FDA Issues Complete Response Letter for RP1 and Nivolumab in Melanoma

On July 22, 2025, the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) regarding the biologics license application for RP1, an investigational oncolytic immunotherapy, in combination with nivolumab (Opdivo) for patients with advanced melanoma who have previously received anti-PD-1 therapy. The FDA cited insufficient data from the phase 1/2 IGNYTE trial, which was designed to evaluate the efficacy and safety of this combination therapy. According to the FDA, the trial results lacked adequate evidence of effectiveness due to concerns over the heterogeneity of the patient population and issues related to trial design, including the contribution of individual components of the treatment regimen.

Dr. Sushil Patel, the CEO of Replimune, the developer of RP1, expressed disappointment over the FDA's decision, noting that the issues highlighted in the CRL were not raised during prior communications with the agency. "We are surprised by this FDA decision and disappointed for patients with advanced melanoma who have limited treatment options," Dr. Patel stated in a press release issued by Replimune. "We strongly believe that RP1 in combination with nivolumab can bring substantial benefit to patients with advanced melanoma."

The IGNYTE trial (NCT03767348) enrolled patients who experienced progression following anti-PD-1 therapy. Data presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting revealed an objective response rate (ORR) of 32.9% among 140 patients treated with RP1. Notably, 15.0% of these patients achieved a complete response (CR), while 17.9% achieved a partial response (PR). Among injected lesions, a significant reduction was observed in 98.7% of cases, with 53.8% showing a complete reduction.

The trial's primary objective was to assess the safety and efficacy of RP1, utilizing modified RECIST v1.1 criteria for evaluation. Secondary endpoints included progression-free survival (PFS) and overall survival metrics. The median follow-up for the primary analysis was reported at 15.5 months, with a comprehensive assessment of safety profiles indicating that treatment-related adverse events (TRAEs) occurred in 89.4% of patients with superficial tumors and 95.5% in those with deep or visceral tumors. Common TRAEs included fatigue, pyrexia, and chills.

In light of the FDA's CRL, Replimune plans to engage with the agency to explore pathways toward accelerated approval for the RP1/nivolumab combination in this patient population. This follows the previous designation of breakthrough therapy granted to RP1 and the acceptance of its biologics license application in November 2024.

As the landscape for advanced melanoma treatment evolves, stakeholders in the oncology community await further developments regarding this promising therapy. The current status of the IGNYTE-3 trial (NCT06264180), which is investigating the efficacy of RP1 in a randomized setting alongside nivolumab for patients previously treated with anti-PD-1 and anti-CTLA-4 therapies, remains a focal point for future research and potential treatment options.