FDA Accepts Third RP1 BLA Resubmission With Nivolumab in Advanced Melanoma

The FDA has accepted for review the resubmission of the biologics license application (BLA) seeking accelerated approval of vusolimogene oderparepvec (RP1) in combination with nivolumab (Opdivo) for the treatment of patients with advanced melanoma.¹ The announcement follows two prior complete response letters issued by the regulatory agency.²

The FDA has labeled this a complete, class 1 response with a goal date of August 2, 2026, and has alerted the developer, Replimune of an advisory committee meeting in late July.

The BLA is based on data from the phase 1/2 IGNYTE trial (NCT03767348), which demonstrated a blinded independent central review–assessed objective response rate (ORR) of 33.6% (95% CI, 25.8%-42.0%) by modified RECIST (mRECIST) and 32.9% (95% CI, 25.2%-41.3%) by RECIST 1.1 in patients with documented progression on an anti–PD-1-containing regimen (n = 140).^1,3

“We are pleased that the FDA has demonstrated urgency in reconsidering the RP1 BLA with an expeditious action date in recognition of the significant unmet need for advanced melanoma patients and support from the broader melanoma community,” Sushil Patel, PhD, chief executive officer of Replimune, stated in a news release.¹ “We look forward to a productive scientific and clinical discussion on the risk/benefit profile of RP1 in this difficult-to-treat setting.”

What was the design of the IGNYTE trial and who was enrolled?

The single-arm IGNYTE trial evaluated the combination of RP1 and nivolumab in patients with unresectable stage IIIB to IV cutaneous melanoma who experienced disease progression after at least 8 weeks of anti–PD-1 therapy.³

To be eligible for enrollment, patients had to have one or more measurable lesions per RECIST 1.1 criteria and at least 1 injectable lesion measuring at least 1 cm in diameter. Exclusion criteria included prior oncolytic therapy, antiviral therapy, or history of serious complications from prior immune checkpoint inhibitor therapy.

RP1 was administered 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 started in the second cycle of RP1 and given at a dose of 240 mg every 2 weeks for up to 8 cycles, followed by 480 mg every 4 weeks for up to 21 additional cycles. RP1 therapy could be continued if clinically indicated.

ORR per mRECIST 1.1 criteria served as the primary end point of the trial. Secondary end points included duration of response (DOR), complete response (CR) rate, progression-free survival (PFS), and overall survival (OS).

What other efficacy and safety outcomes have been reported?

Additional efficacy data from 2025 revealed that the median DOR was 33.7 months (95% CI, 14.1-not reached). With respect to survival, the median PFS for all patients was 3.6 months (95% CI, 2.0-5.0). The 1- and 2-year OS rates were 75.3% (95% CI, 66.9%-81.9%) and 63.3% (95% CI, 53.6%-71.5%), respectively, with the median OS not reached.

The regimen showed a safety profile comparable to the known profiles of oncolytic therapies and immune checkpoint inhibitors. Any-grade and grade 3/4 treatment-related adverse effects (TRAEs) were reported in 90.0% and 12.9% of patients, respectively.

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

At the 2026 ASCO Annual Meeting, updated results from the trial indicated that the regimen upheld encouraging survival, with a median of 32.9 months. The 3-year OS rate was 47.8% and jumped to 83.5% in responders. The ORR remained stable at 33.6%, with a median DOR of 24.8 months; 44.8% of responders remained in response at 3 years. Notably, the OS benefit was seen irrespective of disease stage, PD-L1 expression status, prior anti–CTLA-4 therapy, and primary or secondary anti–PD-1 resistance.

No new safety signals were reported, with most long-term events being grade 1/2.

“The OS analysis from IGNYTE shows that nearly half of all treated patients in the study were alive at three years, including 83.5% of responders to RP1 plus nivolumab,” Kostas Xynos, MD, PhD, MBA, chief medical officer of Replimune, added in a separate news release. “This represents a durable benefit that is rarely seen in anti–PD-1-failed melanoma, a setting with historically limited treatment options.”

References

1. Replimune announces FDA acceptance of RP1 biologics license application resubmission for advanced melanoma. June 26, 2026. Accessed June 26, 2026. News release. Replimune Group, Inc. https://ir.replimune.com/news-releases/news-release-details/replimune-announces-fda-acceptance-rp1-biologics-license
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 June 26, 2026. https://ir.replimune.com/news-releases/news-release-details/replimune-receives-complete-response-letter-fda-rp1-biologics
3. 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
4. Replimune presents 3-year landmark overall survival analysis from IGNYTE clinical trial during oral presentation at the 2026 American Society of Clinical Oncology Annual Meeting. News release. Replimune Group, Inc. May 30, 2026. Accessed June 26, 2026. https://ir.replimune.com/news-releases/news-release-details/replimune-presents-3-year-landmark-overall-survival-analysis