Poor Response to Checkpoint Immunotherapy in Uveal Melanoma Highlights the Persistent Need for Innovative Regional Therapy Approaches to Manage Liver Metastases

Abstract

Uveal melanoma is a cancer that develops from melanocytes in the posterior uveal tract. Metastatic uveal melanoma is an extremely rare disease that has a poor long-term prognosis, limited treatment options and a strong predilection for liver metastasis. Median overall survival has been reported to be 6 months and 1 year mortality of 80%. Traditional chemotherapy used in cutaneous melanoma is ineffective in uveal cases. Surgical resection and ablation is the preferred therapy for liver metastasis but is often not feasible due to extent of disease. In this review, we will explore treatment options for liver metastases from uveal melanoma, with a focus on isolated hepatic perfusion (IHP). IHP offers an aggressive regional therapy approach that can be used in bulky unresectable disease and allows high-dose chemotherapy with melphalan to be delivered directly to the liver without systemic effects. Long-term median overall survival has been reported to be as high as 27 months. We will also highlight the poor responses associated with checkpoint inhibitors, including an overview of the biological rationale driving this lack of immunotherapy effect for this disease. The persistent failure of traditional treatments and immunotherapy suggest an ongoing need for regional surgical approaches such as IHP in this disease.

Prognostic Hematologic Biomarkers Following Immune Checkpoint Inhibition in Metastatic Uveal Melanoma

“…Currently, there is a phase I clinical trial investigating the feasibility of hepatic ablation of melanoma metastases, in conjunction with ipilimumab and nivolumab, to enhance immunotherapy efficacy (HAMMER trial; NCT05169957) [ 49 ]. Besides an increased proportion of patients with LM, UM has a significantly lower tumor mutational burden and less PD-1/PD-L1 expression when compared to cutaneous melanoma which may limit response to ICI [ 50 , 51 ].…”

Regional chemotherapy for uveal melanoma liver metastases

“…IHP/ PHP is indicated for tumors totally or predominantly localized to the liver. The relative contraindications to IHP/PHP include insufficient liver function (bilirubin >1.5 mg/dL, elevated INR, platelet <100 000), portal hypertension, intolerance to heparin, and age >70 [51] . The most common complication of IHP is bone marrow suppression.…”

Do Extracellular RNAs Provide Insight into Uveal Melanoma Biology?

“…The traditional systemic chemotherapy option is not successful in UM because of ocular barriers that affect distribution of drugs in the eye after systemic administration. Additionally, checkpoint inhibitor immunotherapy fails to stop the progression of metastatic UM [ 79 ]. Therefore, radiotherapy with other adjuvant therapies, e.g., target miRNAs (with agomirs or antagomirs), would be of value for the management of UM, whenever the tumor is not extended and enucleation cannot be avoided [ 80 ].…”