Uveal Melanoma: Evidence for Adjuvant Therapy
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. 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. A randomized trial testing adjuvant intravenous fotemustine is currently ongoing, including only high-risk patients. The primary objective is to determine effect on disease-free survival.
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. Platinum-based agents are considered to be among the more active cytotoxic chemotherapeutics in melanoma. 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. Tamoxifen through its estrogen-modifying activity can also inhibit the ability of uveal melanoma cells to metastasize. Synergistic antitumor activity of cisplatin has been observed with tamoxifen and sunitinib. 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).
Activation of the MAPK pathway by mutant GNAQ acts "upstream" to BRAF, and seems to be critical for the development of uveal melanoma. 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. 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 is a 140 kD tyrosine kinase that when activated by hepatocyte growth factor undergoes autophosphorylation and initiates mitogenic pathways. There is an increased expression of c-Met in uveal melanoma with a high risk of metastases. Crizotinib is selective for c-Met, 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. 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).
IFN-α-2b has been shown to prevent metastasis in a mouse ocular melanoma model when high doses are administered intravenously. Dacarbazine, an alkylating agent can sensitize tumors to immune effectors, releasing antigenic determinants and cross-priming, and/or reducing regulatory T cells. Natural killer cell activity is increased in patients treated with the combination. 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 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. Recently reported results of adjuvant therapy with ipilimumab show improved recurrence-free survival in stage III cutaneous melanoma. 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. 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).
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. 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.
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. 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. A randomized trial testing adjuvant intravenous fotemustine is currently ongoing, including only high-risk patients. 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. Platinum-based agents are considered to be among the more active cytotoxic chemotherapeutics in melanoma. 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. Tamoxifen through its estrogen-modifying activity can also inhibit the ability of uveal melanoma cells to metastasize. Synergistic antitumor activity of cisplatin has been observed with tamoxifen and sunitinib. 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. 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. 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. There is an increased expression of c-Met in uveal melanoma with a high risk of metastases. Crizotinib is selective for c-Met, 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. 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).
IFN-α-2b With Dacarbazine
IFN-α-2b has been shown to prevent metastasis in a mouse ocular melanoma model when high doses are administered intravenously. Dacarbazine, an alkylating agent can sensitize tumors to immune effectors, releasing antigenic determinants and cross-priming, and/or reducing regulatory T cells. Natural killer cell activity is increased in patients treated with the combination. 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. Recently reported results of adjuvant therapy with ipilimumab show improved recurrence-free survival in stage III cutaneous melanoma. 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. 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. 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.
SHARE
