FDA Panel Votes 10-3 In Favor of RP1 Plus Nivolumab for Advanced Melanoma

The FDA's Cellular, Tissue, and Gene Therapies Advisory Committee voted 10-3 in favor of the IGNYTE study (NCT03767348) supporting the potential accelerated approval of vusolimogene oderparepvec (RP1; Tudriqev) plus nivolumab (Opdivo) in patients with advanced melanoma who previously received anti–PD-1 therapy.

Although many of the committee members expressed reservations about the study design and interpretation that were highlighted by the FDA, they viewed the benefit seen in IGNYTE as of significant magnitude beyond historical controls and believed the unmet need in this setting justified the use of the response and durability to support an accelerated approval.

Disease Background and Unmet Need

Advanced, unresectable cutaneous melanoma remains a serious and life-threatening disease despite recent progress in systemic therapy. Michael Wong, MD, PhD, FRCPC, presenting disease background on behalf of the applicant, Replimune, Inc, told the committee that more than 110,000 new melanoma cases and roughly 8500 deaths occur annually in the United States, and that about half of patients with advanced disease progress within the first 12 months of treatment. Real-world 5-year survival with distant metastatic disease has improved from 17% in 2016 to approximately 35% in 2026.

Wong noted that lifileucel (Amtagvi), the only approved tumor-infiltrating lymphocyte (TIL) therapy for this population, carries a treatment-related death rate of about 7.5% and requires complex, resource-intensive logistics that limit which patients can access it, arguing that the field needs options that more patients can tolerate and receive.

Applicant's Case for RP1 Plus Nivolumab

Kevin Harrington, MD, PhD, FRCP, FRCR, FRSB, of the Institute of Cancer Research, described RP1 as an HSV-1-derived oncolytic virus engineered to express granulocyte-macrophage colony-stimulating factor (GM-CSF) and a fusogenic glycoprotein, GALV-GP-R⁻, designed to drive local tumor lysis and prime a secondary systemic immune response when the virus is combined with nivolumab.

Kostas Xynos, MD, PhD, MBA, Replimune's chief medical officer, presented the IGNYTE efficacy and safety data underlying the application, including a 3-year overall survival (OS) rate of 47.8% and a median duration of response (DOR) not yet reached at 24.8 months. Xynos characterized the safety profile as manageable, citing a severe adverse event rate of 35.7%, dose interruptions in 22.9% of patients, discontinuations in 7.9%, and an 8.6% rate of death, none of which the company attributed to treatment.

Mohammed Milhem, MBBS, of the University of Iowa, also presenting on behalf of the applicant, offered a clinical perspective drawn from case studies spanning adjuvant, multiply pretreated, and visceral-disease patients. He told the committee he had yet to identify a patient in his own practice suitable for TIL therapy and urged the panel to apply pragmatism, “as patients cannot wait.”

FDA Position

The FDA presented 3 primary issues with the study being considered adequate to support FDA accelerated approval. The FDA stressed the accelerated approval should have the same standard as regular approval, and the bar should not be considered lower. The 3 primary issues led to the main topics of discussion by the committee and presenters.

Applicant's reported ORR and DOR are unreliable and difficult to interpret.

“Interpretation of responses to intratumoral therapies is challenging,” acknowledged Katherine Barnett, MD, acting branch chief of Oncology Branch 2 in the FDA’s Center for Biologics Evaluation and Research. “RECIST criteria were designed to assess response to systemic therapy and may not distinguish the local effect of intratumoral injection from a systemic effect. This is particularly difficult when [intratumoral] therapy is combined with a systemic therapy as in the IGNYTE study.”

By RECIST v1.1 criteria used in the IGNYTE study, focal intervention generally renders treated lesions nonevaluable. Various injected therapies can have high local effect but unclear systemic effect. Up to 5 lesions are target lesions for imaging assessment.

In IGNYTE, many patients were treated with RP1 in multiple target lesions, whereas others had systemic responses without direct injection. The FDA expressed concern that the systemic effect was not adequately demonstrated and additional local interventions or procedures such as biopsies could contribute to response in target lesions rather than the systemic effect. The FDA was concerned that over half of patients did not have uninjected target lesions.

The reported overall response rate (ORR) was 33.6% and the duration of response (DOR) was 24.8% among the 140-patient cohort. Replimune presented a lesion-level analysis showing a similar depth and frequency of response in injected (31.5%) and noninjected (28.7%) target lesions, including in visceral sites such as lung and liver, which the company presented as evidence of a systemic effect. However, the FDA presented their own primary analysis, excluding all patients with all target lesions injected or no target lesions at baseline, and found an ORR of 15.7% and DOR of 14.1 months.

Taken in total, Barnett said that the results were “essentially a different end point” that cannot be compared with historical controls.

Contribution of effect and need for each product not demonstrated

The FDA previously advised that the applicant perform a randomized comparison with nivolumab alone in the IGNYTE trial or the confirmatory IGNYTE-3 trial (NCT06264180). The applicant declined, stating that the known response rate to anti–PD-1 retreatment was between 5% and 7%, making it impossible to enroll patients in such an arm with clinical equipoise. The FDA agreed to review data from the single-arm trial based on the unmet need but sought a greater magnitude of benefit.

Barnett cited several analyses with higher ORRs ranging from 12% to 54% after prior anti–PD-1 therapy, and stated that no single historical control could be compared with the IGNYTE population. She also highlighted that in the CERPASS study (NCT04050436) of RP1 plus cemiplimab (Libtayo) in squamous cell carcinoma, the primary end points were not met, suggesting no synergistic effect. Although a different disease, this raised questions of generalizability of the mechanism of action.

Applicant's submitted overall survival (OS) analysis not interpretable

The exploratory 3-year OS analysis was deemed by the FDA as not interpretable as time-to-event end points are difficult to interpret in single-arm trials.

Cross-trial comparisons are limited, as 29% had stage III disease, 19% had skin-only disease, and 25.7% had been treated in the adjuvant setting, which could lead to more favorable prognosis.

The FDA also identified 3 deaths possibly related to treatment: an injection-site injury, sepsis from a tumor hemorrhage, and capillary leak syndrome. The FDA also noted that nivolumab's known safety profile includes severe immune-mediated toxicities.

Committee Discussion and Voting

Panelists split over how to weigh RECIST-based response data against clinical plausibility. Hussein Tawbi, MD, PhD, argued that the persistence of durable, nonprogressing distant lesions years out is itself evidence of a systemic effect, whereas Raymond Chapman, MD, countered that intratumoral injection of melanoma dates back to 1891 and that almost none of those historical approaches demonstrated a true abscopal effect on uninjected disease, calling the data “fantastic for a phase 2 trial” but “poor for a registrational one.” Jorge Garcia, MD, disputed the notion that unmet need should lower the evidentiary bar, while acknowledging that, in his own clinical practice, physicians already treat outside RECIST's strict framework.

David Miller, MD, and William Gradishar, MD, both described the totality of response and durability data as borderline but clinically meaningful, with Miller stating the finding was “borderline, but acceptable with significant limitations.” Diane Aronson, the patient representative, voted negatively, saying she was thinking of all the patients. “Hope is important, but reality weighed into my vote,” she said.

Many noted that their decision was secured by the fact that the IGNYTE-3 study, with OS results expected in 2030, would provide fuller results, and in the meantime, patients deserved access to this therapy.

Conclusion

The 10-3 vote does not bind the FDA's final decision on BLA 125827, but advisory committee recommendations typically carry significant weight in the agency's review. If accelerated approval is granted, it would likely be contingent on confirmatory evidence from IGNYTE-3, including the overall survival data expected in 2030, to verify the clinical benefit suggested by the response and durability data reviewed at this meeting. For now, the committee's vote reflects a panel that, despite substantial reservations about response assessment, contribution of effect, and survival interpretability, judged the unmet need in anti–PD-1-refractory melanoma sufficient to support moving RP1 plus nivolumab forward.

REFERENCE
Meeting of the Cellular, Tissue, and Gene Therapies Advisory Committee. FDA. July 30, 2026. Accessed July 30, 2025. https://tinyurl.com/2yjnd7r3