Treatment with tebentafusp—a novel bispecific fusion protein—reduced the risk of death from metastatic uveal melanoma by half, compared with available treatments, in a phase III study presented at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021.¹ This is the first phase III study to show a survival benefit in this rare but potentially aggressive type of cancer (also known as ocular melanoma).

Interestingly, the effect of tebentafusp on progression-free survival was more modest than on overall survival. Investigators 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. The survival benefit was seen even in patients without a RECIST [Response Evaluation Criteria in Solid Tumors] objective response,” said presenting author Jessica C. Hassel, MD, Associate Professor and Section Head of Dermato-Oncology at the National Center for Tumor Diseases, University Hospital, Heidelberg, Germany.

Tebentafusp achieved a highly significant and clinically meaningful improvement in overall survival as first-line treatment of metastatic uveal melanoma.

— Jessica C. 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 treatment discontinuations and no treatment-related deaths,” Dr. Hassel added.

“Tebentafusp has the potential to be practice-changing for the management of metastasized uveal melanoma, and it is the first T-cell receptor therapeutic to demonstrate an overall survival benefit,” she stated.

Study Background and Methodology

Tebentafusp recognizes two targets—gp100 (melanocytic protein), which is present in melanoma cells, and a second target on T cells. “[The drug] 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,” Dr. Hassel explained.

The T-cell receptor–binding domain recognizes a specific gp100 peptide present on human leukocyte antigen (HLA)-A*0201, restricting the use of tebentafusp to patients with this HLA type. The 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 with immune checkpoint blockers, which are sometimes used to treat it. Once the cancer becomes metastatic, 1-year survival is about 50%. 

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

The study enrolled patients with advanced uveal melanoma who were HLA-A*0201–positive, had received no prior systemic therapy in the advanced setting, had no prior liver-directed therapy except surgery, and had any lactate dehydrogenase (LDH) level (reflecting tumor burden).

Patients (n = 378) were randomly assigned 2:1 to tebentafusp vs investigator’s choice of therapy (pembrolizumab, ipilimumab, or dacarbazine). They were stratified according to LDH level.

Key Findings

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

At a median follow-up of 14 months, patients randomly assigned to tebentafusp had almost half the risk of dying as those assigned to 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 disease progression or death, P < .001). The 1-year overall 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] 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 pembrolizumab, a similar magnitude of benefit was observed as in the overall trial: a 49% reduction in the risk of death. 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. The objective response rates according to RECIST criteria were 9% with tebentafusp vs 5% with investigator’s choice. However, the disease control rate at 12 weeks was notably higher with tebentafusp: 46% and 27%, respectively.

Tebentafusp improved overall survival vs investigator’s choice by 60% in patients with progressive disease as their best response, according to a landmark analysis at day 100. “Tebentafusp leads to an overall survival benefit even in patients not responding to treatment. The benefit is in slowing down disease progression, not achieving response. However, patients who have tumor shrinkage survive longer,” Dr. Hassel said. “The majority of patients with progressive disease as best response continued tebentafusp beyond disease progression,” she noted.

Toxicity Profile

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

Adverse events were mainly either skin-related or cytokine-mediated, in line with the proposed mechanism of action of tebentafusp. Two patients developed severe cytokine-release syndrome; both continued treatment with good tolerability afterward.

“Most adverse events [with tebentafusp] occurred in the first cycle and subsequently decreased in frequency and severity. Generally, the drug was well tolerated,” said Dr. Hassel. “That’s why tebentafusp is given in a dose-escalating fashion.”

Comment on Study

Antoni Ribas, MD, PhD

“This is the first study to show an improvement in overall survival in patients with uveal melanoma. In more than 50 years of research, no treatment has shown an improvement in overall survival,” said AACR President Antoni Ribas, MD, PhD, Director of Tumor Immunology at UCLA’s Jonsson Comprehensive Cancer Center.

“Tebentafusp is a fusion protein consisting of the T-cell receptor recognizing gp100 fused to CD3, and it becomes a T-cell engager. In this trial of 378 patients, all of whom were HLA-A2–positive to recognize the T-cell receptor, tebentafusp improved overall survival by 50% compared with prior standard-of-care therapy,” he continued. “The treatment was linked to an increased frequency of cytokine release and skin rashes,” he added.

“This study represents several firsts,” Dr. Ribas noted:

• It is the first-ever clinical trial to improve overall survival in uveal melanoma.
• This is the first T-cell receptor therapeutic to be successfully developed.
• It is the first antigen-targeting therapy that improves survival.

“This [drug] will be practice-changing, and we hope to use it in the clinic,” he stated. 

DISCLOSURE: Dr. Hassel has received honoraria from Almirall Hermal GmbH, Bristol Myers Squibb Foundation, MSD, Novartis, Roche Pharma AG, Sanofi Aventis, and Sun Pharma; has served as a consultant or advisor to Sanofi Aventis GmbH and Sun Pharma; and has received institutional research funding from 4SC, BioNTech AG, Bristol Myers Squibb, Genentech/Roche, Idera, Immunocore, Novartis, and Philogen. Dr. Ribas has served in a leadership role for Arcus Biosciences, Lutris, and PACT Pharma; holds stock or other ownership interests in 4c Biomed, Advaxis, Arcus Biosciences, Compugen, CytomX Therapeutics, Five Prime Therapeutics, Highlight, ImaginAb, IsoPlexis, Kite/Gilead, Lutris Pharma, MapKure, Merus, PACT Pharma, RAPT Therapeutics, Rgenix, and Tango Therapeutics; has received honoraria from Amgen, AstraZeneca, Chugai/Roche, Genentech/Roche, Merck Sharp & Dohme, Novartis, Sanofi, and Vedanta Biosciences; has served as a consultant or advisor to Amgen, Chugai Pharma, Merck, Novartis, and Sanofi; and has received institutional research funding from Agilent and Bristol Myers Squibb.

REFERENCE

1. Piperno-Neumann S, Hassel J, Rutkowski P, et al: Phase 3 randomized trial comparing tebentafusp with investigator’s choice in first-line metastatic uveal melanoma. AACR Annual Meeting 2021. Abstract CT002. Presented April 10, 2021.