The FDA’s Cellular, Tissue and Gene Therapies advisory committee voted 10 to 3 in favor of Replimune’s immunotherapy for advanced melanoma in combination with Bristol Myers Squibb’s Opdivo, but trial design was a major sticking point as the panel deliberated.
An FDA advisory committee voted in favor of Replimune’s cancer immunotherapy RP1 despite major misgivings about trial design and the overall efficacy of the drug.
In answer to the question of whether a registrational trial for vusolimogene oderparepvec, dubbed RP1, combined with Bristol Myers Squibb’s PD-1 checkpoint inhibitor Opdivo for patients with advanced melanoma was “evaluable and clinically meaningful,” the FDA’s Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC) voted 10 to 3 in support of approving the therapy.
The FDA is not obligated to follow the recommendations of its advisory committees, though it typically does. An official decision is expected by Aug. 2.
Twice rejected by the FDA, RP1 in combination with Opdivo presented a challenge for regulatory reviewers in terms of parsing data from a Phase 1/2 IGNYTE study, which made use of criteria for measuring anti-cancer effects based on tumor size.
Several members of the committee said RP1 showed important efficacy signals but that criteria needed to be better established for decisions based on response evaluation criteria in solid tumors (RECIST) down the road. Committee members, even those who voted in favor of the combination, were torn by conflicting data that they said made RP1 and Opdivo difficult to review.
Diane Aronson, a patient representative, was one of those thrown by the data.
“The science of the study did trouble me as far as the results, and the RECIST criteria is confounding,” said Aronson, who voted “no.” “Hope is important, but reality weighed into my vote.”
“This is messy data,” said Lawrence Schwartz, chair of the department of radiology at Memorial Sloan Kettering Cancer Center, who ultimately voted “yes.”
The positive adcomm vote for Replimune directly follows the chaotic “no” vote for Capricor’s Duchenne muscular dystrophy gene therapy, marking a turbulent time for advisory committees under changing FDA leadership.
‘A very imperfect endpoint’
The back-and-forth between Replimune and the FDA started in 2021, when the regulator posed concerns that the individual contributions of RP1 and Opdivo together against melanoma were not clear enough to demonstrate that the immunotherapy itself was responsible for the response rate in IGNYTE, Sundeep Agrawal, associate director of clinical programs at the FDA’s oncology center of excellence, said Thursday. Replimune presented overall survival data from the trial this May, reporting that nearly half of the treated patients were still alive at three years.
While the FDA accepted Replimune’s resubmission based on unmet need for patients with advanced melanoma, the agency found that the overall response rate and durability of response results were “unreliable and difficult to interpret,” according to Agrawal. Replimune received its first FDA complete response letter in July 2025 and another in April this year, both of which cited trial design as a main contributor to the rejection.
“Contribution of effect and the need for each product has not been demonstrated, and the applicants that submitted overall survival or [overall survival] data and analysis is not interpretable,” Agrawal said. “Accelerated approval and traditional approval both require demonstration of substantial evidence of effectiveness derived from adequate and well-controlled trials.”
Objective response rate, which measures a reduction in the size of tumors, does not necessarily correlate with patient survival or improvement in quality of life, Agrawal continued. So, while “RP1 does appear to decrease tumor sizes in some patients,” that alone might not be enough to support accelerated approval.
Agrawal added that “the systemic effect of RP1 has not been demonstrated—the need for both RP1 and [Opdivo] is unclear and may expose patients to unnecessary toxicity. Any claim that treatment with RP1 results in patients living longer cannot be proven without a concurrent control group to compare to and is not an evidence-based claim.”
Advisory committee member Jorge Garcia, chair of the division of solid tumor oncology at the University Hospitals Seidman Cancer Center who voted “yes,” said the study suffered from a “very imperfect endpoint” and called for better methods supporting drug development in solid tumor oncology.
Despite the FDA’s reticence, Replimune in its presentation sought to show that RP1 was an effective treatment for patients with advanced melanoma whose disease has progressed following a prior PD-1 therapy. Replimune Head of Regulatory Affairs Kari Jeschke said the biotech had worked closely with the FDA to confirm the study met standards set by the agency based on criteria for objective response rate.
“We have carefully reviewed each patient highlighted by FDA and confirmed that the response assessment was appropriate,” Jeschke said. “In each case, the assessment was per protocol, conducted by the blinded independent review and was confirmed by the initial clinical review team.”
Michael Wong, physician in chief at the Roswell Park Comprehensive Cancer Institute and lead investigator for the IGNYTE trial, said the RP1/Opdivo combination warranted a shift in how the FDA assesses cancer studies.
“My co-investigators and I are seeing patient responses to therapy that we have never seen before, comparable to paradigm shifts we’ve seen with the advent of immune checkpoint inhibitors, with small molecule kinase inhibitors and with hormonal therapy in breast and prostate cancer,” Wong said. “In each of these situations, we have collectively had to reassess conventions and create new methodologies—we are at the same place now with this drug.”
BMO Capital Markets analysts found Replimune’s arguments for approval convincing despite opening commentary from the FDA skewing negative.
“We love receipts, and apparently Replimune does, too; prior regulator support highlights a critical shift at the FDA despite former alignment,” the BMO analysts wrote in the note prior to the adcomm vote. “Presented receipts included FDA clinical review findings in favor of RP1 accelerated approval, indicating IGNYTE was an adequate/well-controlled study demonstrating substantial evidence of efficacy. “
Public comment during the meeting unanimously supported RP1’s approval.
“There is plenty of data out on Opdivo, and if RP1 can augment its effectiveness for some people, that alone should be enough of an argument for approval,” said Sydney Morgan, who was diagnosed with stage 4 melanoma. “Currently, there is no other new treatment for me to try.”
