Treatment with tebentafusp, a novel bispecific fusion protein, reduced the risk of death from metastatic uveal melanoma at 14 months by half, compared with available treatments, in a phase III study presented by Piperno-Neumann et al at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021 (Abstract CT002). This is the first phase III study to show a survival benefit in this rare but potentially lethal type of cancer (also known as ocular melanoma).

Interestingly, the effect of tebentafusp on progression-free survival was more modest than on overall survival, and experts are pursuing reasons for this seemingly counterintuitive finding.

“Tebentafusp achieved a highly significant and clinically meaningful improvement in overall survival as first-line treatment of metastatic uveal melanoma. This is the first investigational therapy in a phase III trial to improve overall survival in uveal melanoma. The survival benefit was seen even in patients without an objective response [per] Response Evaluation Criteria in Solid Tumors (RECIST),” said lead author Jessica Hassel, MD, of University Hospital Heidelberg in Germany.

Tebentafusp achieved a highly significant and clinically meaningful improvement in overall survival as first-line treatment of metastatic uveal melanoma. This is the first investigational therapy in a phase III trial to improve overall survival in uveal melanoma.

— Jessica Hassel, MD

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“Tebentafusp has a manageable safety profile, and adverse events are consistent with its mechanism of action. There were low rates of discontinuations and of treatment-related deaths.... [The agent] has the potential to be practice-changing, as it is the first T-cell receptor [TCR] therapeutic to demonstrate an overall survival benefit,” Dr. Hassel stated.

More on Tebentafusp and Uveal Melanoma

Tebentafusp is a bispecific fusion protein that recognizes two targets—gp100 (melanocytic protein), which is present on melanoma cells, and a second target on T cells.

“Tebantafusp bridges the tumor and the immune cells, enabling the immune cells to attack the tumor. The unique mechanism of action results in redirecting the T cells to attack the gp100-expressing melanoma cells,” said Dr. Hassel.

The T-cell receptor (TCR)-binding domain recognizes a specific gp100 peptide present on human leukocyte antigen (HLA)-A*02:01, restricting the use of tebentafusp to patients with this HLA type. This HLA type is most frequently seen in White patients, the population usually affected by uveal melanoma; about 50% of White patients express it.

Uveal melanoma is rare, but it is the most common eye cancer in adults and represents approximately 3% to 5% of all melanomas. About 50% of patients with uveal melanoma develop liver metastasis, and few benefit from immunotherapy, which is sometimes used to treat it. Once the cancer becomes metastatic, the 1-year survival rate is 50%.

“There is no standard of care for this aggressive cancer once it becomes metastatic,” Dr. Hassel noted.

Study Details and Results

The study enrolled patients with advanced uveal melanoma who were HLA-A*0201–positive, had no prior systemic therapy in the advanced setting, had no prior liver-directed therapy except surgery, and any lactate dehydrogenase (LDH) level (reflecting tumor burden). Patients (n = 378) were randomly assigned 2:1 to receive tebentafusp or investigator’s choice of therapy (either pembrolizumab, ipilimumab, or dacarbazine). They were stratified according to LDH level.

“We saw an early and continuous separation of the survival curves favoring tebentafusp,” said Dr. Hassel.

At a median follow-up of 14 months, patients assigned to tebentafusp had almost half the risk of dying vs those receiving investigator’s choice of therapy. Median overall survival was almost 22 months for tebentafusp vs 16 months for investigator’s choice (representing a significant 49% reduction in the risk of progression or death, P < .001). The 1-year survival rate was 73.2% for patients in the experimental arm vs 58.5% in the investigator’s choice arm.

“The overall survival benefit was observed in all subgroups, independent of age, sex, or geographic region. Patients with a lower tumor load [ie, normal LDH] always had a better hazard ratio for survival compared with those with a higher tumor load [ie, elevated LDH],” she said.

In an intent-to-treat analysis of the tebentafusp arm compared directly with those receiving pembrolizumab, a similar magnitude of benefit was observed as in the overall trial: a 49% reduction in risk of death or disease progression.

The difference in progression-free survival between the two treatment arms was statistically significant favoring tebentafusp but was less robust than for overall survival. Response rates did not explain the survival benefit. Objective response rates according to RECIST criteria were 9% with tebentafusp vs 5% with investigator’s choice of therapy. However, the disease control rate at 12 weeks was notably higher with tebentafusp: 46% vs 27% with investigator’s choice.

Tebentafusp improved overall survival vs investigator’s choice even in patients with progressive disease as their best response, according to a landmark analysis at day 100 restricted to patients with a best response of progressive disease.

Adverse Events

Treatment-related adverse events occurred in all patients; about 45% had severe grades. Treatment-related discontinuations were 2% in the experimental arm vs 4% in the investigator’s-choice arm. There were no treatment-related deaths.

Adverse events were mainly cytokine-mediated, in line with the proposed mechanism of action of tebentafusp. Two patients developed severe cytokine-release syndrome, but both continued treatment.

“Most adverse events [with tebentafusp] occurred in the first cycle, and subsequently decreased in frequency and severity. Generally, the drug was very well tolerated,” concluded Dr. Hassel.

Disclosure: For full disclosures of the study authors, visit abstractsonline.com.