What was the committee asked to consider?
On July 30, the U.S. Food and Drug Administration (FDA) convened the Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC) to consider data intended to support accelerated approval of a regimen combining intratumoral vusolimogene oderparepvec (RP1), a novel oncolytic immunotherapy from Replimune, and systemic nivolumab for adult patients with advanced melanoma who progressed on an anti-PD-1-containing regimen. This meeting was convened after Replimune submitted the application for a third time following two complete response letters FDA issued in July 2025 and April 2026.
The FDA asked the committee to discuss two topics: 1) whether the single-arm IGNYTE study, as designed and conducted, allows for a reliable determination of response rate and durability of response in the proposed population, and 2) the clinical meaningfulness of those results, including whether the observed responses reflect systemic antitumor activity attributable to RP1. Underlying both topics were concerns about response assessment, contribution of effect, and overall survival (OS) interpretability.
Why does this matter for patients and drug development?
Addressing High Unmet Need
The open public hearing included statements on the transformative potential of RP1 from patients, caregivers, advocates, and physicians. Their remarks highlighted the significant unmet need among patients with advanced melanoma, including PD-1-refractory disease, who have exhausted other lines of therapy and/or experienced the often-severe toxicities of existing treatment options. Patient testimonies emphasized that approving RP1 would give more patients access to a tolerable option offering better quality of life and noted that RP1 is more accessible than other options for this patient population, such as tumor-infiltrating lymphocyte (TIL) therapy, which requires treatment at specialized centers and intensive supportive care.
Measures for Assessing Intratumoral Therapies
Presentations and discussions highlighted challenges in evaluating response to intratumoral therapies and the need for tailored measures and regulatory guidance. RECIST v1.1, the standard set of criteria for assessing treatment response, was designed to assess response to systemic therapies; however, the IGNYTE trial applied these criteria to assess response to an intratumoral (i.e., local) treatment. The FDA and committee members acknowledged this tension and the lack of standardized response criteria for intratumoral therapies, calling for guidance and efforts to develop tailored measures to support future trials.
What was discussed?
Replimune’s presentation focused on the significant unmet need in PD-1-refractory melanoma and positive safety and efficacy signals observed in IGNYTE, including an objective response rate (ORR) of 33.6% and median duration of response (DOR) of 24.8 months. The presentation also characterized RP1’s safety profile as manageable. The company addressed concerns about the response-assessment methodology and pointed to responses in non-injected lesions as evidence of systemic antitumor activity. Replimune also presented mechanism-of-action and biomarker data supporting RP1’s dual role in resetting the immune-resistant tumor microenvironment and helping overcome PD-1 resistance. The company also noted that a randomized confirmatory trial, IGNYTE-3, is already underway and could provide further data to resolve outstanding questions and confirm benefit.
In its presentation, the FDA argued that the ORR and DOR results were unreliable and difficult to interpret, that the sponsor had not demonstrated contribution of effect, and that the OS analyses were not interpretable. The FDA pointed to several confounding factors in the sponsor’s response analysis, such as the inclusion of injected lesions in response assessments, treatment and reinjection of lesions following progression, procedures on lesions (including resections and excisional biopsies), and retrospective changes to response designations. In an FDA analysis excluding responses in patients who had all target lesions injected or no target lesions at baseline (22 out of 140 evaluable patients), ORR and DOR results were less favorable: 15.7% ORR and a median DOR of 14.1 months. Because Replimune studied RP1 in combination with an already approved agent, the FDA questioned whether the sponsor had established each component’s contribution and maintained that the sponsor could not attribute survival data to the regimen without a concurrent control.
The committee’s discussion touched on what constitutes a “large magnitude” of effect sufficient to support accelerated approval, whether the ORR and DOR results could be trusted given the methodological issues, and how to weigh clinical meaningfulness against safety, quality of life, and comparisons to existing options like TIL therapy. Members also discussed the broader challenge of evaluating intratumoral therapies under existing frameworks, and the practical advantages of RP1, including ease of administration and off-the-shelf availability, relative to more complex advanced therapies.
What are the outcomes and implications of the meeting?
The committee voted 10 to 3 that “the efficacy results from IGNYTE are evaluable and clinically meaningful.” Those voting yes acknowledged the limitations of IGNYTE, but explained that their votes were swayed by the severity of unmet need, the plausibility that there is a genuine signal of activity, and the ongoing confirmatory randomized clinical trial, IGNYTE-3, that can provide additional evidence to resolve outstanding questions. IGNYTE-3 was initiated based on FDA feedback so that a confirmatory study would be underway at the time of a potential accelerated approval, reflecting how the pathway is intended to operate and shaping how members weighed residual uncertainty in the single-arm data. Those voting no cited methodological concerns in assessing response, unresolved questions about OS and contribution of effect, and risk to patients absent clearly demonstrated benefit.
The discussion reinforced ongoing questions about how existing response criteria (i.e., RECIST v1.1) and regulatory frameworks apply to intratumoral and other novel local therapies, how sponsors can adequately demonstrate contribution of effect, and the extent to which flexibility can be applied in areas of high unmet need.
CTGTAC meeting materials and recording are available here: CTGTAC July 30, 2026 Meeting Announcement