Path Toward Accelerated Approval of RP1 in Advanced Melanoma Remains Unclear After FDA Type A Meeting

Replimune has completed a Type A meeting with the FDA after a complete response letter (CRL) was issued by the regulatory agency for the biologics license application (BLA) seeking the approval of RP1 (vusolimogene oderparepvec) in combination with nivolumab (Opdivo) for the treatment of patients with advanced melanoma.1

Following the meeting, Replimune—the developer of RP1— announced that the company is reviewing the feedback provided by the FDA; however, a path toward accelerated approval of the oncolytic virus–based combination has not yet been determined.

“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,” Sushil Patel, PhD, CEO of Replimune, stated in a news release. “We remain committed to working with the FDA to determine an expeditious path forward for RP1.”

In July 2025, the FDA issued the CRL for the BLA seeking the approval of RP1 in combination with nivolumab for the treatment of adults with advanced melanoma who have previously received a PD-1 inhibitor–containing regimen.2,3 The CRL detailed that the phase 1/2 IGNYTE trial (NCT03767348) did not meet the threshold to be considered an adequate and well-controlled clinical investigation to produce substantial evidence supporting approval.2

What Did Data From the IGNYTE Trial Show?

Findings from the registration-intended cohort of IGNYTE demonstrated that at a median follow-up of 15.4 months (range, 0.5-47.6), patients treated with RP1 plus nivolumab (n = 140) achieved a confirmed overall response rate (ORR) of 33.6% (95% CI, 25.8%-42.0%) per modified RECIST 1.1 criteria by blinded independent central review.4 The complete response (CR) rate was 15.0%, and the partial response (PR) rate was 18.6%.

Per a sensitivity analysis using RECIST 1.1 criteria in the same population, the confirmed ORR was 32.9% (95% CI, 25.2%-41.3%), with CR and PR rates of 15.0% and 17.9%, respectively.

IGNYTE enrolled patients with anti–PD-1–refractory advanced melanoma who had measurable disease, no prior exposure to oncolytic virus therapy, adequate organ function, and an ECOG performance status of 0 or 1.

RP1 was administered to all patients at 1 × 10⁶ pfu/mL in cycle 1, then at 1 × 10⁷ pfu/mL in combination with nivolumab at 240 mg every 2 weeks in cycles 2 through 8. Starting in cycle 9, nivolumab monotherapy was continued at 240 mg, then increased to 480 mg every 4 weeks from cycle 10 through cycle 30.

The primary end points of the study were safety and ORR. Secondary end points included duration of response, disease control rate, progression-free survival, and 1- and 2-year overall survival rates.

What Is the Safety Profile of RP1 Plus Nivolumab?

Safety findings from IGNYTE showed that most adverse effects (AEs) occurred at grade 1 or 2; 89.4% of patients (n = 141) experienced at least 1 any-grade treatment-related AE (TRAE), and 12.8% had grade 3 or 4 TRAEs. The most common any-grade TRAEs included fatigue (32.6%), chills (31.9%), pyrexia (30.5%), nausea (22.0%), and flulike symptoms (17.7%). No grade 5 AEs were reported.

The combination of RP1 and nivolumab is being further investigated in the confirmatory phase 3 IGYNTE-3 trial (NCT06264180), where investigators are enrolling patients with advanced melanoma who have progressed on anti–PD-1 and anti–CTLA-4 therapies or are ineligible for treatment with an anti–CTLA-4 agent.

Is RP1 Being Investigated in Any Other Clinical Trials?

The ongoing, randomized, open-label, multicenter, phase 3 IGNYTE-3 trial (NCT06264180) is evaluating RP1 plus nivolumab vs physician’s choice of therapy in patients with stage IIIB to IV cutaneous melanoma who experienced disease progression following treatment with anti–PD-1 and anti–CTLA-4 therapies, given either in combination or sequenced.5

References

1. Replimune provides update following Type A meeting with FDA. News release. Replimune. September 18, 2025. Accessed September 18, 2025. https://ir.replimune.com/news-releases/news-release-details/replimune-provides-update-following-type-meeting-fda
2. 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 July 22, 2025. https://ir.replimune.com/news-releases/news-release-details/replimune-receives-complete-response-letter-fda-rp1-biologics
3. Replimune announces biologics license application acceptance and priority review for RP1 for the treatment of advanced melanoma. News release. Replimune. January 21, 2025. Accessed July 22, 2025. https://ir.replimune.com/news-releases/news-release-details/replimune-announces-biologics-license-application-acceptance-and
4. Wong M, Bommareddy PK, Middleton MR, et al. Primary analysis of the registration-intended cohort of patients with anti–PD-1–failed melanoma from the IGNYTE trial of RP1 plus nivolumab, including clinical subgroup and initial biomarker data. Presented at: 2024 SITC Annual Meeting; November 6-10, 2024; Houston, TX. Abstract 1504
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. Updated June 18, 2025. Accessed September 18, 2025. https://clinicaltrials.gov/study/NCT06264180