A Turning Point After Two Rejections: FDA Advisers Back Replimune’s Melanoma Virus Therapy

For patients with advanced melanoma whose disease no longer responds to anti-PD-1 drugs, treatment options often narrow rapidly. Replimune is attempting to use a virus to attack tumors directly, then pair it with an immune checkpoint inhibitor to revive an anticancer response. Once shut out, the strategy has now gained another chance to move forward following a meeting of advisers to the U.S. Food and Drug Administration (FDA).

On July 30, the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee voted 10–3 that Replimune had presented sufficient evidence for RP1 to support continued FDA review. The application covers RP1 in combination with nivolumab for adults with unresectable advanced cutaneous melanoma whose disease progressed after treatment with an anti-PD-1-containing regimen.

RP1, formally known as vusolimogene oderparepvec, is a genetically modified herpes simplex virus type 1. It is injected directly into tumors and is designed both to cause cancer cells to rupture and to trigger an immune response through the expression of components including GM-CSF; nivolumab, meanwhile, releases the PD-1 immune brake from another direction. The central regulatory challenge is how to demonstrate that efficacy occurs not only in lesions reachable by the needle and is not attributable to nivolumab alone.

The main evidence comes from 140 evaluable patients in the Phase 1/2 IGNYTE study. The study had no control group, and the relevant melanoma population was added only after the trial had begun, with eligibility criteria and trial procedures subsequently modified multiple times. Based on an independent review, the applicant reported an objective response rate of 33.6%. After excluding cases in which a response was supported only by injected lesions or in which there were no target lesions at baseline, the FDA estimated that the response rate fell to 15.7%. The gap between the two figures is at the heart of the controversy.

FDA reviewers noted that RECIST 1.1, commonly used for solid tumors, was originally designed primarily for systemic therapies. When applied to intratumoral injections, the virus’s local effects, injection-related changes, and systemic immune effects may become conflated. Among the responders identified by the applicant, more than half lacked uninjected target lesions that could confirm a distant antitumor effect. The single-arm design also cannot reliably separate the respective contributions of RP1 and nivolumab. The FDA further concluded that the current overall survival analysis cannot be interpreted.

These questions had already led to significant setbacks. In July 2025, the FDA issued a complete response letter concluding that IGNYTE was not an adequate and well-controlled study and requiring efficacy to be demonstrated in an appropriately controlled trial; according to STAT, the application was subsequently rejected once again. The advisers’ favorable vote this time indicates that most members believe the existing data are sufficient for the review process to move forward, but it does not mean the efficacy dispute has been resolved.

The FDA typically gives considerable weight to advisory committee opinions but is not legally bound by their votes. The final decision must still weigh the unmet medical need, whether the responses are systemic and clinically meaningful, and whether subsequent randomized trials can supply the missing causal evidence. For RP1, the 10–3 vote opens a door; it is not a marketing authorization.