Trial of Nivolumab in Combination With Ipilimumab in Subjects With Previously Untreated Metastatic Uveal Melanoma

Uveal melanoma is a rare disease, accounting for 0.1% of all cancer deaths. This disease arises from melanocytes of the uveal tract and is the most common primary intraocular tumor in adults, with an incidence estimated at 0.6 per 100,000 persons/year in the Western population and seems to have remained stable over time. Metastases in uveal melanoma appear in 6.5%-35% of the patients during the first decade. The clinical and metastatic behavior differs from cutaneous melanoma because of its initially purely hematogenous dissemination and its tendency to metastasize to the liver. Furthermore, the liver is almost a "sentinel lymph node" for uveal melanoma, because it is affected in 95% of patients and it is the sole site of metastasis in most cases. This specific ocular-hepatic tropism remains unexplained. When liver metastases develop, the prognosis is poor and life expectancy is reduced to less than 6 months in the absence of treatment. Only few prognostic factors for survival have been identified. Age, short time interval to metastases development, and tumor burden in the liver have shown a negative impact on survival, whereas patients diagnosed at regular follow-up survive significantly longer, probably due to the earlier diagnosis. Several loco-regional treatment options can be considered if metastases are confined to the liver, including partial hepatic resection or radiofrequency ablation. Curative resection is possible in only a small fraction of patients due to the number, location or size of the metastases. Systemic chemotherapy is usually unsuccessful in metastatic uveal melanoma and results were recently reviewed showing an Overall Response Rate of 4,6 %with 95% CI 3.3-6.3%. There is no proof that conventional chemotherapy prolongs survival with most studies reporting OS between 5 and 12 months. Most therapies are derived from the experience extrapolated from cutaneous melanoma. Only few chemotherapeutic regimens have been studied in phase II trials such as bleomycin /vincristine/ lomustine /dacarbazine (BOLD), fotemustine,9-nitrocamptothecin, temozolomide, bendamustine, gemcitabine/treosulfan, cisplatin/gemcitabine/treosulfan, and dacarbazine/treosulfan with poor results that range from 0 to 15% response rate and less than 12 months overall survival with first line therapy. A phase III trial randomizing patients to chemotherapy or Best Suportive Care (BSC) is not expected to be performed because of difficulty in recruiting due to the low incidence of disease. In the other hand, the best understanding of the biology of cancer disease has allowed us to identify pathways that are important in mechanisms of proliferation, survival or dissemination. Recently Guanine Nucleotide-Binding Protein G (GNAQ) gene oncogenic mutation has been identified in close to 50% of primary uveal melanomas. The emergence of newer agents that target this or other pathways (such as selumetinib, sunitinib, imatinib, vorinostat, antiangiogenics) have resulted in multiple small studies that up to date have failed to show a clear superiority against chemotherapy. To summarize, patients with metastatic uveal melanoma should be included in clinical trials evaluating other options with newer agents with potentially less toxicity and greater efficacy than conventional chemotherapy.