Uveal melanoma: A new generation of therapies offers hope for patients

The summer of 2023 saw the approval of a new treatment option for certain patients with uveal melanoma, a form of cancer that begins in the eye and remains a challenge to treat. Richard Staines looks at the new approaches that are in clinical development.

Until recently, uveal melanoma was a disease that was poorly understood, with a list of treatment options that were limited and disfiguring. In a society that’s so focused on beauty and aesthetics, the loss of an eye has an enormous psychological impact and, even though prosthetics are difficult to notice, impaired vision following an enucleation (removal of the affected eye) has an effect on daily tasks.

No known cause

Uveal melanoma develops from cells called melanocytes, which are found in the middle layer of tissue in the wall of the eyeball (uvea). There is no known cause, but it is not related to sun exposure, although, it is more common in those who are fair-skinned and have grey or blue eyes.

In some people, there may be no symptoms, but it can be picked up by routine eye tests. Some experience issues with their vision, such as flashing lights, blurred vision, or a shadow in one eye.

Recent breakthroughs

However, there have been some breakthroughs in recent years, notably the FDA approval of Immunocore’s Kimmtrak (tebentafusp-tebn) for adults with HLA-A*02:01-positive unresectable and metastatic uveal melanoma in January 2022. This was followed in August 2023 by Delcath Systems’ Hepzato (melphalan for injection/hepatic delivery system), approved by the FDA for eligible adults with uveal melanoma and unresectable liver metastases.

The European vs the US situation

In Europe, Hepzato has been approved for several years, but is not routinely used because of the high burden of clinical training requirements and challenges with reimbursement.

Justin Moser, clinical assistant professor at University of Arizona College of Medicine in Phoenix, said that the situation is likely to be similar in the US following FDA approval. And, despite the approval of two drugs by the FDA, many patients are not covered by available therapies, with clinically unproven immunotherapies used as back-ups.

“Unfortunately, [Kimmtrak] is only available to patients who have HLA A02:01, which is 30-50% of Caucasians. For patients who are not candidates for, or do not respond to Kimmtrak, treatment options are limited, with many recommending clinical trials. Immunotherapies used to treat melanoma of the skin are commonly used, however, these are markedly less effective for metastatic uveal melanoma.”

Hepzato is unlikely to be widely available in the US for the same reasons as in Europe, according to Moser.

“Hepzato is a significant step forward for uveal melanoma, as it will be the only FDA approved therapy for the majority of patients with metastatic disease. Additionally, it has shown to have high response rates in liver metastases, the most common area of disease burden for patients with metastatic melanoma. It is a specialised complex procedure, so, it will likely only be available at specialised centres.”

Potential new generation therapies

As is often the case in pharma and biotech, the approval of these novel agents is paving the way for a potential new generation of therapies.

IDEAYA Biosciences is following closely behind with its combination of darovasertib and crizotinib, a protein kinase C (PKC) inhibitor and cellular mesenchymal-epithelial transcription factor (cMET) inhibitor. This is in phase 3 development for first line HLA-A2 negative metastatic uveal melanoma following a supportive phase 2 readout earlier this year. It is also in phase 2 development for HLA-A2-positive metastatic disease and in the neoadjuvant setting, and this latter indication could make it a direct competitor for Kimmtrak, as well as a wider patient group with the disease.

Other novel approaches include Roche’s RO7293583, an anti-TYRP1/CD3 T-cell engager, which is in phase 1 development for several melanomas including uveal melanoma. It is a bispecific monoclonal antibody that acts by targeting tyrosinase-related protein 1 (TYRP1) on the surface of cancer cells, as well as the CD3 receptor on the surface of T-cells. This activates and directs cytotoxic T-lymphocytes to tumour cells expressing the protein, resulting in the destruction of the malignant cells.

US-based Merck & Co and Syndax are attempting to combine the former’s blockbuster PD-1 checkpoint inhibitor pembrolizumab with a Class 1 histone deactylase (HDAC) inhibitor entinostat. And, at the beginning of November 2023, the FDA endorsed the design and planned analysis for a phase 3 trial of Aura Biosciences’ belzupacap sarotalocan (bel-sar) in early-stage choroidal melanoma. Bel-sar is from a novel class of virus-like drug conjugate therapies that Boston, Massachusetts-based Aura is developing for various oncology indications.

iOnctura, meanwhile, a biotech based in Geneva and Amsterdam, has prioritised uveal melanoma as a target indication for its IOA-244, a PI3Kδ inhibitor that has potential in several other different types of cancer. This is being tested in the phase 1a/1b DIONE-01 study, which consists of parallel cohorts including uveal melanoma, and has completed the dose escalation phase testing safety and tolerability.

According to iOnctura’s chief medical officer, Michael Lahn, IOA-244 can be considered a new type of PI3Kδ inhibitor because of its allosteric binding mechanism and patients could see its benefits without experiencing the side effects from previous drugs that work along this pathway, such as hyperglycemia, dermatitis and rash, stomatitis, diarrhoea, nausea, and fatigue.

Lahn said: “By blocking this molecule, we can stop cancer cells dividing. Secondly, inhibiting PI3K-delta redresses the balance of the immune system, decreasing the levels of immunosuppressing Tregs and increasing levels of anti-tumour CD8+ T cells. This enables the patient’s own immune system to better fight the cancer.”