FDA Grants Conditional Approval to Melanoma Drug Tudrik Despite Internal Opposition

The US Food and Drug Administration (FDA) has decided to grant conditional approval to the melanoma treatment Tudrik despite opposition from its internal review team.

According to Fierce Pharma on the 4th local time, the FDA conditionally approved Replicune’s Tudrik on the 6th of last month in combination with Bristol Myers Squibb’s (BMS) immuno-oncology drug Opdivo. The indication covers adults with unresectable, advanced cutaneous melanoma whose disease has progressed after anti-PD-1 therapy.

Clinical review documents recently released by the FDA indicate that internal opinions differed during the approval process. In July, an external advisory committee voted 10-3 to recommend approval, saying that the efficacy results from Replicune’s Ignite clinical trial were evaluable and clinically meaningful.

However, the working review team argued for issuing a third complete response letter (CRL), saying the application “did not include an adequate and well-controlled investigation demonstrating substantial evidence of effectiveness.”

The situation changed after Asha Das, director of the Office of Clinical Evaluation under the Center for Biologics Evaluation and Research (CBER), and the FDA’s oncology center recommended conditional approval. Das said the recommendation took into account “a situation involving an unmet medical need in a serious and life-threatening disease.”

The FDA oncology division, led by Dr. Angelo De Claro, said during the review that it had “identified several issues with the trial design, conduct and data integrity.” However, citing strong support from the advisory committee and speakers at the public hearing, it concluded that “some patients are willing to accept substantial uncertainty given the unmet need and lack of alternative therapies.”

The FDA review team raised concerns about the lack of a control group in the Ignite study and methodological issues with the assessment. It noted that allowing investigators to reinfuse Tudrik into tumors even after disease progression deviated from guidelines for evaluating solid tumors. The team believed this could have inflated the objective response rate (ORR) and durability of response.

Replicune countered that establishing an anti-PD-1 monotherapy control group would be unethical because the patients enrolled in the trial had already failed that treatment. Many oncologists expressed the same position at the public hearing.

During the approval process, the FDA acknowledged that Tudrik could have a local antitumor effect but cautioned that evidence of a systemic effect had not been effectively demonstrated. The review team also noted that the 3-year response durability data mentioned at the meeting were not included in the approval application package and therefore could not be verified.

Tudrik had previously been denied FDA approval twice, in July last year and April this year. Under the conditional approval, Replicune is conducting the late-stage Ignite-3 confirmatory trial. The study compares the combination of Tudrik and Opdivo with physician’s choice of therapy and, as of August, had enrolled about one-third of its target patient population. Results for the primary endpoint, overall survival, are targeted for 2030.