FDA Issues CRL for RP1 Plus Nivolumab in Advanced Melanoma

The FDA has issued a complete response letter (CRL) for a biologics license application (BLA) seeking the approval of vusolimogene oderparepvec (RP1) in combination with nivolumab (Opdivo) for the treatment of adult patients with advanced melanoma who have progressed on an anti–PD-1–containing regimen.¹

According to the CRL, the FDA cited deficiencies related to the findings from the single-arm phase 1/2 IGNYTE trial (NCT03767348) of RP1 plus nivolumab in this patient population, as well as from the phase 3 IGNYTE-3 trial (NCT06264180) of the investigational combination compared with treatment of physician’s choice in patients with advanced melanoma who have progressed on PD-1– and CTLA-4–directed agents.

The deficiencies for IGNYTE included:

• The inability to isolate the individual contribution of RP1 to the efficacy of the regimen when administered in combination with nivolumab
• The heterogeneity of the population of patients enrolled in the trial
• The lack of clarity surrounding response assessments, including surgical interventions, which had the potential to confound response data

The deficiencies for IGNYTE-3 included:

• The limited number of patients who have been treated to date (10% of the planned trial population)
• The fact that the response assessment was solely investigator-assessed
• The lack of duration of response (DOR) data
• A lack of pre-specification and adequate type 1 error control for the submitted analysis resulted in difficulty interpreting progression-free survival (PFS) data

The FDA noted that the clinical evidence presented in these studies does not meet the regulatory approval standards. The agency further noted that findings from the additional exploratory analyses of IGNYTE are insufficient to change the initial conclusion that the trial is not an adequate, well-controlled study demonstrating substantial evidence of the efficacy of the combination in this population.

What is the regulatory history of RP1 plus nivolumab?

This is the second CRL issued for the combination in this indication. Previously, in July 2025, the FDA issued a CRL for the BLA seeking approval of the combination, citing issues with the design of the IGNYTE trial that led to a lack of substantial evidence to support approval.² This CRL noted items to be addressed regarding the trial’s design, including the need to demonstrate the isolated contribution of RP1 to the overall efficacy profile of the combination.

Based on this feedback, Replimune, the developer of RP1, requested a Type A meeting with the FDA, during which the company and the regulatory agency discussed a path toward the potential accelerated approval of the combination.³ Following the Type A meeting, Replimune resubmitted the BLA, which the FDA accepted for review.⁴ The resubmitted BLA included additional trial data, study information, and analyses.

What was the design of the IGNYTE trial?

IGNYTE is a single-arm trial evaluating RP1 in combination with nivolumab in patients with unresectable stage IIIB to IV cutaneous melanoma who experienced disease progression following at least 8 weeks of anti–PD-1 therapy.⁵

Eligible patients were required to have at least 1 measurable lesion per RECIST 1.1 criteria and at least 1 injectable lesion measuring 1 cm or greater. Patients were excluded if they had received prior oncolytic therapy, were receiving antiviral therapy, or had experienced serious complications from prior immune checkpoint inhibition.

Patients received RP1 at an initial dose of 1 × 10⁶ plaque-forming units (PFU)/mL, followed by 7 additional doses at 1 × 10⁷ PFU/mL every 2 weeks. Nivolumab was initiated at the second RP1 dose and administered at 240 mg every 2 weeks for up to 8 cycles, then at 480 mg every 4 weeks for up to 21 additional cycles. Additional RP1 doses were permitted if clinically indicated.

The primary end point of the trial was overall response rate (ORR) per modified RECIST 1.1 criteria. Secondary end points included DOR, complete response (CR) rate, PFS, and overall survival (OS).

What were some of IGNYTE’s key efficacy and safety findings?

Findings from the study published in the Journal of Clinical Oncology demonstrated that evaluable patients with advanced melanoma who experienced confirmed progression on prior anti–PD-1 therapy (n = 140) achieved an ORR of 32.9% (95% CI, 25.2%-41.3%), including a CR rate of 15.0% (95% CI, 9.5%-22.0%). Furthermore, the median DOR was 33.7 months (95% CI, 14.1-not reached). Additionally, the respective 1- and 2-year OS rates were 73.5% (95% CI, 66.9%-81.9%) and 63.3% (95% CI, 53.6%-71.5%).

The safety profile of RP1 plus nivolumab was consistent with the known profiles of oncolytic therapies and immune checkpoint inhibitors. Treatment-related adverse effects (TRAEs) of any grade occurred in 90.0% of patients, with 12.9% of patients experiencing grade 3 or 4 TRAEs.

The most common TRAEs of any grade included fatigue (32.9%), chills (32.1%), pyrexia (30.7%), and nausea (22.1%). Grade 4 TRAEs occurred in 3.6% of patients and included cytokine release syndrome, hepatic cytolysis, increased lipase, myocarditis, and splenic rupture. Notably, no treatment-related deaths were reported.

References

1. Complete response letter for BLA 125827. FDA. Accessed April 10, 2026. https://download.open.fda.gov/crl/CRL_BLA125827_20260410.pdf
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 April 10, 2026. https://ir.replimune.com/news-releases/news-release-details/replimune-receives-complete-response-letter-fda-rp1-biologics
3. Replimune provides update following Type A meeting with FDA. News release. Replimune. September 18, 2025. Accessed April 10, 2026. https://ir.replimune.com/news-releases/news-release-details/replimune-provides-update-following-type-meeting-fda
4. Replimune announces FDA acceptance of BLA resubmission of RP1 for the treatment of advanced melanoma. News release. Replimune. October 20, 2025. Accessed April 10, 2026. https://ir.replimune.com/news-releases/news-release-details/replimune-announces-fda-acceptance-bla-resubmission-rp1-0
5. Wong MK, Milhem MM, Sacco JJ, et al. RP1 combined with nivolumab in advanced anti-PD-1-failed melanoma (IGNYTE). J Clin Oncol. 2025;43(33):3589-3599. doi:10.1200/JCO-25-01346