FDA Issues CRL for RP1 Plus Nivolumab for Advanced Melanoma

FDA

The FDA has issued a complete response letter (CRL) to the biologics license application seeking the approval of vusolimogene oderparepvec (RP1) in combination with nivolumab (Opdivo) for the treatment of adults with advanced melanoma who have previously received a PD-1 inhibitor–containing regimen.1,2

The CRL stated that the phase 1/2 IGNYTE trial (NCT03767348) was not considered to be an adequate and well-controlled clinical investigation that could provide substantial evidence to support approval.1 Additionally, the FDA also informed Replimune—RP1's developer—that the IGNYTE data could not be adequately interpreted due to the heterogeneity of the enrolled patient population.

The CRL also outlined items to address related to the confirmatory trial study design, including contribution of components. No safety issues were identified in the CRL.

Replimune announced it will request a Type A meeting, and the company plans to discuss a path toward accelerated approval for the agent.

IGNYTE Trial Background

Data from the IGNYTE trial, which evaluated the safety and efficacy of the combination in patients with anti–PD-1–experienced cutaneous melanoma, showed that at a median follow-up of 15.4 months, patients 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.3 The complete response (CR) and partial response (PR) rates were 15.0% and 18.6%, respectively.

A sensitivity analysis using RECIST 1.1 criteria showed a confirmed ORR of 32.9% (95% CI, 25.2%-41.3%), with respective CR and PR rates of 15.0% and 17.9%.

The IGNYTE trial enrolled 140 patients with anti–PD-1–refractory cutaneous melanoma who had at least 1 measurable and injectable lesion, no prior exposure to oncolytic virus therapy, adequate organ function, and an ECOG performance status of 0 or 1.

Patients received RP1 at 1 × 10⁶ pfu/mL in cycle 1, and in cycles 2 through 8, RP1 was given at 1 × 10⁷ pfu/mL in combination with nivolumab at 240 mg every 2 weeks. Starting in cycle 9, nivolumab monotherapy was continued at 480 mg every 4 weeks 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.

Regarding safety, the combination regimen was generally well tolerated, with most adverse effects (AEs) reported at grade 1 or 2. The most common treatment-related AEs included chills (34.0%), fatigue (33.3%), pyrexia (31.4%), nausea (22.4%), and flulike symptoms (19.2%). 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.

References

1. 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
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 July 22, 2025. https://ir.replimune.com/news-releases/news-release-details/replimune-announces-biologics-license-application-acceptance-and
3. 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.