What Is Tebentafusp?
Tebentafusp is an FDA-approved medication for adult patients with HLA-A*02:01-positive unresectable or metastatic uveal melanoma. This medication works by engaging the body's immune system to fight cancer. It is a bispecific protein designed to recognize a specific protein called gp100, which is found on uveal melanoma cells when presented by HLA-A*02:01. Simultaneously, tebentafusp activates CD3 on T cells, which are a type of immune cell, directing them to target and destroy the cancer cells.
In addition to its approved use, tebentafusp is currently being investigated in clinical trials for other forms of melanoma and certain sarcomas. These studies aim to further understand its safety and effectiveness as a single agent or in combination with other anti-cancer treatments.
Uses and Conditions Under Study
Tebentafusp is primarily studied for various forms of melanoma, a type of skin cancer that can also affect the eyes. Its FDA approval is specifically for uveal melanoma that is unresectable or has spread to other parts of the body (metastatic) in patients with a specific genetic marker (HLA-A*02:01-positive). This condition is being investigated in ten trials, including those for Metastatic Uveal Melanoma, Uveal Melanoma, Locally Advanced Unresectable Uveal Melanoma, Melanoma, Uveal, Mestastatic Uveal Melanoma, and Metastatic Uveal Melanoma in the Liver. Tebentafusp's mechanism of action, which targets a protein found on these cancer cells, makes it a potential treatment option.
Beyond uveal melanoma, tebentafusp is also being explored for other types of melanoma. These include Malignant Melanoma and Advanced Melanoma, which are being studied in two trials. The drug's ability to engage T cells against melanoma-associated proteins may offer benefits in these broader melanoma populations.
Furthermore, tebentafusp is under investigation for other cancers, such as Clear Cell Sarcoma (CCS), in one trial. This indicates a potential broader application for the drug in cancers that may share similar protein targets or immune evasion mechanisms. One trial also specifically focuses on patients with HLA-A*0201 Positive Cells Present, which is a key eligibility criterion for tebentafusp treatment, highlighting the importance of this genetic marker for the drug's efficacy.
Dosing
Tebentafusp is administered intravenously (IV) and is also being studied in a subcutaneous (SC) formulation. The most commonly described dosing regimen involves a step-up approach to help patients tolerate the treatment. Patients typically receive 20 micrograms on Day 1, followed by 30 micrograms on Day 8. Starting on Day 15 and continuing weekly thereafter, the dose is increased to 68 micrograms.
In some investigational settings, particularly for liver-directed therapy, a different dosing strategy has been explored. One trial describes administering 3 mg/kg of ideal body weight, with a maximum dose of 220 mg, infused via a hepatic artery catheter. This approach targets the medication directly to the liver, where uveal melanoma often metastasizes.
Tebentafusp is typically given weekly. The specific duration of treatment can vary depending on the patient's response and tolerability, with some protocols continuing therapy for several months or longer.
Side Effects
The most common side effects of Tebentafusp are related to skin reactions, often referred to as cutaneous events. In a clinical trial for metastatic uveal melanoma (NCT03070395), 83% of patients taking Tebentafusp experienced skin events such as rash, itching, or dry skin, compared to 25% of patients receiving investigator's choice treatment.
Other common side effects reported in patients treated with Tebentafusp, compared to investigator's choice, include:
- Fatigue: 51% of patients on Tebentafusp experienced fatigue, compared to 33% on investigator's choice.
- Nausea: 43% of patients on Tebentafusp experienced nausea, compared to 22% on investigator's choice.
- Pyrexia (fever): 39% of patients on Tebentafusp experienced fever, compared to 10% on investigator's choice.
- Hypotension (low blood pressure): 38% of patients on Tebentafusp experienced hypotension, compared to 8% on investigator's choice.
- Edema (swelling): 36% of patients on Tebentafusp experienced edema, compared to 15% on investigator's choice.
- Diarrhea: 29% of patients on Tebentafusp experienced diarrhea, compared to 18% on investigator's choice.
A specific side effect associated with the mechanism of action of Tebentafusp is Cytokine Release Syndrome (CRS). In the same trial, 89% of patients treated with Tebentafusp experienced CRS of any grade, with 5% experiencing severe (Grade 3 or 4) CRS. This condition is typically managed with supportive care.
Clinical Trial Results
Metastatic Uveal Melanoma (MUM)
The effectiveness of Tebentafusp in treating metastatic uveal melanoma was evaluated in a Phase 3, randomized, open-label clinical trial (NCT03070395). The study included 378 patients with previously untreated metastatic uveal melanoma. Patients were randomly assigned to receive either Tebentafusp (252 patients) or investigator's choice of treatment (126 patients), which included pembrolizumab, ipilimumab, or dacarbazine.
The primary goal of the study was to assess overall survival (OS). Patients treated with Tebentafusp lived significantly longer than those on investigator's choice. The median overall survival for patients receiving Tebentafusp was 21.7 months, compared to 16.0 months for those on investigator's choice. This represents a 49% reduction in the risk of death for patients treated with Tebentafusp. The 1-year overall survival rate was 73% for patients on Tebentafusp, compared to 58% for those on investigator's choice.
Secondary endpoints also showed favorable results for Tebentafusp. The median progression-free survival (PFS), which measures the time patients live without their disease getting worse, was 3.3 months for Tebentafusp-treated patients, compared to 2.9 months for those on investigator's choice. The objective response rate (ORR), which is the percentage of patients whose tumors shrank or disappeared, was 11% (28 out of 252 patients) for Tebentafusp, compared to 5% (6 out of 126 patients) for investigator's choice. Additionally, the disease control rate (DCR), which includes patients with complete response, partial response, or stable disease, was 46% for Tebentafusp, compared to 27% for investigator's choice.
Currently Recruiting Trials
Several clinical trials are actively seeking participants to further investigate Tebentafusp for various cancers. These studies aim to understand how Tebentafusp works, its safety, and its effectiveness, sometimes alone and sometimes in combination with other treatments. One Phase 2 study, NCT07276386, is recruiting up to 18 patients with metastatic uveal melanoma that has spread to the liver. This trial explores sequential treatment using percutaneous hepatic perfusion (PHP) with melphalan/HDS, followed by Tebentafusp. For patients with advanced clear cell sarcoma who are HLA-A*02:01 positive, a Phase 2 trial (NCT06942442) is comparing Tebentafusp to a physician's choice arm, aiming for 47 participants. Another study, NCT06626516, is a Phase 1/2 trial for HLA-A*0201 positive patients with metastatic uveal melanoma, evaluating Tebentafusp-tebn alone or in combination with liver-directed therapies, with an enrollment target of 109 individuals. Two Phase 2 trials are investigating Tebentafusp in a neoadjuvant setting for uveal melanoma: NCT06414590 for locally advanced unresectable primary uveal melanoma (19 participants), and NCT07057596 for metastatic uveal melanoma (19 participants). For previously untreated metastatic uveal melanoma in HLA-A*0201 positive patients, a Phase 2 study (NCT06070012) is enrolling 44 participants to receive Tebentafusp. Additionally, a Phase 2 trial (NCT06627244) is combining Tebentafusp with Yttrium-90 (Y-90) radioembolization for 30 patients with metastatic uveal melanoma that has spread to the liver. In the Phase 3 setting, NCT06246149 is an adjuvant study comparing Tebentafusp to observation in 290 patients with high-risk primary uveal melanoma. Finally, a large Phase 3 trial (NCT05549297) for previously treated advanced melanoma is comparing Tebentafusp monotherapy, Tebentafusp plus pembrolizumab, or investigator's choice, with a goal of enrolling 540 participants.Where to Participate
Clinical trials for Tebentafusp are currently active across a wide geographic area, offering opportunities for participation in many regions. These studies are being conducted at 43 sites located in 34 cities across 24 states. Some of the top cities with multiple participating sites include:- Philadelphia, Pennsylvania
- Boston, Massachusetts
- Pittsburgh, Pennsylvania
- Phoenix, Arizona
- Rochester, Minnesota
- Jacksonville, Florida
- Miami, Florida
- Edgewood, Kentucky
- Aurora, Colorado
- New York, New York