FDA rejects Replimune Melanoma Therapy Again
FDA has issued Replimune a complete response letter (CRL), declining to approve its BLA for vusolimogene oderparepvec in combination with nivolumab for advanced melanoma.
In a 4/10 letter, the agency said a reanalysis of clinical data and review of additional evidence failed to demonstrate “substantial evidence of effectiveness” for the therapy in adults with unresectable advanced cutaneous melanoma who had progressed on prior PD-1 therapies.
The decision follows the company’s resubmission of its application in 10/2025, which attempted to address deficiencies outlined in a prior CRL issued in 7/2025. However, FDA reviewers — who were newly assigned to the resubmission to maintain objectivity — unanimously concluded that the updated data package remained inadequate.
FDA’s rejection centered on shortcomings in two studies: the Phase 2 RPL-001-16 trial and the ongoing Phase 3 RP1-104 study. For RPL-001-16, reviewers reiterated longstanding concerns about the single-arm trial design, which did not allow the agency to isolate the contribution of vusolimogene oderparepvec when used alongside nivolumab. The agency also cited heterogeneity in the patient population and multiple issues with how tumor responses were assessed, including the confounding effects of surgical procedures, reinjection of tumors, and inconsistent application of standard RECIST criteria.
Notably, FDA found that more than half of responding patients lacked non-injected lesions, making it difficult to determine whether the therapy produced systemic anti-tumor effects.
The RP1-104 study, intended as a confirmatory Phase 3 trial, was also deemed insufficient to support approval at this stage, FDA said. The resubmission included an early, unplanned analysis representing just 10% of the planned enrollment, with response assessments conducted solely by investigators and lacking key durability data.
The agency emphasized that it had repeatedly advised Replimune — dating back to 2021 — to conduct a randomized controlled trial capable of demonstrating efficacy and isolating the contribution of each component of the combination therapy.
While the FDA acknowledged its regulatory flexibility in high unmet-need settings like advanced melanoma, it concluded that the submitted data do not meet statutory standards for approval under the Public Health Service Act.
“The evidence as presented does not meet the evidentiary standards required for regulatory approval,” the agency wrote, adding that exploratory analyses did not alter its earlier conclusions.
The therapy’s regulatory path has been closely watched following reports of internal disagreement during the previous review cycle.
According to prior reporting, Richard Pazdur, then-head of FDA’s Oncology Center of Excellence, intervened in the earlier review to overrule a decision by CBER director Vinay Prasad, who had supported approval of the therapy under the agency’s accelerated approval framework.
Pazdur ultimately determined that the application did not meet the evidentiary threshold required for approval, aligning with concerns about the interpretability of the single-arm data and the inability to disentangle the treatment effect of the oncolytic virus from nivolumab.
The latest CRL indicates that those core scientific concerns remain unresolved, despite the company’s attempt to bolster its application with additional analyses and early Phase 3 data.
Regarding next steps, FDA said Replimune must conduct and submit results from “adequate and well-controlled” trials to support any future approval. The agency indicated willingness to work with the company on revised study designs, including potential modifications to the ongoing RP1-104 trial.