Tebentafusp for the treatment of metastatic uveal melanoma.

Uveal melanoma is a rare disease; nevertheless, it is the most common primary intraocular malignancy among adults. Approximately half of affected patients will suffer from metastatic disease, mostly to the liver. No standard-of-care treatment exists for these patients. Median progression-free survival and overall survival for all types of treatment, including checkpoint inhibitors, have remained poor. However, the most recent phase III study results for tebentafusp, a member of a new-in-class molecule, are raising hopes for stage IV uveal melanoma patients. In this review, we examine the current literature, focusing on the most recent trial results for this new reagent. We evaluate the latest clinical results for tebentafusp and aim to shed light on its immunological strategy.

Uveal melanoma is a rare disease but is the most common tumor of the eye among adults. In approximately half patients who have uveal melanoma, it will spread to other parts of the body, mostly to the liver. There is no standard type of therapy for these patients. So far, all existing therapies have shown poor outcomes. However, the new treatment tebentafusp has shown encouraging results in a recent clinical study. In this review, we discuss the latest study results for tebentafusp and outline how it works as a treatment for uveal melanoma.

Tebentafusp: a novel drug for the treatment of metastatic uveal melanoma.

On January 25, 2022, the U.S. Food and Drug Administration (FDA) approved the use of tebentafusp, a bispecific glycoprotein 100 (gp100) peptide-human leukocyte antigen (HLA)-directed CD3 T-cell activator, for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma (mUM). Pharmacodynamic data indicate that tebentafusp targets a specific HLA-A*02:01/gp100 complex, activating both CD4+/CD8+ effector and memory T cells that induce tumor cell death. Tebentafusp is administered to patients via intravenous infusion daily or weekly, depending on the indication. Phase III trials have documented a 1-year overall survival of 73%, overall response rate of 9%, progression-free survival of 31% and disease control rate of 46%. Common adverse events reported are cytokine release syndrome, rash, pyrexia, pruritus, fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache and vomiting. Compared to other types of melanomas, mUM presents with a distinct profile of genetic mutations, which phenotypically results in limited survival efficacy when using traditional melanoma treatments. The low current treatment efficacy for mUM, alongside a poor long-term prognosis and high mortality rates, gives precedence for the approval of tebentafusp to be groundbreaking in its clinical impact. This review will discuss the pharmacodynamic and pharmacokinetic profile, and the clinical trials used to evaluate the safety and efficacy of tebentafusp.

Immunotherapies for the Treatment of Uveal Melanoma-History and Future.

BACKGROUND: Uveal melanoma is the most common primary intraocular malignancy among adults. It is, nevertheless, a rare disease, with an incidence of approximately one case per 100,000 individuals per year in Europe. Approximately half of tumors will eventually metastasize, and the liver is the organ usually affected. No standard-of-care treatment exists for metastasized uveal melanoma. Chemotherapies or liver-directed treatments do not usually result in long-term tumor control. Immunotherapies are currently the most promising therapy option available. METHODS: We reviewed both relevant recent literature on PubMed concerning the treatment of uveal melanoma with immunotherapies, and currently investigated drugs on ClinicalTrials.gov. Our own experiences with immune checkpoint blockers are included in a case series of 20 patients. RESULTS: Because few clinical trials have been conducted for metastasized uveal melanoma, no definitive treatment strategy exists for this rare disease. The outcomes of most immunotherapies are poor, especially compared with cutaneous melanoma. However, encouraging results have been found for some very recently investigated agents such as the bispecific tebentafusp, for which a remarkably increased one-year overall survival rate, and similarly increased disease control rate, were observed in early phase studies. CONCLUSIONS: The treatment of metastatic uveal melanoma remains challenging, and almost all patients still die from the disease. Long-term responses might be achievable by means of new immunological strategies. Patients should therefore be referred to large medical centers where they can take part in controlled clinical studies.