FDA Issues CRL to Replimune for Vusolimogene Oderparepvec With Nivolumab for Advanced Melanoma

The FDA issued a complete response letter (CRL) for the biologics application for vusolimogene oderparepvec (RP1; Replimune Group, Inc.) in combination with nivolumab (Opdivo; Bristol Myers Squibb) for the treatment of advanced melanoma. The manufacturer, Replimune, reports that the CRL states that the IGNYTE is not considered to be an “adequate and well-controlled clinical investigation that provides substantial evidence of effectiveness.” In addition, the FDA stated the trial cannot be adequately interpreted because of the patient population’s heterogeneity.¹

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Vusolimogene oderparepvec is based on a proprietary strain of herpes simplex virus that is engineered and genetically armed with a fusogenic protein, GALV-CPR, and GM-CSF. It is intended to maximize the tumor-killing potency, immunogenicity of tumor cell death, and the activation of a systemic antitumor immune response in patients. Currently, it is also undergoing investigation in trials enrolling patients with nonmelanoma skin cancers, such as Merkel cell carcinoma, basal cell carcinoma, and angiosarcoma.^2,3

IGNYTE-3 (NCT06264180)⁴ is a randomized, controlled, multicenter, open-label phase 3 clinical study assessing vusolimogene oderparepvec in combination with nivolumab compared with physician’s choice of treatment in patients with unresectable stage IIIb through IV cutaneous melanoma. The enrolled patients had progressed on an anti-PD-1– and an anti-CTLA-4–containing regimen (which were administered either as a combination regimen or in sequence), or they were not candidates for treatment with an anti-CTLA-4 therapy.⁴

The study consists of 3 separate phases: a 28-day screening period; a treatment period, which will last up to approximately 2 years; and a follow-up period of up to 3 years following the completion of treatment. Following the screenings, the enrolled patients were randomly assigned to receive either vusolimogene oderparepvec or the physician’s choice of treatment, which included 1 of the following regimens: nivolumab with relatlimab-rmbw (Opdualag; Bristol Myers Squibb); an anti-PD-1 monotherapy, either nivolumab or pembrolizumab (Keytruda; Merck); or a single-agent chemotherapy (dacarbazine [Bristol Myers Squibb], temozolomide [Temodar; Merck], or paclitaxel [Taxol; Bristol Myers Squibb]/albumin-bound paclitaxel [Abraxane; Bristol Myers Squibb]).^4-6

Melanoma is the fifth most common cancer, with an estimated 100,000 new cases and 8000 deaths in the US during 2024. Typically, standard of care includes treatment with immune checkpoint blockade, which about half of patients either will not respond to or will progress after treatment. Because options are limited following immune checkpoint blockade therapy and no standard of care is available, there is an urgent need for treatment options for this patient population.²

Replimune has reported plans to request a Type A meeting and expects it will be granted within 30 days. Additionally, they aim to urgently interact with the FDA to find a path forward for the timely accelerated approval of vusolimogene oderparepvec, providing more care opportunities for patients with advanced disease who have limited options. Of note, the FDA’s CRL did not raise any safety issues related to vusolimogene oderparepvec.¹

“We are surprised by this FDA decision and disappointed for advanced melanoma patients who have limited treatment options, as highlighted by the granting of breakthrough status at the time we provided the IGNYTE primary data,” Sushil Patel, PhD, CEO of Replimune, said in a news release. “The issues highlighted in the CRL were not raised by the agency during the mid- and late-cycle reviews. Additionally, we had also aligned on the design of the confirmatory study. We strongly believe that [vusolimogene oderparepvec] in combination with nivolumab can bring substantial benefit to advanced melanoma patients.”¹

REFERENCES

1. Replimune. Replimune Receives Complete Response Letter from FDA for RP1 Biologics License Application for the Treatment of Advanced Melanoma. News release. July 22, 2025. Accessed July 22, 2025. https://ir.replimune.com/news-releases/news-release-details/replimune-receives-complete-response-letter-fda-rp1-biologics

2. GlobeNewswire. Replimune Announces Biologics License Application Acceptance and Priority Review for RP1 for the Treatment of Advanced Melanoma. News release. January 21, 2025. Accessed July 18, 2025. https://www.globenewswire.com/news-release/2025/01/21/3012616/0/en/Replimune-Announces-Biologics-License-Application-Acceptance-and-Priority-Review-for-RP1-for-the-Treatment-of-Advanced-Melanoma.html

3. Replimune. Pipeline – Novel oncolytic immunotherapies built on our proprietary RPx platform. Accessed July 18, 2025. https://www.replimune.com/pipeline

4. VO and Nivolumab vs Physician's Choice in Advanced Melanoma That Progressed on Anti-PD-1 & Anti-CTLA-4 Drugs (IGNYTE-3). ClinicalTrials.gov identifier: NCT06264180. Updated June 18, 2025. Accessed July 18, 2025. https://www.clinicaltrials.gov/study/NCT06264180

5. Luke JJ, Kong G, Gullo G, Robert C. A randomized, controlled, multicenter, phase 3 study of vusolimogene oderparepvec (VO) combined with nivolumab vs treatment of physician’s choice in patients with advanced melanoma that has progressed on anti–PD-1 and anti–CTLA-4 therapy (IGNYTE-3). J Clin Oncol. 2025;42(Number 16 suppl). doi:10.1200/JCO.2024.42.16_suppl.TPS9604

6. Ferruggia K. FDA Gives Priority Review to Vusolimogene Oderparepvec for Melanoma. Pharmacy Times. January 22, 2025. Accessed July 18, 2025. https://www.pharmacytimes.com/view/fda-gives-priority-review-to-vusolimogene-oderparepvec-for-melanoma