FDA Approval Path Remains Unclear for RP1 in Melanoma

Following its Type A meeting with the FDA, Replimune reported that a forward pathway “has not been determined” to obtain accelerated approval for its oncolytic immunotherapy RP1 (vusolimogene oderparepvec) for the treatment of patients with advanced melanoma.¹

The company announced in January 2025 that the FDA had accepted its biologics license application (BLA) for use of RP1 in combination with nivolumab (Opdivo) in the advanced melanoma setting.² However, the company subsequently reported in July 2025 that it had received a complete response letter (CRL) from the FDA, explaining that it would not be approving the BLA.³

Specifically, Replimune shared that the FDA did not consider the IGNYTE trial, which supported the BLA, “to be an adequate and well-controlled clinical investigation that provides substantial evidence of effectiveness.”³ The FDA also concluded that the heterogenous population of the trial meant the results could not be “interpreted adequately.” The regulatory agency also identified issues related to the design of the confirmatory phase 3 IGNYTE-3 trial (NCT06264180), including the “contribution of components.” The Type A meeting was intended to address the issues identified in the FDA’s CRL.

Commenting in a news release following the meeting, Sushil Patel, PhD, CEO of Replimune, stated, “The feedback from the melanoma community, including patients and physicians, clearly highlights the unmet need in advanced melanoma and the compelling risk-benefit profile of RP1 observed in the IGNYTE trial. We remain committed to working with the FDA to determine an expeditious path forward for RP1.”¹

What Were the IGNYTE Trial Results Supporting the FDA Application for RP1 in Melanoma?

The primary analysis of the IGNYTE trial supporting the BLA showed that among 140 patients with advanced melanoma, the confirmed overall response rate (ORR) by independent central review was 33.6% (n = 47; 95% CI, 25.8%-42.0%), including a 15.0% (n = 21) complete response rate by modified RECIST 1.1 (mRECIST 1.1) criteria.⁴ Using RECIST 1.1, the ORR was 32.9% (n = 46; 95% CI, 25.2%-41.3%). The median duration of response (DOR) per mRECIST 1.1 was 21.6 months (95% CI, 14.5-not reached [NR]).

RP1 was also clinically active in patients with primary anti–PD-1 resistance, yielding an ORR of 34.4% in this population overall, and an ORR of 26.2% in patients who previously received PD-1 and CTLA-4 inhibitors. Regarding overall survival (OS), the 1- and 2-, and 3-year OS rates were 75.3% (95% CI, 66.9%-81.9%), 63.3% (95% CI, 53.6%-71.5%), and 54.8%, respectively. The median OS had not been reached at the time of the analysis.

Safety data showed that most treatment-related adverse events (TRAEs) were grade 1 or 2. Grade 3 or higher TRAEs were experienced by 12.8% of patients. The most frequently occurring TRAEs across all grades included fatigue (32.6%), chills (31.9%), pyrexia (30.5%), nausea (22.0%), and influenza-like illness (17.7%). Grade 3/4 TRAEs reported included fatigue, diarrhea, asthenia, arthralgia, decreased appetite (0.7% each). There were no RP1-related deaths.

Is RP1 Being Investigated in a Phase 3 Melanoma Trial?

Despite the CRL from the FDA, the confirmatory phase 3 IGNYTE-3 trial is currently enrolling patients with advanced melanoma who have progressed on anti–PD-1 and anti–CTLA-4 therapy, or who are not candidates for anti–CTLA-4 treatment.⁵ The targeted enrollment for the trial is 400 patients and the study is being conducted at multiple clinical sites. Patients in the study are receiving RP1 in combination with nivolumab. The primary end point of the trial is OS, and secondary end points include progression-free survival and ORR.³ The estimated primary completion date is January 1, 2029.

REFERENCES:

1. Replimune provides update following Type A meeting with FDA. News release. Replimune. September 18, 2025. Accessed September 19, 2025. https://tinyurl.com/cz7xf4eb

2. Replimune announces biologics license application acceptance and priority review for RP1 for the treatment of advanced melanoma. News release. Replimune. January 21, 2025. Accessed September 19, 2025. https://tinyurl.com/3tk32yy6

3. Replimune receives complete response letter from FDA for RP1 biologics license application for the treatment of advanced melanoma. News release. Replimune. July 22, 2025. Accessed September 19, 2025. https://tinyurl.com/2x2zvr58

4. Robert C, Milhem MM, Sacco JJ, et al. Primary efficacy, safety, and survival data from the registration-intended cohort of patients with anti-PD-1-failed melanoma from the IGNYTE clinical trial with RP1 combined with nivolumab. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA46

5. 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. Last updated June 18, 2025. Accessed September 19, 2025. https://clinicaltrials.gov/study/NCT06264180