The FDA’s Cellular, Tissue, and Gene Therapies Adivosry Committee (CTGTAC) voted 10 to 3 that the benefit-risk profile of vusolimogene oderparepvec (RP1) in combination with nivolumab (Opdivo) is favorable for adult patients with advanced melanoma who have progressed on a prior anti–PD-1–containing regimen.1 The vote, came ahead of an August 2, 2026, Prescription Drug User Fee Act (PDUFA) target action date and followed 2 complete response letters (CRLs) across a biologics license application (BLA) process that had stretched through 3 review cycles.
“I did vote no it’s my profession to have the level of evidence and evaluation. I’m not in the clinically meaningful side of things, so my vote is driven by that. There is so much uncertainty to what that overall response rate is,” Karla Ballman, PhD, consultant, Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Consultant, Division of Medical Oncology, Department of Oncology, and chair, Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, said during the meeting.
“I voted yes for various reasons, but I also share some [hesitation] that other people have explained. The FDA did a wonderful job in pointing out some deficits of this trial design. Ninety-six percent of patients had 12 weeks or more of PD-1–based therapy, and they had confirmatory scans confirming they had progression. This is a very hard-to-treat patient population. The only thing that changed was these patients [received] RP1 and had some [complete responses] and some partial responses. I do believe, and some of the data does show that these patients are getting benefit from RP1. With that being said, we do need the phase 3 data to fully answer this question. Also as a community, we need to figure out how to better design trials for intratumoral therapies,” Melinda L. Yushak, MD, MPH, assistant professor, Department of Hematology and Medical Oncology at Emory University School of Medicine, and co-chair, Melanoma Working Group at Winship Cancer Institute of Emory University, said during the meeting.
The Question Before the Committee
Committee members were asked to weigh whether data from the phase 1/2 IGNYTE trial (NCT03767348), a single-arm study, demonstrated substantial evidence of effectiveness for RP1 plus nivolumab in patients whose melanoma had progressed on anti–PD-1 therapy, despite the trial’s lack of a randomized comparator.
RP1 entered the regulatory pipeline in November 2024, when the FDA granted breakthrough therapy designation to the combination and Replimune submitted a BLA under the accelerated approval pathway.2 The agency accepted the application with priority review in January 2025, setting an initial PDUFA date of July 22, 2025.3 On July 21, 2025, the FDA issued a CRL, finding that IGNYTE was not an adequate and well-controlled clinical investigation capable of providing substantial evidence of effectiveness, and citing heterogeneity within the enrolled patient population along with unresolved questions about the trial’s design; the agency did not raise safety concerns.4
Replimune scheduled a Type A meeting with the FDA in September 2025, submitting a briefing book addressing the patient population, criteria used to define anti–PD-1 resistance, and literature supporting the combination’s contribution of components.5 The FDA accepted a resubmitted BLA in October 2025 under a Class II timeline, setting a PDUFA date of April 10, 2026.6 That cycle produced a second CRL, with the agency again concluding that IGNYTE could not be considered a well-controlled trial.7 In June 2026, the FDA accepted a third resubmission as a complete, Class I response, setting the current August 2, 2026, PDUFA date and scheduling the advisory committee meeting whose outcome is detailed above.8
The IGNYTE trial enrolled 140 patients with advanced melanoma who had confirmed disease progression on an anti–PD-1–based regimen used for at least 8 weeks.9 By independent central review, the confirmed overall response rate (ORR) was 33.6% using modified RECIST v1.1 criteria, including a 15.0% complete response (CR) rate, and 32.9% by standard RECIST v1.1 criteria. Median duration of response exceeded 35 months in an earlier analysis, and response rates varied by subgroup, with an ORR of 27.0% among patients previously exposed to both anti–PD-1 and anti–CTLA-4 therapy and 34.3% among those with a single degree of resistance to anti–PD-1 therapy.
A 3-year landmark overall survival (OS) analysis presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, and referenced during the discussion, showed a median OS of 32.9 months, with 1-year, 2-year, and 3-year OS rates of 75.3%, 61.5%, and 47.8%, respectively; the median OS was not reached among responders, compared with 18.5 months among non-responders.10Data on deep and visceral tumor injections, including into lung and liver lesions, were also discussed, with committee members noting the feasibility of these injections and the low rate of self-resolving pneumothorax events among lung injections.11
Although the FDA is expected to decide by August 2, 2026, the confirmatory phase 3 IGNYTE-3 trial (NCT06264180), which is randomly assigning patients to RP1 plus nivolumab against a physician’s choice comparator, remains ongoing and is expected to serve as the basis for any post-marketing confirmatory requirement attached to an approval for clinicians managing anti–PD-1–refractory melanoma.
1. Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC) Meeting. July 30, 2026. Accessed July 30, 2026. https://tinyurl.com/2n96zk7u
2. Replimune receives breakthrough therapy designation for RP1 and submits RP1 biologics license application to the FDA under the accelerated approval pathway. News release. Replimune. November 21, 2024. Accessed July 23, 2026. https://tinyurl.com/2p8ym2tj
3. Replimune announces biologics license application acceptance and priority review for RP1 for the treatment of advanced melanoma. News release. Replimune. January 21, 2025. Accessed July 23, 2026. https://tinyurl.com/94jc39by
4. 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 July 23, 2026. https://tinyurl.com/2335n7sk
5. Replimune announces Type A meeting scheduled with FDA. News release. Replimune. September 2, 2025. Accessed July 23, 2026. https://tinyurl.com/y95a24u6
6. Replimune announces FDA acceptance of BLA resubmission of RP1 for the treatment of advanced melanoma. News release. Replimune. October 20, 2025. Accessed July 23, 2026. https://tinyurl.com/5yad7vza
7. Complete response. April 10, 2026. FDA. Accessed April 10, 2026. https://tinyurl.com/ys3etmrj
8. Replimune announces FDA acceptance of RP1 biologics license application resubmission for advanced melanoma. News release. Replimune Group, Inc. June 26, 2026. Accessed July 23, 2026. https://tinyurl.com/4sdytzn4
9. Replimune announces positive topline primary analysis data by independent central review from IGNYTE clinical trial of RP1 plus nivolumab in anti-PD1 failed melanoma. News release. Replimune Group, Inc. June 6, 2024. Accessed July 23, 2026. https://tinyurl.com/mr3jxyh5
10. Wong MKK, Sacco JJ, In GK, et al. A 3-year landmark overall survival analysis of RP1 plus nivolumab in patients with anti–PD-1–failed melanoma from the IGNYTE clinical trial. J Clin Oncol. 2026;44(suppl 16):9518. doi:10.1200/JCO.2026.44.16_suppl.9518
11. In GK, Wong MKK, Sacco JJ, et al. Response analysis for injected and non-injected lesions and of the safety and efficacy of superficial and deep/visceral RP1 injection in the registrational cohort of anti–PD-1–failed melanoma patients of the IGNYTE trial. J Clin Oncol. 2025;43(suppl 16):9537. doi: 10.1200/JCO.2025.43.16_suppl.9537
