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Immunotherapy Drug Tebentafusp Improves Survival in Advanced Uveal Melanoma

, by Edward Winstead

An image showing T cells (dark blue) killing uveal melanoma cells (red) after treatment with tebentafusp.

Credit: Cancers. July 2019. doi: 10.3390/cancers1107097. CC BY 4.0.

UPDATE: On January 25, 2022, the Food and Drug Administration approved tebentafusp (Kimmtrak) for the treatment of some people with uveal melanoma. Under the approval, tebentafusp can be used in people whose cells express a protein called HLA-A*02:01 and whose cancer can’t be removed surgically or has spread to other parts of their body. The approval is based on the results of a large clinical trial, described in the story below.

An investigational immunotherapy drug has helped patients with uveal melanoma, an aggressive cancer of the eye, live longer than other patients who received current treatments for the disease, according to the results of a large clinical trial.

The drug, tebentafusp, is a type of treatment called a bispecific fusion protein. It works by helping immune cells get close enough to cancer cells to attack them. The clinical trial evaluated the drug as an initial treatment for people with metastatic uveal melanoma

In the trial, 378 patients with previously untreated metastatic uveal melanoma were randomly assigned to receive tebentafusp or one of three established therapies that their doctors could select. The three options for patients in the comparison, or control, group included two immune checkpoint inhibitors and a chemotherapy drug.

The median overall survival was 21.7 months for patients receiving tebentafusp versus 16 months for patients in the control group, the researchers found.

“This is the first clinical trial to report an improvement in overall survival for patients with metastatic uveal melanoma,” said Jessica Hassel, M.D., of the University Hospital Heidelberg in Germany, who presented the findings on April 10 at the virtual annual meeting of the American Association for Cancer Research (AACR).

Uveal, or ocular, melanoma is often detected only after the disease has spread from the eye to other parts of the body, such as the liver. There is no standard treatment for metastatic uveal melanoma. Once the disease has spread, many patients do not survive for a year.

“The results of this trial are encouraging,” said John Schiller, Ph.D., of NCI’s Center for Cancer Research, who investigates the disease but was not involved in the study. “The drug was able to show some benefit, mainly because metastatic ocular melanoma has such a poor prognosis, and the current treatments work so poorly.”

Although the findings show an incremental improvement in overall survival, Dr. Schiller continued, whether the treatment can lead to “long-term control of the disease in a substantial portion of patients” is not yet clear.

Overcoming Resistance to Immune Checkpoint Inhibitors

Immune checkpoint inhibitors can greatly improve the survival of people with melanomas of the skin, but these treatments are much less effective against uveal melanoma, according to Dr. Hassel.

One possible reason, she continued, may be that uveal melanomas tend to have fewer genetic alterations than melanomas of the skin. Studies have suggested that immune checkpoint inhibitors are more effective against tumors that have many genetic mutations.

“We wanted to see whether the bispecific fusion protein could overcome the resistance that metastatic uveal melanomas have to immunotherapy drugs such as immune checkpoint inhibitors,” Dr. Hassel said in an interview.

Tebentafusp binds to one molecule on melanoma cells and another on T cells, which are a type of immune cell. The drug brings the T cells close enough to the melanoma cells to kill them.

Specifically, one end of tebentafusp recognizes a part of a protein called gp100 that tends to be produced in abundance in melanoma cells, including uveal melanoma cells. The other end of tebentafusp binds to and activates T cells to attack the nearby gp100-expressing melanoma cells, according to the researchers.

A major limitation, however, is that for tebentafusp to recognize and bind to gp100-expressing cancer cells, these cells must also express a specific type of human leukocyte antigen (HLA), known as HLA-A*02:01. HLAs, which are present on the surfaces of most cells in the body, play an important part in the body’s immune response to foreign substances. 

HLA-A*02:01 is present in approximately half of all Whites, which is the population most affected by uveal melanoma, according to Dr. Hassel.

“Bispecific fusion proteins are an up-and-coming therapeutic strategy,” said Dr. Schiller, who is developing treatments for uveal melanoma based on HPV vaccine technology. “Given the tricks of modern molecular biology, the [bispecific fusion protein] technology is pretty much limited only by the investigator’s imagination.”

No Standard Treatment for Metastatic Uveal Melanoma

Because there is no standard treatment for metastatic uveal melanoma, Dr. Hassel and her colleagues designed the trial so that the doctors of patients in the control group could select from three treatment options that are currently used to treat the disease: the immunotherapy drugs ipilimumab (Yervoy) and pembrolizumab (Keytruda) or the chemotherapy drug dacarbazine.

In the trial, 9% of the patients in the tebentafusp group had their tumors shrink in response to treatment, compared with 5% in the control group.

The most common side effects among patients receiving tebentafusp included skin rashes, fever, and itching. Some patients also experienced a common side effect of immunotherapy drugs known as cytokine release syndrome. These side effects were generally manageable, according to the researchers.

The rate of patients who discontinued treatment because of side effects was lower in the tebentafusp group than the control group (2% versus 4.5%, respectively).

This study was sponsored by Immunocore, the maker of tebentafusp. The company has said it will apply to the Food and Drug Administration later this year for approval of the drug for the treatment of metastatic uveal melanoma.

At a press briefing before the AACR meeting, Antoni Ribas, M.D., Ph.D., of UCLA, called the study “practice changing” and said he hoped to be able to use the drug in the clinic.

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