FDA Grants Conditional Approval to Melanoma Oncolytic Virus T-VEC After Internal Opposition Overturned

On the sixth of last month, the U.S. Food and Drug Administration (FDA) granted conditional approval to Replimune’s melanoma treatment, tuodricab (ingredient: vusolimogene oderparepvec), in combination with Bristol Myers Squibb’s (BMS) immuno-oncology drug Opdivo. The approval covers adults with unresectable, advanced cutaneous melanoma whose disease has progressed after anti-PD-1 therapy. The unusual decision came after senior officials overturned opposition from the FDA’s working-level review team following two previous refusals to approve the drug.

Tuodricab is the second oncolytic virus therapy to receive FDA approval in roughly 10 years, following Amgen’s Imlygic in 2015. It uses a genetically engineered herpes simplex virus (HSV-1) that is injected directly into tumors, where it both ruptures cancer cells and stimulates the immune system through the released tumor antigens to attack cancer cells throughout the body.

Internal FDA conflict and senior officials’ decision

The FDA’s working-level review team argued that the tuodricab application “did not include an adequate and well-controlled investigation demonstrating substantial evidence of effectiveness,” calling for issuance of a third complete response letter (CRL). The team pointed out that the IGNYTE trial had no control group and that allowing tuodricab to be reinjected into tumors even after disease progression deviated from solid tumor evaluation guidelines. As a result, it believed the objective response rate (ORR) and durability of response may have been inflated.

In July, an external advisory committee recommended approval by a vote of 10 to 3. The balance shifted after Asha Das, director of the Office of Clinical Evaluation at the Center for Biologics Evaluation and Research (CBER), and the FDA’s Oncology Center supported the recommendation. Das explicitly cited “an unmet medical need in a serious and life-threatening disease” as grounds for approval. The FDA oncology division, led by Dr. Angelo De Claro, also supported approval, stating that “some patients are willing to accept substantial uncertainty given the absence of alternative therapies.”

Melanoma is in fact the fifth most common cancer in the United States, with approximately 112,000 new cases expected in 2026. For patients who develop resistance to existing PD-1 inhibitors, the median overall survival (OS) after disease progression is less than 1 year, leaving virtually no treatment alternatives. Replimune also argued that establishing an anti-PD-1 monotherapy control group would be unethical for patients who had already failed that drug, and many oncologists expressed the same view at the public hearing.

Approved, but challenges remain

The clinical review documents released by the FDA included another caveat. Although the agency acknowledged that tuodricab may have a local antitumor effect, it said the evidence for a systemic effect had not been effectively demonstrated. It also noted that the 3-year durability-of-response data mentioned at the public hearing were not included in the approval package, making verification impossible.

In the IGNYTE phase 1/2 trial, the ORR was 24.2% and the median duration of response was 14.1 months in the efficacy-evaluable population assessed strictly by the FDA—91 patients with at least one noninjected lesion. Replimune’s overall dataset showed an ORR of 32.9%, but the gap between that figure and the FDA-accepted figure demonstrates that the methodological controversy is real.

South Korea’s biopharmaceutical industry also watching

Industry experts believe the approval sent a signal across the global oncolytic virus market. Funding and attention could return to the previously stagnant field of oncolytic virus development. In South Korea, SillaJen, ViroCure and Kolon Life Science are developing oncolytic virus therapies. GI Innovation is conducting a phase 2 trial in South Korea and the United States in patients with metastatic melanoma, combining its immuno-oncology candidate GI-102 with MSD’s Keytruda.

To maintain the conditional approval, Replimune must conduct the confirmatory IGNYTE-3 study. The trial is comparing the tuodricab-Opdivo combination with physician’s choice therapy in a randomized controlled design and, as of August, had enrolled approximately one-third of its target patient population. Results for the primary endpoint, overall survival, are targeted for 2030. Because failure to demonstrate improved survival in the confirmatory trial could lead to withdrawal from the market, this approval is not the end but the beginning of another test.