Will the FDA approve a resubmitted biologics license application for RP1 plus nivolumab in advanced melanoma after progression on anti–PD-1 therapy?
The FDA has accepted the resubmission of a biologics license application (BLA) seeking the approval of vusolimogene oderparepvec (RP1) in combination with nivolumab (Opdivo) for the treatment of patients with advanced melanoma who have progressed on an anti–PD-1–containing regimen.1
The FDA has assigned a target action date of April 10, 2026, based on a class II resubmission timeline.
The resubmission of the BLA follows a July 2025 complete response letter (CRL) issued by the regulatory agency for the initial application for RP1 plus nivolumab in the same indication.2 In the CRL, the FDA explained 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.
In the months following the CRL, Replimune—the developer of RP1—has worked with the FDA to address feedback from the letter, including a Type A meeting with the regulatory agency.1,3 The resubmitted BLA features additional information, data, and analyses, and Replimune announced that the FDA considered this resubmission a complete response to the CRL.1
“We are pleased the agency has accepted the resubmission of our BLA for RP1,” Sushil Patel, PhD, chief executive officer of Replimune, stated in a news release. “RP1 plus nivolumab offers a strong risk benefit profile where there are few options for patients with advanced melanoma who have progressed on PD-1–based therapy. We look forward to working closely with the agency to expedite this review as much as possible for patients’ benefit.”
FDA Acceptance of BLA Resubmission for RP1 Plus Nivolumab in Advanced Melanoma
The FDA has accepted the resubmission of the BLA for RP1 in combination with nivolumab for treating patients with advanced melanoma who have progressed on an anti–PD-1 regimen, assigning a target action date of April 10, 2026.
Clinical findings from the supporting IGNYTE trial in evaluable patients demonstrated meaningful efficacy for RP1 plus nivolumab, including an ORR of 32.9% and a CR rate of 15.0%, alongside a median DOR of 33.7 months.
The combination had a safety profile where TRAEs of any grade occurred in 90.0% of patients, but TRAEs did not lead to any deaths.
What did data from the IGNYTE trial show for RP1 plus nivolumab in advanced melanoma?
Findings from the study published in the Journal of Clinical Oncology showed that evaluable patients with advanced melanoma with confirmed progression on anti–PD-1 therapy (n = 140) experienced an overall response rate (ORR) of 32.9% (95% CI, 25.2%-41.3%), including a complete response (CR) rate of 15.0% (95% CI, 9.5%-22.0%).4 The median duration of response (DOR) was 33.7 months (95% CI, 14.1-not reached). The 1- and 2-year overall survival (OS) rates were 73.5% (95% CI, 66.9%-81.9%) and 63.3% (95% CI, 53.6%-71.5%), respectively.
The study included patients at least 18 years of age with unresectable stage IIIB to IV cutaneous melanoma who experienced confirmed disease progression following at least 8 weeks of treatment with an anti–PD-1 agent, either as monotherapy or as part of a combination regimen. Treatment in the adjuvant setting as the last line of therapy was permitted. Other key inclusion criteria comprised at least 1 measurable lesion per RECIST 1.1 criteria and injectable lesions with a longest diameter of at least 1 cm. Patients were excluded if they had received prior oncolytic therapy, were receiving current antiviral therapy, or had serious complications with prior immune checkpoint inhibition.
All patients in the single-arm, registration-intended cohort 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 it was administered at 240 mg every 2 weeks for up to 8 cycles, followed by 480 mg once every 4 weeks for up to an additional 21 cycles. Additional doses of RP1 beyond the planned 8 were allowed if clinically indicated.
ORR per modified RECIST 1.1 criteria served as the trial’s primary end point. Secondary end points included DOR, CR rate, progression-free survival, and 1- and 2-year OS rates.
What is the safety profile of RP1 plus nivolumab in advanced melanoma?
Treatment-related adverse effects (TRAEs) of any grade occurred in 90.0% of patients, including 12.9% of patients who had a grade 3/4 TRAE. The most common TRAEs of any grade that occurred in at least 20% of patients included fatigue (32.9%), chills (32.1%), pyrexia (30.7%), and nausea (22.1%).
Grade 4 TRAEs (3.6%) included cytokine release syndrome, hepatic cytolysis, increased lipase levels, myocarditis, and splenic rupture, which were all reported in 1 patient each. TRAEs did not lead to any deaths.
References
Replimune announces FDA acceptance of BLA resubmission of RP1 for the treatment of advanced melanoma. News release. Replimune. October 20, 2025. Accessed October 20, 2025. https://ir.replimune.com/news-releases/news-release-details/replimune-announces-fda-acceptance-bla-resubmission-rp1-0
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 October 20, 2025. https://ir.replimune.com/news-releases/news-release-details/replimune-receives-complete-response-letter-fda-rp1-biologics
Replimune provides update following Type A meeting with FDA. News release. Replimune. September 18, 2025. Accessed October 20, 2025. https://ir.replimune.com/news-releases/news-release-details/replimune-provides-update-following-type-meeting-fda
Wong MK, Milhem MM, Sacco JJ, et al. RP1 combined with nivolumab in advanced anti-PD-1-failed melanoma (IGNYTE). J Clin Oncol. Published online July 8, 2025. doi:10.1200/JCO-25-01346
