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 oncolytic immunotherapy based on herpes simplex virus type‑1 (HSV‑1). As of July 22, 2025, the U.S. FDA issued a Complete Response Letter (CRL) for the BLA seeking approval of RP1 plus nivolumab in advanced melanoma after PD‑1 inhibitor failure; the agency cited that the phase 1/2 IGNYTE trial was not an adequate and well‑controlled study to provide substantial evidence of effectiveness. A randomized confirmatory phase 3 trial (IGNYTE‑3) is ongoing. (ir.replimune.com, onclive.com)

Mechanism of action

• Vector design: RP1 is HSV‑1 engineered to delete ICP34.5 (conferring tumor‑selective replication) and ICP47 (intended to enhance antigen presentation via restored TAP function and to upregulate early US11 expression), and to express two transgenes: human GM‑CSF and a fusogenic gibbon ape leukemia virus glycoprotein with R‑sequence deleted (GALV‑GP R-). The GALV‑GP R- promotes syncytia formation and immunogenic tumor cell death, while GM‑CSF recruits and stimulates antigen‑presenting cells. (sec.gov, aacrjournals.org, pmc.ncbi.nlm.nih.gov)

• Immunologic effects: Preclinical and translational data demonstrate local tumor lysis with systemic antitumor activity, increases in intratumoral CD8+ T cells and PD‑L1 expression, and gene signatures of immune activation; synergy with PD‑1 blockade has been observed. (aacrjournals.org, ir.replimune.com)

Efficacy

Advanced melanoma after anti–PD‑1 failure (IGNYTE, phase 1/2) - Design: Intratumoral RP1 (≤8 biweekly doses; additional dosing permitted) plus nivolumab for up to 2 years; blinded independent central review. (ascopubs.org) - Primary results (peer‑reviewed JCO publication, July 2025; n=140): ORR 32.9% by RECIST v1.1 with 15.0% complete responses; median duration of response 33.7 months; 1‑ and 2‑year overall survival 75.3% and 63.3%. Responses occurred at similar frequency and depth in injected and non‑injected (including visceral) lesions. (scholars.duke.edu) - Conference primary analysis (SITC/ESMO 2024; n=140): ORR 33.6% (mRECIST v1.1 BICR) and 32.9% (RECIST v1.1); subgroup ORR 27.7% in prior anti‑PD‑1+anti‑CTLA‑4 and 35.9% with primary PD‑1 resistance; median DOR from response initiation 21.6 months. (ir.replimune.com)

Cutaneous squamous cell carcinoma (CERPASS, randomized phase 2) - RP1 + cemiplimab vs cemiplimab alone (n=211). The study did not meet co‑primary endpoints (CRR, ORR). CRR was higher but not statistically significant with RP1+cemi (38.1% vs 25.0%; p=0.040 [threshold p<0.025]); ORR was similar (52.5% vs 51.4%). Benefit appeared greater in locally advanced disease (CRR 48.1% vs 22.6%). (ir.replimune.com, onclive.com)

Transplant recipients with advanced skin cancers (ARTACUS, phase 1b/2, monotherapy) - Interim results (AACR 2024; n=27 enrolled; 23 evaluable): ORR 34.8% with 21.7% complete responses; increased CD8+ T cells and PD‑L1 expression observed post‑treatment. No allograft rejection reported. (aacrjournals.org, ascopost.com)

Safety

• In IGNYTE (melanoma) the combination had a predominantly grade 1–2, constitutional‑type AE profile. In the JCO report, treatment‑related AEs were 77.1% grade 1/2, 9.3% grade 3, 3.6% grade 4, and no grade 5 events. Conference reports similarly noted low rates of grade ≥3 AEs and no treatment‑related deaths. Typical events included fatigue, chills, pyrexia, influenza‑like illness, injection‑site pain, nausea, diarrhea, and rash. (scholars.duke.edu, ir.replimune.com, onclive.com)

• Procedural safety: Deep/visceral injections (e.g., lung, liver) were feasible; pneumothorax occurred with lung injections in a minority of procedures and resolved. (targetedonc.com)

• In ARTACUS (monotherapy in solid‑organ transplant recipients), RP1 was well‑tolerated without evidence of graft rejection; common AEs were fatigue, chills, and fever. (aacrjournals.org, ascopost.com)

Development status and ongoing studies

• Regulatory: FDA CRL (July 22, 2025) for RP1+nivolumab in advanced melanoma; the agency cited trial adequacy/heterogeneity concerns and requested items related to confirmatory trial design (e.g., contribution of components). Replimune plans further discussions with FDA. (ir.replimune.com, onclive.com)

• Ongoing: IGNYTE‑3, a global randomized phase 3 study of RP1 + nivolumab versus physician’s choice in advanced melanoma post‑PD‑1 and anti‑CTLA‑4 (or ineligible for anti‑CTLA‑4). (replimune.gcs-web.com)

Further reading

• IGNYTE JCO paper (peer‑reviewed): RP1 + nivolumab in anti‑PD‑1‑failed melanoma (efficacy, durability, safety) — https://doi.org/10.1200/JCO-25-01346. (scholars.duke.edu)
• ASCO 2024 abstract (trial design and early outcomes): https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.9517. (ascopubs.org)
• SITC 2024/ESMO 2024 press summary (primary analysis, biomarker data): https://ir.replimune.com/news-releases/news-release-details/replimune-presents-late-breaking-abstract-featuring-data-ignyte. (ir.replimune.com)
• CERPASS randomized CSCC study overview (JCO TPS): https://ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.TPS9593; initial results summaries: https://ir.replimune.com/news-releases/news-release-details/replimune-shares-initial-primary-analysis-results-cerpass and https://www.onclive.com/view/rp1-plus-cemiplimab-misses-response-end-points-in-locally-advanced-or-metastatic-cscc. (ascopubs.org, ir.replimune.com, onclive.com)
• ARTACUS (transplant recipients) AACR 2024 abstract: https://aacrjournals.org/cancerres/article/84/7_Supplement/CT003/742305; summary: https://ascopost.com/news/april-2024/rp1-immunotherapy-in-solid-organ-transplant-recipients-with-skin-cancer/. (aacrjournals.org, ascopost.com)
• Vector design details (SEC filing): https://www.sec.gov/Archives/edgar/data/1737953/000173795325000009/repl-20250331.htm. (sec.gov)

Notes: RP1 remains investigational. Reported outcomes derive from a single‑arm phase 1/2 study in melanoma (IGNYTE) and from a randomized phase 2 in CSCC (CERPASS) that did not meet its primary endpoints; benefit‑risk continues to be evaluated in ongoing randomized trials. (scholars.duke.edu, ir.replimune.com)

Last updated: Sep 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.