Published on September 13, 2021
Immunotherapies and Targeted Therapies for Uveal Melanoma
Uveal melanoma, a cancer of the eye, is considered a relatively simple tumor type, genetically speaking. Its comparatively low level of mutations, among other factors, has made it difficult to treat using immune checkpoint inhibitors, which have lengthened life for people with melanoma of the skin. Targeted treatments for melanoma of the skin also have tended not to work for people with uveal melanoma because these different melanoma types generally don’t share the same mutations. In fact, there is currently no treatment approved by the U.S. Food and Drug Administration (FDA) for metastatic uveal melanoma.
That may be changing. An immunotherapy called tebentafusp recently demonstrated that it could increase survival in some individuals with metastatic uveal melanoma. Meanwhile, several high-frequency mutations have been identified that may provide targets for new therapies, said Marlana Orloff, MD, of Thomas Jefferson University and the Sidney Kimmel Cancer Center in Philadelphia, in a virtual presentation at the annual meeting of the American Society of Clinical Oncology (ASCO), held in June 2021.
“Uveal melanoma, though rare, is the most common primary malignant intraocular tumor in adults,” Dr. Orloff said. Approximately 2,500 cases are diagnosed in the United States each year, and the median age at diagnosis is between 50 and 60 years, she added.
Patients diagnosed with uveal melanoma that has not spread to other parts of the body may receive localized treatments such as surgery or radiation therapy, but the cancer may return. “Despite a very effective primary therapy, approximately 50% will recur with metastatic disease,” said Dr. Orloff.
A Novel Immunotherapy
There are currently four immune checkpoint inhibitors that have been approved for the treatment of metastatic melanoma, but results of studies of these drugs in uveal melanoma have been underwhelming.
Immune checkpoint inhibitors work by blocking proteins that instruct immune cells not to kill the body’s own cells. Cancer cells take advantage of these immune checkpoints, using them to tell the immune system to leave them alone. Checkpoint inhibitors tend to work best in cancers with many mutations because it is more obvious to the immune system in the first place that there is something wrong with the cancer cells and they need to be eliminated. However, tebentafusp directly recruits immune cells to kill cancer cells.
Data presented in April 2021 at the American Association for Cancer Research Annual Meeting show that tebentafusp helps certain patients with metastatic uveal melanoma live longer. Tebentafusp is a bispecific fusion protein, meaning it attaches to two different targets. One end of the drug attaches to gp100, a protein expressed by melanoma cells. The other end attaches to immune cells called T cells, leading them to kill the melanoma cells.
The drug only recognizes gp100 in patients with a certain HLA type. (HLAs are molecules cells use to display pieces of cellular proteins to the immune system.) Most people with uveal melanoma are white, and about half of white patients have this HLA type.
The researchers enrolled 378 patients in a clinical trial, randomly assigning some people to tebentafusp and others to their doctor’s choice of therapies. A little more than 73% of patients who receive tebentafusp lived one year or longer after starting the treatment, compared to around 58% of patients who received their doctor’s choice of therapy. The company that makes tebentafusp, Immunocore, announced on Aug. 24 that the FDA will decide whether to approve the new drug by Feb. 23, 2022.
Zeroing in on Mutations
Metastatic melanomas of the skin can have mutations in genes like BRAF or KIT, and patients may receive targeted therapies following testing for these mutations. Uveal melanoma comes with mutations to a different set of genes. More than 80% of all uveal melanoma cases involve mutations in the GNAQ or GNA11 genes, Dr. Orloff said. Patients may also have mutations in the BAP1 or SF3B1 genes.
Mutations in uveal melanoma cells may serve as biomarkers that predict a patient’s course of disease. For instance, a scientific abstract presented at ASCO indicated that uveal melanoma patients with the SF3B1 malignancy were less likely to develop liver metastases than patients without this mutation, Dr. Orloff said. Loss of function in BAP1 gene mutations have been associated with an increased risk of metastatic disease, she said.
Researchers are also trying to use mutated genes as therapeutic targets in uveal melanoma, Dr. Orloff said. The GNAQ and GNA11 genes are difficult to target directly, she noted, but there have been attempts at targeting signaling pathways downstream of them. A PKC inhibitor known as darovasertib (LXS-196, IDE-196), which has not been approved by the FDA, has shown some effectiveness, she noted. In an analysis of 75 patients with metastatic uveal melanoma who received this drug alone, 61% showed a reduction in target lesions. Dr. Orloff noted that “this was a heavily pretreated population,” including patients who had previously tried multiple other treatments. The one-year overall survival rate was 57%, with patients living a median 13.2 months, she said.
Darovasertib is also being studied in combination with targeted drugs, including binimetinib (Mektovi) and crizotinib (Xalkori), that have previously been approved to target tumors with other mutations. Ongoing clinical trials are underway to further explore the potential of GNAQ, GNA11, BAP1, and SF3B1 as therapeutic targets, she added.
“There are a number of interesting drugs currently in clinical trial, and certainly further therapeutic strategies may consider combination approaches to overcome some of the resistance that we often see with targeted therapy,” Dr. Orloff said.