1504 Primary analysis of the registration-intended cohort of patients with anti–PD-1–failed melanoma from the IGNYTE trial of RP1 plus nivolumab, including clinical subgroup and initial biomarker data

<h3>Background</h3> Patients with advanced melanoma progressing on anti–PD-1 therapy have limited and toxic treatment options. RP1 (vusolimogene oderparepvec) is an HSV-1–based oncolytic immunotherapy expressing GM-CSF and a fusogenic glycoprotein (GALV-GP-R–). The registration-intended cohort from the IGNYTE trial tested RP1 combined with nivolumab in melanoma patients with confirmed progression while being treated with anti–PD-1 mono- or combination therapy. <h3>Methods</h3> Melanoma patients with confirmed progressive disease during anti–PD-1 ± anti–CTLA-4 for ≥8 weeks as the last prior treatment were enrolled (NCT03767348). RP1 was given intratumorally at 1×10⁶ PFU/mL, then Q2W (1×10⁷ PFU/mL; ≤7 doses) with IV nivolumab (240mg); nivolumab was then given alone (240mg Q2W or 480mg Q4W) for ≤2 years, with further RP1 allowed if indicated. The primary endpoint was ORR by independent review (IR) using modified RECIST (mRECIST v1.1); responses were also assessed by RECIST v1.1. Tumor biopsies were collected at screening and D43; IHC was performed for CD8+ T-cells and PD-L1. <h3>Results</h3> Of the 140 enrolled patients, 48.6% had stage IVb/c/d disease, 65.7% had primary anti–PD-1 resistance, 56.4% were PD-L1 negative, and 43.6% had prior anti–PD-1 + anti–CTLA-4. Confirmed ORR by IR was 33.6% (15.0% CR) by mRECIST v1.1 (32.9% by RECIST v1.1). Responses were of both injected and non-injected, including visceral, lesions, with similar frequency, depth, and kinetics. Among responders, 98.7% of injected (n=79) and 98.4% of non-injected lesions (n=123) had reductions, with 93.7% and 79.7%, respectively, reduced by ≥30%. The median DOR (range) was 21.6 months (1.2–43.5 months). ORR was 35.9% in patients with primary anti–PD-1 resistance, 27.7% in patients who received prior anti–PD-1 + anti–CTLA-4, 52.3% in PD-L1 positive and 25.3% in PD-L1 negative patients. One- and two-year OS rates (95% CI) were 75.3% (66.9–81.9) and 63.3% (53.6–71.5); median not reached. Most treatment-related AEs were grade 1–2 (grade 3–4; 12.8%). Biomarker assessment showed immune activation as measured by increased CD8+ T-cell infiltration (20/50) and PD-L1 levels (CPS; 26/49) vs baseline in available biopsies, with additional biomarker analyses to be presented. <h3>Conclusions</h3> RP1 + nivolumab was well tolerated and provided durable, clinically meaningful antitumor activity in patients with advanced melanoma and confirmed disease progression during prior anti–PD-1 treatment. This included a 35.9% ORR in patients with primary refractory disease. Biomarker data demonstrated that RP1 + nivolumab increased immune activation markers consistent with the ability to treat primary refractory disease. <h3>Trial Registration</h3> NCT03767348. <h3>Ethics Approval</h3> The study was conducted in accordance with the ethical principles originating from the Declaration of Helsinki and was approved by the institutional review board/ethics committee at each participating site. Written informed consent was obtained from all patients prior to the conduct of any study-related procedures.