TCR Bispecific Boosts Survival in Uveal Melanoma

A bispecific fusion protein designed to redirect T cells toward a melanoma-associated antigen nearly halved the risk of death among patients with an aggressive form of eye cancer, researchers reported during the first session of the virtual American Association for Cancer Research (AACR) Annual Meeting 2021, being held April 10–15.

In a phase III randomized trial of 378 patients with untreated metastatic uveal melanoma, 73% of those who received the bispecific protein therapy, known as tebentafusp (Immunocore), were alive 1 year later. In comparison, 58% of those prescribed a checkpoint inhibitor or chemotherapeutic agent of the investigator's choice met that same benchmark. The disease-control rate was greater in the tebentafusp-treated cohort as well—45% versus 28%.

Adverse events associated with tebentafusp treatment were predictable and manageable, noted Jessica Hassel, MD, of the University Hospital Heidelberg in Germany, who presented the findings. The rate of treatment discontinuation was lower in the tebentafusp arm compared with the investigator's choice arm—2% versus 4.5%, respectively.

If approved, tebentafusp would represent the first major pharmacologic advance for the treatment of metastatic uveal melanoma, a rare disease for which no other therapy has been shown to improve overall survival. “It's going to become the standard of care for these patients,” said site investigator Jose Lutzky, MD, of the University of Miami Miller School of Medicine in Florida.

Yet, the drug—which pairs an anti-CD3 immune effector cell-binding domain with a high-affinity gp100-directed T-cell receptor (TCR)—won't be an option for everyone with advanced uveal melanoma. Because the immune-mobilizing TCR part of tebentafusp recognizes gp100 peptides presented exclusively on HLA-A*02:01 molecules, the therapy's reach is limited to the 40% of individuals globally, mainly Caucasians of European descent, who harbor that HLA polymorphism.

According to David Berman, MD, PhD, head of R&D at Immunocore, the company hopes to extend the reach of its various TCR bispecifics in development by advancing products built around either other common HLA subtypes or “non-classical” MHC molecules that might allow for universal TCR-based products.

As for tebentafusp, Immunocore plans to file for regulatory approval later this year. Trials involving patients with nonmetastatic uveal melanoma could follow. “We do believe this is a platform that can be used in the adjuvant setting,” Berman said.

At the AACR meeting, trial investigators also detailed exploratory analyses from a phase I/II trial of tebentafusp in 127 patients with previously treated metastatic uveal melanoma. In one presentation, the researchers highlighted several tumor and circulating biomarkers—including a specific ratio of macrophages to T cells found in pretreatment biopsies and levels of IL6 in the blood—that were predictive of favorable clinical outcomes. In another, they showed that tebentafusp triggered transient increases in assorted inflammatory cytokines and chemokines in the blood. The drug also changed the tumor microenvironment to promote cytotoxic CD8+ T-cell infiltration.

“We can redirect T cells and convert immune deserts into very active immune environments,” Berman said.

Despite those beneficial immune effects, very few patients experienced radiographic responses in any of the trials—just 5% in the second-line study and 9% in the pivotal first-line one. Many more patients achieved stable disease. Even among those for whom disease progression was the best outcome, a landmark analysis 100 days post-treatment revealed a pronounced survival benefit with tebentafusp, with the risk of death down 60% compared with patients who received other therapies.

The bottom line: “The response rate is not particularly high,” Lutzky said, “but the survival data are really amazing.” –Elie Dolgin

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