Systemic Therapy in Metastatic Melanoma

Melanoma is the most aggressive form of skin cancer, contributing to about 76,000 new cases and more than 9,000 deaths in 2014. ¹ Depending on the stage of the disease, 5-year melanoma survival can range from 15% to 97%. Patients with local and distant metastases have a 5-year survival of about 60% and 15%, respectively. ²

The incidence of melanoma is rising, partly because of the increasing number of skin biopsies being performed. ³ If melanoma is diagnosed early, surgical excision is the treatment of choice. In patients with oligometastatic disease (cancer that has spread, but only to 1 or a small number of sites), complete surgical excision of the metastases may provide prolonged overall survival (OS) and delay the need to use systemic therapy. ⁴

Recently, many new drug therapies have shown promising results in clinical trials, which may improve the prognosis of metastatic disease. This article reviews currently available systemic treatment options for the management of metastatic melanoma, the role of cytotoxic chemotherapy and interleukin-2 (IL-2), and the latest therapies available, including immune checkpoint inhibitors.

Cytotoxic Chemotherapy and Interleukin-2

Cytotoxic chemotherapy does not have an established role in the initial treatment of metastatic melanoma. Currently, cytotoxic chemotherapy is used in patients who have not responded to immunotherapy or molecular targeted therapy. The most commonly used drugs include dacarbazine and its prodrug, temozolomide. Several studies have failed to demonstrate a survival benefit using a single-agent chemotherapy with either dacarbazine or temozolomide. ^5,6

Other agents used in metastatic melanoma include nitrosoureas (fotemustine), platinum compounds (cisplatin, carboplatin), vinca alkaloids (vincristine),
and taxanes (paclitaxel). None of these agents provide a survival benefit, but an objective response may be seen in a minority of cases. Combination chemotherapy regimens have not shown an advantage over singleagent dacarbazine or temozolomide. ^7,8

High-dose IL-2 has been used in cases of metastatic melanoma with good performance status (PS) and organ function. Studies have shown a complete response rate of 3% to 7% and a prolonged disease-free survival in a minority of patients. ^9-11 The use of highdose IL-2, however, is limited by the high incidence of adverse effects (AEs), which include bacterial sepsis, pulmonary edema, arrhythmias, fever, and on some occasions, death due to complications. ¹⁰ The use of IL-2 requires admission of the patient to a specialized unit for AE monitoring and management. Because of its ability to “cure” a minority of patients, a role still exists for IL-2 therapy in the treatment of younger, healthy patients with no evidence of organ dysfunction at baseline.

Immune Checkpoint Inhibitors

Checkpoint inhibitors are a class of drugs that unmask the immune system to fight against cancer cells. This class of drugs has shown significant activity and survival advantage in recent phase 2 and 3 trials. The class includes the anticytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody ipilimumab and monoclonal antibodies targeting the programmed death 1 protein (PD-1) or its ligand (PD-L1).

Anti-CTLA-4 Antibodies: Ipilimumab

Cytotoxic T-lymphocyte antigen 4 is the antigen responsible for inhibition of cytotoxic T-cell-mediated immunity against foreign antigens presented by the antigen presenting cells (APCs). The APCs cause activation of the T cells when peptide fragments of intracellular proteins are presented in combination with mixed histocompatibility complex molecules. This step requires interaction of a costimulatory molecule (B7) on the APCs with a cluster of differentiation 28 protein (CD28) receptor located on T cells. CTLA-4 competes with CD28 to bind with the B7 molecule, thereby inhibiting the activation of the cytotoxic T cells (Figure 1). This pathway is thought to help with development of tolerance to host tissue antigens. Ipilimumab is a human monoclonal antibody that inhibits this CTLA-4 molecule and facilitates T-cell mediated antitumor activity. ¹² By blocking the CTLA-4 molecule, ipilimumab also mediates its autoimmune AEs on the host tissues.