What does the future hold for uveal melanoma, a historically untreatable disease?

Abstract

Uveal melanoma (UM), which encompasses pigmented tumors arising from the iris, ciliary body and choroid, is the most common primary intraocular malignancy in adults, with an incidence of approximately five cases per million [1]. A total of 98%of patients with UM are Caucasian and incidence increases with age. Approximately half of all patients develop metastatic disease within 15–20 years of initial diagno‐ sis, with up to 90% of patients developing hepatic metastases [1]. Metastatic UM has historically portended a dismal prognosis, with an overall survival of less than 1 year from diagnosis. Outcome can be predicted using either cytogenetic or gene expression ana lysis of the primary tumor. Starting in the late 1980s, cytogenetic ana lysis of metastatic UMs led to the finding that monosomy 3 (and specifically 3p loss) and 8q24 duplication portended a worse prognosis than disomy 3 and 6p gain [2]. More recently, gene expression profiling demonstrated that UMs fall into two distinct classes with diverging 5‐year risk of metastasis – Class I, with as low as 2% risk, and Class II, with approximately 72% risk [3]. Once metastases occur, therapeutic options are limited. Over the past decade, multiple Phase II trials have been conducted with traditional cytotoxic chemothera‐ peutic agents such as temozolomide, immunologic agents such as interferon, and targeted agents such as imatinib, among others. The overall objective response rates on these trials are universally low, with observed progression‐free survivals typically less than 3 months. Hepatic‐directed therapy has demonstrated reasonable objective response rates, but the impact of these therapies on overall survival is not clear [4]. Multiple agents have recently been approved by the US FDA for treatment of advanced melanoma, including the BRAF inhibitors vemurafenib [5] and dabrafenib [6]; the MEK inhibitor trametinib and the CTLA‐4 inhibitor ipilim‐ umab [7]. Although vemurafenib and dabrafenib have been demonstrated to improve survival in patients with cutaneous melanoma harboring BRAF mutations, they are not a viable therapeutic option for patients with UM, a disease that only rarely har‐ bors such mutations [8]. Immune checkpoint inhibitors such as ipilimumab, which also improves survival in patients with advanced cutaneous melanoma [7], represent another potential treatment approach for those with advanced UM. A retro spective review of clinical outcomes of metastatic UM patients receiving ipilimumab identi‐ fied an immune‐related response rate of 5% and the disease‐control rate was 28% at 24 weeks, results that appear similar to that seen in cutaneous melanoma [9]. A smaller series reported an identical disease control rate at 23 weeks [10]. Recent advances in our understanding of the biology of UM have provided potential therapeutic strategies. A critical insight into the mechanism of UM tumor “...with a better understanding of the genetic and epigenetic changes that underlie distinct classes of tumor behavior, future interventions may be identified...”