Nivolumab

While a positive advisory committee meeting seemed to up the odds of approval for Replimune’s twice-snubbed melanoma drug in July, the fate of vusolimogene oderparepvec was anything but certain. In the end, however, two votes of confidence from leaders at the FDA’s Office of Clinical Evaluation and the Oncology Center of Excellence sealed its fate, overruling review staffers’ concerns and paving the way for last month’s accelerated nod for Tudriqev. External advisors to the FDA voted 10 to 3 in July that efficacy results from Replimune’s Ignyte study were evaluable and clinically meaningful. Still, the assigned FDA review team continued to feel that the application did “not include an adequate and well-controlled investigation demonstrating substantial evidence of effectiveness,” in turn calling to issue another complete response letter, a clinical review memo (PDF) recently posted to the FDA’s website shows. With a third Trudiqev rejection seemingly on the horizon, Asha Das, M.D., director of the Office of Clinical Evaluation under the Center for Biologics Evaluation and Research (CBER) stepped in, as the Oncology Center of Excellence also recommended an accelerated approval, according to separate review memos. Trudiqev received its long-awaited FDA go-ahead on Aug. 6 for use in combination with Bristol Myers Squibb’s Opdivo for adults with unresectable advanced cutaneous melanoma whose disease progressed on prior anti-PD-1 therapy. Given the accelerated nature of the approval, Replimune will have to vet Trudiqev’s clinical benefit in a confirmatory study. In a memo bearing the name of Das and her deputy director, the FDA officials noted that their recommendation for approval was made “in the context of a serious, life-threatening disease with critical unmet need, in which the biologically plausible treatment signal, even at its most conservative estimate represents a clinically meaningful advance over available alternatives, and in which a randomized controlled confirmatory trial is already underway.” In its memo, the FDA’s oncology department, led by Angelo de Claro, M.D., recognized that its review “identified several trial design, conduct, and data integrity issues.” But recognizing strong support from the advisory committee and public hearing speakers, the department acknowledged that “some patients are willing to accept substantial uncertainty given the unmet need and lack of alternative available therapies.” After considering the adcomm discussions and existing clinical data, “we conclude that accelerated approval is acceptable in the context of this uncertainty,” de Claro’s team said in its memo. The FDA’s concerns with Ignyte, principally laid out ahead of the advisory committee meeting earlier this summer, took issue with the study’s lack of a control arm, plus other methodological concerns. Parrying those claims, Replimune argued that a control arm of anti-PD-1 therapy alone would have been unethical as the study enrolled patients for whom those drugs hadn’t succeeded—a position echoed by multiple oncologists who spoke during the adcomm’s public comment period. The FDA also suggested that Ignyte made multiple deviations from the established guidelines for evaluating solid tumors, mainly by allowing investigators in the trial to reinject Trudiqev into tumors even after a patient’s disease had progressed—as well as number of patients who had all of their target lesions injected. FDA reviewers ultimately contended that the trial’s assessment methodology could inflate the ORR and durability or response seen on the study drug. Replimune did not immediately respond to Fierce Pharma’s request for comment on the approval details. In the newly posted clinical review documents, both memos by Das and de Claro point to multiple remaining uncertainties around Replimune's data. But they took on the advisory committee's view that the drug has shown enough clinically meaningful data despite all the methodological limitations. During the advisory committee meeting, the experts on the panel were in agreement that Replimune’s trial had issues, but they still felt there were enough signs of efficacy to justify an approval. While the way the trial was run “was maybe not perfect,” Hussein Tawbi, M.D., a melanoma expert from MD Anderson Cancer Center, said during the meeting, “at the end, there were tumors that shrank, both the injected ones and the non-injected ones, that resulted in clinical benefit for patients that otherwise don’t have any other options available to them.” In its approval, the FDA conceded that the drug may possess a local anti-tumor effect, while caveating that evidence for a systemic effect had not been effectively presented. As for issues specifically raised during the adcomm, in a summary memo covering the entire multidiscipline review team, FDA staffers noted that three-year duration of response data referenced during the meeting had not been submitted in Replimune’s approval package, and therefore could not be considered verified. The reviewers also flagged uncertainties around the 23 patients deemed complete responders in Ignyte, which they said raise “further uncertainty” about the Trudiqev’s potential systemic effect. Lastly, the FDA staff took issue with a Replimune exploratory analysis comparing injected versus non-injected lesions—meant to vouch for Trudiqev’s systemic bona fides—noting that it had confounding issues. The analysis was also based on a definition of “‘measurability’” established by Replimune “rather than standard response criteria” and done after the company had reviewed primary efficacy results. This in turn introduced the “potential for bias,” the FDA reviewers wrote in the summary memo. They caveated that while unmet medical need alone can’t be the basis for an approval, “it is an important consideration in determining the most appropriate regulatory pathway forward,” pointing to an interim analysis of tumor response data from Ignyte as a potential way to speed up evidence generation when a rejection seemed likely. The drug had a bumpy path to approval before ultimately winning an accelerated nod last month. Trudiqev was initially rejected in July of 2025 over similar concerns around the phase 1/2 Ignyte study, with the FDA again turning down Replimune’s application back in April, dubbing the company’s data package “insufficient.” For now, Replimune’s confirmatory study for Trudiqev looks to be the late-stage Ignyte-3 study, which is comparing Trudiqev plus Opdivo to a physician’s choice of therapy. As of August, the study had enrolled about a third of its target patient population and was aiming for a primary overall survival endpoint readout in 2030. While vouching for approval of Trudiqev, the memo from de Claro’s office stressed that it’s “unclear” if prior concerns about Ignyte-3’s design have been resolved, urging Replimune to meet with the agency’s primary review team as soon as possible.