FDA CTGTAC Votes in Favor of RP1/Nivolumab Data in Advanced Melanoma

The FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) voted 10 to 3 that the efficacy results from the phase 1/2 IGNYTE trial (NCT03767348) are evaluable and clinically meaningful for vusolimogene oderparepvec (RP1) in combination with nivolumab (Opdivo) for the treatment of adult patients with unresectable advanced cutaneous melanoma that progressed on an anti–PD-1–based regimen.^1-3

Replimune first submitted a biologics license application (BLA) in November 2024, seeking the approval of the combination based on data from the single-arm IGNYTE study, and the BLA received a priority review designation in January 2025.⁴ The FDA issued a complete response letter (CRL) in June 2025, in which the regulatory agency cited that the single-arm IGNYTE trial was not considered an adequate and well-controlled investigation capable of providing substantial evidence of effectiveness, due in part because to the heterogeneous trial population made it difficult to isolate the contribution of RP1.

After a second BLA submission was accepted in October 2025, it was followed by a second CRL in April 2026, which raised concerns regarding deficiencies related to both IGNYTE and the confirmatory phase 3 IGNYTE-3 trial (NCT06264180). A third BLA submission was accepted in June 2026.

Through the two discussion topics posed to the committee, the FDA sought input on whether IGNYTE, as designed and conducted, allows for a reliable determination of the expected response rate and durability of response in the proposed population, and on the clinical meaningfulness of the reported response rate and duration of response.¹ Specifically, the FDA questioned whether the observed responses are indicative of systemic antitumor activity attributable to RP1 or nivolumab.

“There were several reasons why I chose to vote yes,” Hussein A. Tawbi, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, said following the vote.¹ “I start with the idea that the concept, biologically, is validated even before RP1 came into existence; the idea of using oncolytic virus therapy for cancer makes sense. There’s a reason to expect synergy, biologically, with PD-1 antibodies…Second, the way the study was conducted was maybe not perfect, but it starts from the fact that the intent was not registrational. We need to be, as a community, a lot more intentional about registrational studies. Single-arm registrational studies are for indications that have no other therapeutic options. We need to plan for this, [rather than] retrospectively [going] back and starting to tally up the responses. With that in mind, this is an incredibly difficult patient population [to treat]…[In] the end, tumors [shrank], both injected ones and noninjected ones, that resulted in clinical benefit for patients who otherwise don’t have other options available to them…This supports the idea that this should be a therapy available to patients in the short term until the phase 3 trial reads out.”

The CTGTAC’s recommendation is nonbinding, and the FDA will consider it as it completes its review of the BLA. The target goal date for review is August 2, 2026.⁴

What data have been reported from IGNYTE?

IGNYTE was a phase 1/2, single-arm, dose-escalation and -expansion study that was initiated in 2018; an anti–PD-1–refractory cutaneous melanoma cohort was added in 2019.^2,3 This cohort enrolled 140 patients with unresectable stage IIIB to IV cutaneous melanoma who had confirmed progression after at least 8 weeks of nivolumab or pembrolizumab (Keytruda), given alone or in combination, with the immune checkpoint inhibitor required to have been the last line of prior therapy.

Patients received intratumoral RP1 at 1×10⁶ plaque-forming units (PFU)/mL followed by 1×10⁷ PFU/mL plus nivolumab; RP1 was given for up to 8 doses per course, with reinitiation permitted per protocol-specified criteria. Nivolumab was started at 240 mg with the second RP1 dose and given every 2 weeks for up to 8 cycles, then continued at 480 mg every 4 weeks for up to an additional 21 cycles.

The primary end points were objective response rate (ORR) and duration of response (DOR) by independent review committee (IRC) assessment per RECIST 1.1 criteria.

As reported by Replimune, the confirmed ORR in this population (n = 47) was 33.6% (95% CI, 25.8%-42.0%), comprising a 16.4% complete response (CR) rate and a 17.1% partial response rate.³ The median DOR was 24.8 months (95% CI, 14.8-not estimable [NE]), and the median time to response was 3.9 months. At a March 8, 2026, data cutoff, the median OS was 32.9 months (95% CI, 25.8-46.0), with a 3-year OS rate of 47.8% (95% CI, 38.6-56.5). The median progression-free survival was 3.6 months (95% CI, 2.0-5.0).

In the 140-patient cohort, any-grade treatment-emergent adverse effects (TEAEs) occurred in 97.9% of patients, grade 3 or higher TEAEs in 31.4%, and serious AEs in 35.7%. TEAEs led to death in 8.6% of patients. The most common any-grade TEAEs were fatigue (45.0%), pyrexia (38.6%), chills (32.1%), musculoskeletal pain (30.7%), and diarrhea (29.3%).

AEs of special interest raised by the FDA included tumor hemorrhage, sepsis, and capillary leak syndrome.²

What was the FDA’s position on RP1 plus nivolumab?

In its briefing materials, the FDA argued that IGNYTE is not an adequate and well-controlled investigation providing substantial evidence of effectiveness, noting that accelerated approval carries the same statutory evidentiary requirement as traditional approval.²

The FDA’s central contention was that the application of response criteria in IGNYTE compromised the reliability and interpretability of the reported ORR and DOR. Since RECIST 1.1 was designed to assess systemic therapies, the agency said responses to intratumoral therapy are difficult to interpret, and it noted that focal intervention generally renders injected lesions nonevaluable.

In an FDA analysis excluding patients who had all target lesions injected or no target lesions at baseline, the ORR fell to 15.7% (95% CI, 10.1%-22.8%) with a median DOR of 14.1 months (95% CI, 10.7-NR); a sensitivity analysis removing those patients from the population left an evaluable population (n = 89) that experienced an ORR of 24.7% (95% CI, 16.2%-35.0%).

The FDA also cited reinjection of lesions beyond progression, confounding by biopsies and surgical procedures, retrospective histology reclassification of responses, non-evaluable assessments, and the retrospective implementation of the IRC as factors that may have artifactually inflated the results.

In its presentations, Replimune countered that injected lesions should not be excluded because the intervention was prespecified in the protocol, and that RP1’s dual mechanism of action drives a systemic T-cell response against injected and non-injected lesions.³ The company pointed to an analysis of non-injected measured lesions showing an ORR of 28.7% (95% CI, 20.4%-38.2%) and argued that a patient-by-patient review confirmed no impact on response assessment.

The FDA further argued that the magnitude of objective response from the single-arm study was not sufficient to overcome concerns about the contribution of effect of each component, particularly absent a reliable historical control, and that the OS analysis was not interpretable given the lack of a concurrent control and potential responder selection bias.²

The agency had advised Replimune to conduct a randomized trial with nivolumab alone as the control; the company maintained that such a design lacked equipoise.^2,3 Replimune argued that the 33.6% ORR is nearly 5 times the approximate 5% to 7% response rate expected with further anti–PD-1 monotherapy after definitive progression, and that the 2024 accelerated approval of lifileucel (Amtagvi) using the single-arm phase 2 C-144-01 trial (NCT02360579), which showed an ORR of 31.5% in patients with advanced melanoma that had progressed on anti–PD-1 therapy (n = 73), provides precedent. The randomized phase 3 IGNYTE-3 confirmatory trial is ongoing, with OS data expected in 2030.^2,3

References

1. Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC) Meeting. July 30, 2026. Accessed July 30, 2026. https://www.youtube.com/live/7x4xuKJti1o
2. BLA 125827 vusolimogene oderparepvec (RP1): FDA briefing document. FDA. July 30, 2026. Accessed July 30, 2026. https://www.fda.gov/media/193879/download
3. BLA 125827 vusolimogene oderparepvec (RP1): sponsor presentation. Replimune. July 30, 2026. Accessed July 30, 2026.
4. FDA Advisory Committee to Weigh RP1 Plus Nivolumab in Anti–PD-1–Pretreated Advanced Melanoma. OncLive. Published July 29, 2026. Accessed July 30, 2026. https://www.onclive.com/view/fda-advisory-committee-to-weigh-rp1-plus-nivolumab-in-anti-pd-1-pretreated-advanced-melanoma
5. FDA Accepts Third RP1 BLA Resubmission With Nivolumab in Advanced Melanoma. OncLive. Published June 26, 2026. Accessed July 30, 2026. https://www.onclive.com/view/fda-accepts-third-rp1-bla-resubmission-with-nivolumab-in-advanced-melanoma