A Shift After Two Rejections: FDA Accelerates Approval of Replimune’s Melanoma Therapy

For patients with advanced melanoma whose disease has progressed after PD-1 immunotherapy, treatment options are limited, forcing regulators to make a difficult trade-off between “providing a new option now” and “requiring more complete evidence.” The U.S. Food and Drug Administration (FDA) has now chosen to allow earlier access, granting accelerated approval to Replimune’s vusolimogene oderparepvec (RP1), marketed as Tudriqev, in combination with nivolumab for the treatment of adults with unresectable advanced cutaneous melanoma whose disease progressed after prior anti-PD-1 therapy.

RP1 is an oncolytic immunotherapy engineered from herpes simplex virus type 1 and injected directly into tumors, with the aim of destroying cancer cells and triggering an immune response; nivolumab, meanwhile, releases the inhibition imposed by the PD-1 immune checkpoint. The rationale for the combination is to turn tumor breakdown caused by local injection into an immune attack that reaches lesions throughout the body.

The approval was based primarily on the Phase 1/2 IGNYTE trial. Among 140 patients whose anti-PD-1 treatment had failed, the company’s analysis showed an objective response rate of approximately one-third, with some responses lasting for a considerable period. FDA advisers concluded that this response signal, together with patients’ unmet medical need, was sufficient to support conditional early market entry. However, accelerated approval does not mean the therapy has been proven to extend life or improve patients’ daily functioning.

The controversy stems from the fact that IGNYTE was not a randomized pivotal trial designed specifically for this application, but a single-arm study that underwent multiple amendments. All participants received RP1 and nivolumab, with no concurrent control group, making it impossible to directly distinguish whether the observed effects came from RP1, retreatment with nivolumab, or the combination of the two. FDA reviewers also noted that differences in patients’ prior treatments and disease burden made historical comparisons across trials difficult to substantiate.

The assessment of tumor responses also presented technical challenges. RP1 is injected directly into lesions, and the local treatment itself may cause tumors to shrink. Practices in the trial—including injections, biopsies, surgery, and continued dosing after treatment—further complicated imaging assessments. In documents for the advisory meeting, the FDA stated that some assessment methods hindered its ability to verify the response rate and duration of response, while the overall survival analysis from a single-arm study could not be interpreted reliably.

Background

The decision marks an interim conclusion to an unusually circuitous review process. The FDA rejected the application twice, in July 2025 and April 2026, with core reasons including the inability to confirm RP1’s independent contribution to the combination therapy, heterogeneity in the patient population, and the possibility that response assessments were confounded by other interventions. This reversal does not eliminate those scientific questions, but instead defers the answers to post-marketing verification.

The ongoing Phase 3 IGNYTE-3 trial will enroll approximately 400 patients and randomly compare RP1 plus nivolumab with physician’s choice of treatment. Overall survival will be the primary endpoint, with progression-free survival and objective response rate as secondary endpoints. Trial registration data estimate that the primary analysis will not be completed until January 2029. If the study fails to confirm clinical benefit, the FDA may require changes to the indication or even withdraw the approval. Tudriqev has therefore received an entry ticket with a deadline and an obligation to verify benefit, rather than an endpoint to the evidence controversy.