Uveal Melanoma: Evidence for Adjuvant Therapy

Maria M. Choudhary, MD Pierre L. Triozzi, MD Arun D. Singh, MD ’

Introduction

Considerable progress has been made in identifying patients at risk for metastatic death. Uveal melanomas are characterized by mutations in G proteins (GNAQ and GNA11).1–3 Monosomy-3, loss of 6q, and gain of 8q in the primary tumor are associated with a worse prognosis.4 Gene expression profiling is being applied to tumors to classify tumor gene expression as ‘‘class 1,’’ associated with a low risk of metastasis, and ‘‘class 2,’’ associated with a high risk.5,6 Unfortunately, after development of metastatic disease there seems to be no significant survival difference between the treated and untreated patients.7,8 Given these findings, adjuvant therapy to prevent progression of subclinical microscopic metastatic disease to detectable macroscopic disease seems logical. We provide a summary of published, current, and future adjuvant therapy trials for uveal melanoma. ’

Published Trials Randomized Trials

Only 2 adjuvant therapy randomized control trials have been published for patients with uveal melanoma. One study enrolled 348 patients evaluating dacarbazine,9 a cytotoxic agent as adjuvant therapy after treatment of the primary tumor, whereas the second study assessed bacille Calmette-Guerin; an immune modulator in 113 patients.10 Neither study was able to demonstrate a survival difference between the adjuvant treated and the observation group. These studies are almost 2 decades old and did not take into account the genetic INTERNATIONAL OPHTHALMOLOGY CLINICS Volume 55, Number 1, 45–51 r 2015, Lippincott Williams & Wilkins

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prognostic factors making it difficult to estimate the number of patients actually at risk of metastases in the treatment and observation groups.9,10 Nonrandomized Trials

Two studies evaluated systemic adjuvant interferon (IFN) therapy in patients with uveal melanoma. These studies used historical controls matched for clinical prognostic factors. The larger of the 2 studies included 121 patients and took into account age, sex, largest tumor diameter, and time between primary therapy and adjuvant treatment for the control group.11 Second study also accounted for sex, tumor localization, and tumor dimensions in the historic controls.12 Neither study showed any survival benefit between the cases and controls.11,12 Another nonrandomized trial of adjuvant intra-arterial hepatic (iah) fotemustine also using historic controls matched for clinical and tumor characteristic failed to show any survival benefit.13 All these studies predate the introduction of molecular prognostication tools making it difficult to estimate the number of patients at risk of developing metastases in the treatment and control groups. Therefore, these studies might be underpowered to draw a statistically significant conclusion. ’

Current Clinical Trials Fotemustine

An alkylating agent that has been administered through both intravenous and iah routes. No difference in overall survival was observed between the 2 routes in patients with liver metastases from uveal melanoma.14 Adjuvant iah fotemustine in 22 patients was compared with a 3:1 matched control group; a survival benefit was seen in the studied group but was not found to be statistically significant.13 A randomized trial testing adjuvant intravenous fotemustine is currently ongoing, including only high-risk patients.15 The primary objective is to determine effect on disease-free survival. Cisplatin, Sunitinib, and Tamoxifen

Combination of immunomodulators with standard of care cytotoxic chemotherapeutic agents has been evaluated for the treatment of cancers. The underlying hypothesis is suppression of the host immune reaction generated in response to release of antigens by the demise of cancer cells. Also, some targeted therapeutics can have differential effects on specific components of the immune system, leading to enhanced or reduced antitumor effects.16 Platinum-based agents are considered to be www.internat-ophthalmology.com

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among the more active cytotoxic chemotherapeutics in melanoma.17 Sunitinib inhibits receptor tyrosine kinases, which signal through several pathways, including the mitogen-activated protein kinase (MAPK) pathway. It has antiangiogenic and antiproliferative effects and has demonstrated activity in patients with metastatic uveal melanoma in a pilot study.18 Tamoxifen through its estrogen-modifying activity can also inhibit the ability of uveal melanoma cells to metastasize.19 Synergistic antitumor activity of cisplatin has been observed with tamoxifen and sunitinib.20,21 A pilot trial of adjuvant therapy with cisplatin, sunitinib, and tamoxifen has been completed in patients with high-risk uveal melanoma after completion of primary therapy and results are awaited (ClinicalTrials.gov Identifier: NCT00489944). MAPK Inhibitors

Activation of the MAPK pathway by mutant GNAQ acts ‘‘upstream’’ to BRAF, and seems to be critical for the development of uveal melanoma.2 The MEK inhibitor, selumetinib showed increased progression-free survival (15.9 vs. 7 wk) and response rate (15% vs. 0%) when compared with treatment with temozolomide, essentially an oral formulation of dacarbazine in a phase II trial.22,23 Difference in the overall survival was not reported to be significant. Additional trials of MEK inhibitors in metastatic uveal melanoma are underway. Its use as a single agent in the adjuvant setting is under investigation (ClinicalTrials.gov Identifier: NCT02068586). The major limitation of MAPK pathway inhibitors in the treatment of melanoma has been the lack of durable response; these drugs tend to work for an average of 6 to 10 months. It is possible that adjuvant therapy with MAPK pathway inhibitors may lead to a more aggressive recurrence that will confound the overall survival. c-MET Inhibitors

c-MET is a 140 kD tyrosine kinase that when activated by hepatocyte growth factor undergoes autophosphorylation and initiates mitogenic pathways.24 There is an increased expression of c-Met in uveal melanoma with a high risk of metastases.25 Crizotinib is selective for cMet, anaplastic lymphoma kinase, and ROS1 leading to its use in non– small cell lung cancer. This has been studied in mouse models of uveal melanoma and treated mice showed a significant reduction in development of metastases compared with their untreated counterparts.26 A phase II trial of adjuvant crizotinib in patients with class 2 tumors by gene expression profiling is currently underway and recruiting patients (ClinicalTrials.gov Identifier: NCT02223819). www.internat-ophthalmology.com

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IFN-a-2b With Dacarbazine

IFN-a-2b has been shown to prevent metastasis in a mouse ocular melanoma model when high doses are administered intravenously.27 Dacarbazine, an alkylating agent can sensitize tumors to immune effectors, releasing antigenic determinants and cross-priming, and/or reducing regulatory T cells.28 Natural killer cell activity is increased in patients treated with the combination.29 Furthermore, the sequential nature of the program selected allows assessment of the effects of a chemical and a cytokine independently. Accrual in the adjuvant trial has been completed, and results will be forthcoming (ClinicalTrials.gov Identifier: NCT01100528). Ipilimumab

Ipilimumab is a monoclonal antibody that blocks CTLA-4, a negative T-cell regulator and, therefore, acts as an immune ‘‘checkpoint.’’ In phase III trials in patients with advanced cutaneous melanoma, ipilimumab improved the overall survival with a durable response when compared with gp100 vaccine and dacarbazine.30,31 Recently reported results of adjuvant therapy with ipilimumab show improved recurrencefree survival in stage III cutaneous melanoma.32 The antitumor effects of ipilimumab in metastatic uveal melanoma have not been defined. Response rates in retrospective analyses have been approximately 5%, and overall survivals have ranged from 5.2 to 9.6 months.33–35 Effects on the overall survival are not yet known. A phase I/II trial of adjuvant ipilimumab in patients with high-risk uveal melanoma is underway (ClinicalTrials.gov Identifier: NCT01585194). Dendritic Cell (DC) Vaccine

Vaccines have been an attractive though not yet clinically approved adjuvant therapy for melanoma. DC vaccines loaded with tumor antigens elicits tumor-specific immune responses capable of killing cancer cells without inducing meaningful side effects have shown promise.36 Currently there are 2 ongoing trials: a phase III randomized, open-label trial of vaccination with DCs loaded with autologous tumor RNA in patients treated for uveal melanoma with monosomy 3 and without evidence of metastatic disease (ClinicalTrials.gov Identifier: NCT01983748) along with an open-label nonrandomized phase II intervention study of a vaccine consisting of autologous DCs transfected with melanoma antigens in HLA-A2-positive patients with high-risk uveal melanoma with expression of tyrosinase and/or gp100 (ClinicalTrials.gov Identifier: NCT00929019). The latter is an exploratory study aiming to demonstrate proof of principle. The primary endpoints are in vivo-induced immunologic response and secondary study endpoints are progression-free survival, overall survival, and toxicity. www.internat-ophthalmology.com

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Future Trials Histone Deacetylase (HDAC) Inhibitors

HDAC regulates DNA expression and because of this can potentially shift uveal melanoma cells from the class 2 to the class 1 signature. HDAC inhibitors have been shown to induce differentiation of uveal melanoma cells and dormancy of micrometastatic disease.37 HDAC inhibitors, including suberolanilide hydroxamic acid and valproic acid, are used clinically and are being considered for adjuvant testing in patients with high-risk uveal melanoma.23,38 Hypomethylating Agents

DNA methylation is mediated by DNA methyl-transferase. In melanoma models frequent, intermittent, low concentrations of the DNA methyl-transferase inhibitor, decitabine has been shown to suppress proliferation and promote cellular differentiation.39 Frequent, intermittent, low-dose decitabine also induced alterations in potential host regulators of MITF in the tumor stroma.39 Host immune cells were also modified.40 An adjuvant trial of low-dose decitabine, which is in clinical use, in patients with high-risk uveal melanoma is being activated. ’

Conclusions

To date no adjuvant therapy regimen has shown any promising results. Existing cytotoxic and immunotherapeutic regimens are now being more rationally applied using tumor genetic criteria to identify high-risk patients. Several novel cytotoxic, immune modulatory, and targeted compounds are being investigated in the metastatic setting that may be applicable to the adjuvant setting. Approaches that promote uveal melanoma cellular differentiation and/or dormancy have shown promise in preclinical studies.

The authors declare that they have no conflicts of interest to disclose.



References

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Uveal melanoma: evidence for adjuvant therapy.

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