Tebentafusp

• Tebentafusp is a first-in-class bispecific gp100 peptide-HLA-directed CD3 T-cell engager.
• It is specifically indicated for the treatment of unresectable or metastatic uveal melanoma.
• The drug’s mechanism involves activating T-cells to recognize and eliminate tumor cells expressing the gp100 protein.
• Common side effects include cytokine release syndrome, skin reactions, and elevated liver enzymes.
• Clinical trials have demonstrated improved overall survival for patients treated with Tebentafusp compared to other systemic therapies.

What is Tebentafusp?

Tebentafusp is a novel bispecific protein that has emerged as a groundbreaking treatment in oncology. It is specifically designed as a gp100 peptide-HLA-directed CD3 T-cell engager, meaning it can simultaneously bind to a specific protein found on melanoma cells (gp100 presented by HLA-A*02:01) and to CD3 receptors on T-cells. This dual binding brings the immune cells into close proximity with the cancer cells, facilitating a targeted immune response. Tebentafusp is the first and only therapy approved for the treatment of unresectable or metastatic uveal melanoma, a rare and aggressive eye cancer.

Uveal melanoma is a rare but aggressive cancer, with an incidence of approximately 5.1 per million adults in the United States annually, according to data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program. Historically, treatment options for metastatic uveal melanoma have been limited, with poor prognoses. Tebentafusp offers a new therapeutic avenue for eligible patients, providing a targeted approach where conventional treatments have often fallen short.

Tebentafusp: Mechanism of Action and Clinical Uses

The Tebentafusp mechanism of action is unique in its ability to harness the body’s own immune system to fight cancer. It consists of two distinct domains: one that recognizes and binds to the gp100 protein presented on the surface of uveal melanoma cells via the HLA-A*02:01 molecule, and another that binds to the CD3 receptor on T-cells. By bridging these two cell types, Tebentafusp activates the T-cells, prompting them to release cytotoxic molecules that directly kill the melanoma cells. This targeted engagement ensures that the immune response is focused on the cancer cells, minimizing damage to healthy tissues.

The primary Tebentafusp uses and indications are for adult patients with unresectable or metastatic uveal melanoma who are HLA-A*02:01-positive. Clinical trials have demonstrated that Tebentafusp significantly improves overall survival compared to investigator’s choice of therapy, which typically included pembrolizumab, ipilimumab, or dacarbazine. This makes Tebentafusp a crucial option for patients facing this challenging diagnosis, offering a new standard of care where few effective systemic treatments existed previously.

Potential Side Effects of Tebentafusp

Like all medical treatments, Tebentafusp side effects can occur, and patients should be closely monitored for adverse reactions. The most common side effects are related to its immune-activating mechanism, particularly cytokine release syndrome (CRS) and skin-related toxicities. CRS is a systemic inflammatory response that can range from mild to severe and is managed with supportive care, including corticosteroids if necessary. Skin reactions, such as rash, pruritus (itching), and erythema (redness), are also frequently observed and typically managed with topical treatments or antihistamines.

Other potential side effects reported in clinical trials include:

• Fatigue
• Nausea and vomiting
• Diarrhea
• Fever
• Chills
• Hypotension (low blood pressure)
• Edema (swelling)
• Elevated liver enzymes (e.g., AST, ALT)

Patients receiving Tebentafusp are typically managed in a hospital setting, especially during the initial doses, to promptly address any severe side effects, particularly CRS. Close monitoring and proactive management are essential to ensure patient safety and optimize treatment outcomes.