimulating factor (GM-CSF). RP1 has demonstrated potent GALV-GP R-enhanced anti-tumor activity and immunogenic cell death in preclinical studies. Initial clinical data in solid tumors have been promising, including in patients with anti-PD1 failed disease. The Phase 1 part of the study demonstrated a tolerable safety profile for RP1 and RP1 + nivolumab (nivo) and determined the recommended phase 2 dose (RP2D). The objective of the Phase 2 part of the study is to evaluate the safety and efficacy of RP1 combined with nivo in patients (pts) with non-melanoma skin cancers (NMSC), melanoma, and other tumors, with data relating to NMSC patients with heads and neck tumors being reported here <h3>Materials/Methods</h3> The Phase 2 portion of this trial is enrolling approximately 270 pts across five cohorts, including 60 pts in an NMSC cohort with or without prior treatment with anti-PD-1/PD-L1. Pts in the Ph 2 portion receive up to 10 mL of RP1 intratumorally into one or more superficial and/or deep seated/visceral lesions at the RP2D identified in the Phase 1 portion of the study (1 × 10⁶ PFU/mL × 1 followed by 1 × 10⁷ PFU/mL × 7, Q2W combined with nivo at 240 mg IV Q2W for 4 months then 480 mg IV Q4W for up to a total of 2 years from the second RP1 dose). Pts may receive additional doses of RP1 with or without nivo if they meet protocol-specified criteria. The primary objectives of the Ph 2 part of the study are to assess the safety and overall response rate (ORR). Secondary objectives include duration of response, complete response rate, disease control rate, PFS, 1-year and 2-year survival rates. <h3>Results</h3> As of 25 May 2021, 33 NMSC pts were enrolled in the Phase 2 with 26 pts (CSCC: 15, BCC: 4, MCC: 3 and angiosarcoma: 4) having at least 1 post baseline scan or died. The interim objective response rate (ORR; confirmed and unconfirmed) in CSCC as of 6^th June 2021 was 60% with 46.6% complete response rate and duration of response median not reached. ORR in BCC, MCC and angiosarcoma were 25%, 75% and 66% respectively. Responses have also been observed to be durable and to deepen over time. Increases in PD-L1 and CD8 staining in tumor biopsies were seen in treated patients. Adverse events (AE) observed >20% include fatigue, pruritus, constipation, decreased appetite, nausea. Two pts had serious AEs related to RP-1 (dehydration and hypotension) that was resolved without sequelae. No treatment related deaths were observed. Data in relation to patients with head and neck disease specifically will be reported. <h3>Conclusion</h3> RP1 + nivo combination was generally well tolerated and provided a durable anti-tumor activity in pts with skin cancers. The trial is currently enrolling patients in US, UK and EU.