The treatment landscape for uveal melanoma, a rare eye cancer with historically limited therapeutic options, is experiencing a significant transformation with recent approvals and promising developments in clinical trials.
Recent Treatment Breakthroughs
The FDA's approval of Immunocore's Kimmtrak (tebentafusp-tebn) in January 2022 marked a crucial milestone for HLA-A*02:01-positive unresectable and metastatic uveal melanoma patients. This was followed by the August 2023 approval of Delcath Systems' Hepzato for adults with uveal melanoma and unresectable liver metastases.
Despite these advances, significant challenges remain. Justin Moser, clinical assistant professor at University of Arizona College of Medicine in Phoenix, notes that Kimmtrak's availability is limited to "30-50% of Caucasians" who are HLA A02:01 positive. Additionally, while Hepzato shows promising response rates for liver metastases, its complex administration requirements may restrict its availability to specialized centers.
Emerging Pipeline Candidates
IDEAYA Biosciences is advancing a novel combination therapy of darovasertib and crizotinib, targeting protein kinase C (PKC) and cellular mesenchymal-epithelial transcription factor (cMET). The treatment has progressed to phase 3 development for first-line HLA-A2 negative metastatic uveal melanoma, with additional phase 2 studies ongoing in HLA-A2-positive metastatic disease and neoadjuvant settings.
Roche has entered the field with RO7293583, an innovative anti-TYRP1/CD3 T-cell engager. This bispecific monoclonal antibody works by targeting tyrosinase-related protein 1 on cancer cells while engaging T-cells through CD3 receptor binding, potentially offering a new mechanism of action for treating uveal melanoma.
Novel Therapeutic Approaches
Several companies are pursuing unique strategies to combat this challenging disease. Merck & Co and Syndax are investigating the combination of pembrolizumab with the HDAC inhibitor entinostat. Meanwhile, Aura Biosciences received FDA endorsement for their phase 3 trial design of belzupacap sarotalocan in early-stage choroidal melanoma.
iOnctura's IOA-244, a novel PI3Kδ inhibitor, represents another promising approach. According to Michael Lahn, iOnctura's chief medical officer, the drug's allosteric binding mechanism could offer improved efficacy without the typical side effects associated with PI3K inhibition. "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," Lahn explains.
Disease Background and Unmet Need
Uveal melanoma develops from melanocytes in the eye's uvea, with no known cause, though it occurs more frequently in fair-skinned individuals with grey or blue eyes. Unlike skin melanoma, it is not related to sun exposure. The disease can be asymptomatic or present with vision problems, including flashing lights, blurred vision, or shadows in the affected eye.
Current treatment options often involve significant trade-offs, including potential vision loss and psychological impact from eye removal procedures. While recent approvals have expanded the therapeutic arsenal, the need for more widely applicable and less invasive treatments remains critical for this challenging cancer.
