Randomized, Ph3 Clinical Study Comparing Vusolimogene Oderparepvec in Combination With Nivolumab Vs Treatment of Physician's Choice in Patients With Advanced Melanoma That Progressed on Anti-PD-1 and Anti-CTLA-4 Containing Treatment

Overview

Vusolimogene oderparepvec (RP1) is an investigational, intratumorally injected, herpes simplex virus type 1 (HSV‑1)–based oncolytic immunotherapy engineered to enhance direct tumor lysis and stimulate systemic anti‑tumor immunity. It has been studied most extensively in advanced melanoma (often after anti–PD‑1 failure) in combination with nivolumab, and in other skin cancers. On July 22, 2025, the FDA issued a Complete Response Letter declining accelerated approval for RP1+nivolumab in advanced melanoma; no safety issues were cited, and the agency’s concern centered on the adequacy and interpretability of the single‑arm IGNYTE trial. Replimune held a Type A meeting with FDA on September 16, 2025 to discuss next steps. (ir.replimune.com)

Mechanism of action

• Backbone and edits: RP1 is derived from a potent clinical HSV‑1 strain with deletions in ICP34.5 (to confer tumor-selective replication) and ICP47 (to enhance antigen presentation via increased US11 expression). (pubmed.ncbi.nlm.nih.gov)
• Transgenes: RP1 encodes human GM‑CSF and a truncated, constitutively fusogenic gibbon ape leukemia virus envelope glycoprotein (GALV‑GP R‑). The fusogenic protein promotes tumor cell–cell fusion and immunogenic cell death, increasing antigen release and innate/adaptive immune activation; preclinical models show enhanced local and abscopal anti‑tumor effects and synergy with PD‑1 blockade. (pubmed.ncbi.nlm.nih.gov)

Efficacy

Advanced melanoma after anti–PD‑1 therapy (IGNYTE, phase 1/2, single‑arm RP1 + nivolumab) - Population: 156 patients (46% previously received ipilimumab+nivolumab; 51% stage IVM1b–d). (ascopubs.org) - Objective response rate (ORR): 31.4%; complete response (CR): 12.2% (investigator‑assessed). Responses occurred in injected and uninjected (including visceral) lesions; median duration of response >24 months at the Nov 6, 2023 cutoff with 78% ongoing. (ascopubs.org)

Confirmatory/outcomes studies under way - IGNYTE‑3 (phase 3): randomized RP1+nivolumab vs physician’s choice in advanced melanoma progressing on anti–PD‑1±anti–CTLA‑4; primary endpoint overall survival. (Trial registration NCT06264180.) (ascopubs.org)

Non‑melanoma skin cancers - Early IGNYTE cohort in anti–PD‑1‑failed non‑melanoma skin cancers (mixed tumor types): preliminary ORR ~30% (company report; early, non‑comparative). (ir.replimune.com) - CERPASS (phase 2, randomized cemiplimab ± RP1 in advanced cutaneous squamous cell carcinoma): did not meet co‑primary endpoints (ORR and CR rate by blinded review), though CR rate numerically higher with RP1+cemo (38.1% vs 25%); additional endpoints maturing. (Top‑line company disclosure.) (globenewswire.com)

Immunocompromised (transplant recipients) - ARTACUS (phase 1/2, single‑arm RP1 monotherapy): interim analyses reported ORR 34.8% (8/23 evaluable; 5 CRs) with no observed allograft rejection to the data cutoff; conference/company reports. (ir.replimune.com)

Note: Except where specified, the above efficacy results come from meeting abstracts or company communications; peer‑reviewed, fully published clinical outcomes for RP1 in these settings remain limited as of October 2025. (ascopubs.org)

Safety

• In IGNYTE (RP1+nivolumab), treatment‑related adverse events were predominantly grade 1–2 and consistent with expected oncolytic therapy “flu‑like” effects; one grade 5 immune‑mediated myocarditis was attributed to nivolumab. (ascopubs.org)
• In CERPASS, adding RP1 to cemiplimab increased mostly transient grade 1–2 events; isolated grade 3–4 immune‑related events occurred; no grade 5 RP1‑related events were reported in the top‑line analysis. (ir.replimune.com)
• In ARTACUS interim reports (RP1 monotherapy in transplant recipients), RP1 was generally well tolerated without evidence of allograft rejection to the cutoff. (ir.replimune.com)

Further reading

• Development of the RP1 platform and mechanism (J Immunotherapy of Cancer, 2019, peer‑reviewed). (pubmed.ncbi.nlm.nih.gov)
• IGNYTE melanoma cohort results (ASCO 2024 abstract). (ascopubs.org)
• IGNYTE‑3 phase 3 design (ASCO 2024 abstract). (ascopubs.org)
• ARTACUS transplant study design and interim results (ASCO abstract; company update). (ascopubs.org)
• CERPASS randomized CSCC study (ASCO trial-in-progress abstract; top‑line results). (ascopubs.org)
• FDA regulatory updates: BLA acceptance/priority review and Complete Response Letter (company releases; trade coverage). (ir.replimune.com)

If additional peer‑reviewed publications of clinical outcomes become available, those should supersede the meeting‑abstract and company‑reported figures summarized here.

Last updated: Oct 2025

Key Inclusion Criteria:

* Male or female who is 12 years of age or older at the time of signed informed consent.

* Patients with histologically or cytologically confirmed unresectable or metastatic Stage IIIb through IV/M1a through M1d cutaneous melanoma.

* Confirmed disease progression (PD) on an approved anti-PD-1 and an anti-CTLA-4 treatment, administered either as a combination regimen (eg, nivolumab + ipilimumab) or in sequence.

1. Treatment with prior anti-PD-1 therapy must have continued for a minimum of 8 weeks

2. Patients who in the physician's judgement are not candidates for treatment with an anti-CTLA-4 antibody are eligible

* Has documented BRAF V600 mutation status. Patients with BRAF mutation should have received prior BRAF-directed therapy (with or without a MEK inhibitor) prior to enrollment in the study, unless deemed not clinically indicated at Investigator's discretion due to concurrent medical condition or prior toxicity.

* Has at least 1 measurable and injectable tumor of ≥1 cm in longest diameter (or shortest diameter for lymph nodes).

* Has adequate hematologic function.

* Has adequate hepatic function.

* Has adequate renal function.

* Prothrombin time (PT) ≤1.5 × ULN and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤1.5 × ULN

* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 1 for patients 18 years and older or a Lansky performance score (PSc) ≥80 for patients 12 to 17 years of age.

* Life expectancy of at least 3 months.

* Female and male patients of reproductive potential must agree to avoid becoming pregnant or impregnating a partner and adhere to highly effective contraception requirements during the treatment period and for at least 6 months after the last dose of study treatment.

* Women of childbearing potential must have a negative serum beta-human chorionic gonadotropin (β-hCG) test within 72 hours before the first dose of study treatment.

Key Exclusion Criteria:

* Primary mucosal or uveal melanoma.

* More than 2 lines of systemic therapy for advanced melanoma.

* Known acute or chronic hepatitis.

* Known human immunodeficiency virus (HIV) infection.

* Active significant herpetic infections or prior complications of HSV-1 infection.

* Had systemic infection requiring IV antibiotics or other serious active infection requiring antimicrobial, antiviral, or antifungal treatment within 14 days prior to dosing.

* With active significant herpetic infections or prior complications of HSV-1 infection.

* Evidence of spinal cord compression or at high risk of spinal cord compression.

* Known active central nervous system (CNS) metastases and/or carcinomatous meningitis at time of screening.

* Serum lactate dehydrogenase (LDH) \>2 × ULN.

* Major surgery ≤2 weeks prior to starting study drug.

* Prior malignancy active within the previous 3 years, except for locally curable cancers that have apparently been cured

* History of significant cardiac disease including myocarditis or congestive heart.

* History of life-threatening toxicity related to prior immune.

* Active, known, or suspected autoimmune disease requiring systemic treatment.

* History of (noninfectious) pneumonitis that required steroids or has current pneumonitis.

* Prior oncolytic virus or other therapy given by intratumoral administration.

* Requires intermittent or chronic use of systemic (oral or IV) antivirals with known antiherpetic activity (eg, acyclovir).

* Has received a live vaccine within 28 days prior to the first dose of study treatment.

* Systemic anticancer therapies within 5 half-lives or 4 weeks of the first dose, whichever is shorter.

* Conditions requiring treatment with immunosuppressive doses (\>10 mg per day of prednisone or equivalent) of systemic corticosteroids other than for corticosteroid replacement therapy within 14 days after enrollment.