Rare Diseases Report 2021

Metastatic uveal melanoma: New drugs in pipeline, but prognoses remain grim

Publish date: December 14, 2021

Treatments in development could make advances

Physicians are working on several fronts to develop new treatments. A 2021 review of clinical trials found numerous trials regarding checkpoint inhibition, one devoted to a vaccine, and several involving checkpoint inhibitors. The review author notes that “the low mutational burden and poor immunogenicity of UM tumors may underlie poor responses and resistance to [immune checkpoint inhibitors] alone.”⁶

Earlier this year, grant-funded researchers reported encouraging news on the G protein inhibitor front. Their study found that FR900359, a selective inhibitor of the Gq/11/14 subfamily of heterotrimeric G proteins, could hold promise for “treating UM and potentially other diseases caused by constitutively active Gq/11.”⁷

In another 2021 study, this one with no reported funding, researchers explored the tumor microenvironment of UM and reported that their findings “provided a robust gene-based prognostic signature for predicting prognosis of UM patients and proposed a potential targeted therapy for preventing UM metastasis.”⁸

Experimental drug may add months of life

Physicians often recommend that patients take part in clinical trials. Earlier this year, researchers reported that a drug called tebentafusp – a bispecific fusion protein – slightly boosted metastatic UM survival in an open-label, phase 3 clinical trial when used as a first-line treatment. Patients were randomly assigned to tebentafusp, 1 of 2 immunotherapy drugs (ipilimumab or pembrolizumab), or the chemotherapy drug dacarbazine. Those who took tebentafusp vs. the other options lived longer with an estimated 1-year overall rate of 73.2% (95% CI: 66.3-78.9) vs. 57.5% (95% CI: 47.0-66.6), respectively. Fewer than 4% of those on tebentafusp needed to stop it because of adverse effects, and no treatment-related deaths occurred.⁹

Dr. Orloff is one of the coauthors of this study.

The National Cancer Institute provided more details about the industry-funded research and noted that median overall survival for patients who received the drug was 21.7 months vs. 16 months for the control group.

Not every patient is eligible for this treatment, however. A coauthor told the American Association for Cancer Research that “the major limitation of tebentafusp is that it can only be used in patients who have a specific HLA [human leukocyte antigen] type.” Patients must be HLA-A*0201-positive.¹⁰

In August 2021, the FDA granted priority review for tebentafusp.¹¹And in September 2021, a company called TriSalus announced the first patient enrollment in a “clinical study evaluating the administration of SD-101, an investigational toll-like receptor 9 (TLR9) agonist in adults with metastatic uveal melanoma.”¹²

According to the company, the research “is designed to evaluate the intravascular administration of SD-101 into uveal melanoma liver metastasis lesions in combination with checkpoint inhibitors using the novel Pressure-Enabled Drug Delivery (PEDD) approach.” This strategy is “designed to overcome the inherent intratumoral pressure of solid tumors,” the company said.

Dr. Materin serves on a scientific advisory board for Castle Biosciences. Dr. Orloff is a consultant for Immunocore, which funded the tebentafusp study, and serves on a scientific advisory board for TriSalus. Dr. Seedor reports no disclosures.