A randomized, controlled, multicenter, phase 3 study of RP1 (vusolimogene oderparepvec) combined with nivolumab vs physician’s choice of therapy in patients with advanced melanoma that has progressed on anti–PD-1 and anti–CTLA-4 therapy (IGNYTE-3).

TPS9597 Background: Melanoma is the fifth most common cancer, with over 100,000 new cases and 8000 related deaths projected in the US for 2025. First-line systemic treatment with immune checkpoint inhibitors (ICIs) improves the objective response rate (ORR) and extends progression-free survival (PFS) and overall survival (OS) for patients with advanced disease. Among available treatments, combination anti–PD-1 (nivolumab) + anti–CTLA-4 (ipilimumab) therapy is associated with the highest ORR and best PFS and OS. However, only around half of patients respond to treatment, and limited options exist for patients whose melanoma then progresses following anti–PD-(L)1 ± anti–CTLA-4. RP1 (vusolimogene oderparepvec) is a herpes simplex virus type 1–based oncolytic immunotherapy that expresses human granulocyte-macrophage colony-stimulating factor and a fusogenic glycoprotein (GALV-GP-R − ). IGNYTE-3 will evaluate the OS and clinical benefit of RP1 + nivolumab for patients with advanced cutaneous melanoma whose disease has progressed after anti–PD-1 and anti–CTLA-4 therapy (or who are ineligible for anti–CTLA-4 therapy) vs physician’s choice. RP1 + nivolumab has demonstrated durable, clinically meaningful anti-tumor activity (ORR, 33.% per independent central review), with minimal toxicity (NCT03767348). Repetitive intralesional and intravisceral injections were well tolerated in advanced ICI-refractory melanoma. All patients had confirmed progression on prior anti–PD-1 therapy. Methods: IGNYTE-3 (NCT06264180) is a global, randomized, controlled, phase 3 trial. Key eligibility criteria include age ≥12 years, stage IIIB–IVM1a–M1d cutaneous melanoma, disease progression on ≥12 weeks of an anti–PD-1 and anti–CTLA-4 treatment (administered in combination or in sequence, with anti–PD-1 last), ≥1 measurable and injectable tumor, and adequate hematologic, hepatic, and renal function. Patients who are not candidates for anti–CTLA-4 therapy may enroll following progression on anti–PD-1 therapy alone. Patients with BRAF V600-mutant melanoma should have received anti–BRAF ± anti–MEK–targeted therapy prior to enrollment, where appropriate. Patients (N ≈ 400) will receive RP1 + nivolumab or physician’s choice (nivolumab + relatlimab, anti–PD-1 monotherapy rechallenge [nivolumab or pembrolizumab], or single-agent chemotherapy [dacarbazine, temozolomide, or paclitaxel/albumin-bound paclitaxel]). The primary endpoint of the study is OS; the key secondary endpoints are PFS and ORR per RECIST 1.1. Clinical trial information: NCT06264180 .