On January 26, the U.S. Food and Drug Administration (FDA) granted approval to tebentafusp-tebn (Kimmtrak) for the treatment of adult patients with HLA-A*02:01–positive, unresectable or metastatic uveal melanoma.
Tebentafusp’s approval establishes several firsts: as the first T-cell receptor therapeutic to receive regulatory approval from the FDA; the first bispecific T-cell engager to receive regulatory approval from the FDA to treat a solid tumor; and the first and only therapy for the treatment of unresectable or metastatic uveal melanoma to be approved by the FDA.
“Uveal melanoma is a devastating disease that has historically resulted in death within a year of metastasis for our patients,” said John Kirkwood, MD, Director of the Melanoma Center at the UPMC Hillman Cancer Center. “The approval of tebentafusp represents a major paradigm shift in the treatment of metastatic uveal melanoma, and for the first time offers hope to those with this aggressive form of cancer.”
The approval of tebentafusp is based on the results of the phase III IMCgp100-202 clinical trial, which were published in September 2021 by Nathan et al in The New England Journal of Medicine. The randomized pivotal trial evaluated overall survival with tebentafusp compared to investigator’s choice (either pembrolizumab, ipilimumab, or dacarbazine) in patients with previously untreated metastatic melanoma. Nearly 400 patients were randomly assigned in a 2:1 ratio to receive either tebentafusp or investigator’s choice of therapy.
Data from the trial showed that tebentafusp demonstrated a median overall survival benefit as a first-line treatment. The overall survival hazard ratio in the intent-to-treat population favored tebentafusp (hazard ratio = 0.51, 95% confidence interval = 0.37–0.71, P < .0001) over investigator’s choice (82% pembrolizumab; 13% ipilimumab; 6% dacarbazine). In the clinical trials, across both arms, patients stopped treatment for disease progression, unless the patient was otherwise deriving benefit, or for unacceptable toxicity.
Treatment-related adverse reactions were manageable and consistent with the proposed mechanism among patients treated with tebentafusp. The most common grade 3 or higher adverse reactions were rash (18%), pyrexia (4%), and pruritus (5%). In the 245 patients treated with tebentafusp, grade 3 cytokine-release syndrome occurred in < 1% of patients and was generally well managed. There were no grade 4 or fatal cytokine-release syndrome events observed. A boxed warning is included for cytokine-release syndrome, as it has the potential to become serious or life-threatening if not managed appropriately.
Tebentafusp was granted Breakthrough Therapy designation for unresectable or metastatic uveal melanoma by the FDA in February 2021. The biologics license application approval followed review under the Real-Time Oncology Review program, an initiative of the FDA's Oncology Center of Excellence designed for efficient delivery of safe and effective cancer treatments to patients. The approval was granted 4 weeks ahead of the assigned Prescription Drug User Fee Act date of February 23, 2022. Tebentafusp is being reviewed under the FDA’s Project Orbis initiative, which enabled concurrent review by the health authorities in partner countries that have requested participation.