The 10-year survival rate for patients with metastatic melanoma has historically been less than 10%. However, recent successes with immunotherapy and BRAF-targeted therapy have ushered in a new era in systemic therapy of this disease. These therapies have been associated with significant improvements in patient outcomes in several randomized phase III trials. Not only have these breakthroughs increased the likelihood of long-term survival in patients with melanoma, but they have also spurred the investigation of a new generation of agents for treatment of melanoma. This article reviews both current options for systemic treatment of metastatic melanoma and promising investigational approaches. We also discuss important considerations in choosing among systemic therapy options, to match the unique goals of therapy for individual patients.
Until recently, metastatic melanoma had historically been a challenging disease to treat, with a 10-year survival rate of less than 10%. Dacarbazine was the benchmark systemic therapy for this disease for more than 3 decades after its initial approval by the US Food and Drug Administration (FDA) in 1975. Numerous attempts to improve upon the survival of patients with metastatic disease had met with failure in the past. Over the last several years, however, phase III trials have reported significantly improved outcomes associated with several new therapies for advanced melanoma.[3,4] The availability of these new agents in the setting of metastatic disease marks the dawn of a new era of systemic therapy for this life-threatening malignancy. Our understanding of the biology of melanoma continues to increase steadily, and as a result, several other promising therapeutic approaches are on the horizon. In this article, we summarize the systemic therapies now available for melanoma, with a focus on the recently approved agents for cutaneous melanoma; discuss important considerations in selecting a treatment from the available options; and highlight some of the promising investigational approaches for this disease.
Therapeutic Options for Stage IV Melanoma
The mainstay of treatment for stage IV melanoma is systemic therapy to address both clinically detectable and subclinical sites of metastases. Systemic therapies commonly used for metastatic melanoma can be broadly classified into three groups: cytotoxic chemotherapy, molecular targeted therapy, and immunotherapy. The former two groups reflect drugs that work directly against the cancer cells, usually by interfering with cellular processes relevant to cancer cell proliferation.
Immunotherapeutic interventions usually work indirectly via modulation of the host immune responses against cancer cells. The various systemic therapies that were used prior to 2011 have been reviewed in detail elsewhere. Historically, cytotoxic chemotherapeutic agents with modest antitumor efficacy in metastatic melanoma have included alkylating agents (dacarbazine, temozolomide, nitrosoureas), the microtubular toxins (eg, paclitaxel), and the platinum analogs. Combinations of cytotoxic agents yielded somewhat higher response rates than monotherapy, but were associated with greater toxicity and did not extend overall survival (OS) significantly. High-dose interleukin-2 (HD IL-2) was associated with a durable complete response (CR) in some patients, but its utilization was limited by a low objective response rate (ORR), treatment-associated toxicities, and a paucity of predictive biomarkers. Historical attempts to combine cytotoxic chemotherapy with immunotherapy (the “biochemotherapy” regimens) were sometimes associated with a higher ORR, but these regimens did not result in reproducible, significant improvement in OS compared with chemotherapy alone. Fortunately, there have recently been major advances on the fronts of molecular targeted therapy and immunotherapy, which are leading to significant improvements in patient outcomes, including OS.
Laboratory and clinical observations have long suggested that melanoma is susceptible to immune therapeutic approaches. T cells reactive to melanoma-associated antigens have been documented in the peripheral blood of patients with metastatic melanoma; responses have been noted both to melanocyte differentiation antigens (eg, tyrosinase or MART-1 [Melanoma Antigen Recognized by T cells 1]) and to cancer-testis antigens selectively expressed in melanoma cells (eg, MAGE [melanoma-associated antigens], NY-ESO-1). Recent studies using whole-exome sequencing and tandem mini-genes have also identified patient-specific mutations encoding proteins that elicit T-cell responses in tumor-infiltrating lymphocytes.[7,8]
Complementing these laboratory observations, the clinical success of HD IL-2 in inducing durable CRs in some patients with metastatic melanoma provided “proof of concept” for the field of cancer immunotherapy, and fuelled the investigation of several immunotherapeutic approaches over the last few decades. These approaches have included efforts to amplify the number and/or function of tumor-reactive T cells (eg, through lymphokines similar to IL-2, vaccines, or adoptive T-cell therapy approaches), or to modulate signals that regulate T-cell function (eg, by use of immune checkpoint inhibitors or costimulatory agonists). The persistent efforts of both laboratory immunologists and clinical immunotherapists have paid off handsomely over the last few years with the striking success of cancer immune therapies, a select few of which are discussed below.
Immune Checkpoint Inhibitors
T-cell activation is triggered by engagement of the T-cell receptor (TCR) with antigen, presented in the context of major histocompatibility complex (MHC) antigen. Binding of the T cell’s CD-28 antigen to B7 expressed on the surface of the antigen-presenting cell (APC) delivers a costimulatory signal to the T cell. These activation events result in T-cell proliferation and the release of cytokines that facilitate antitumor immune response. However, after T-cell activation, the counter-regulatory processes ensue, including expression of cytotoxic T-lymphocyte antigen (CTLA)-4, an antigen that competes for binding to B7 and transmits an inhibitory signal to the T cell.[9-12] CTLA-4 is also constitutively expressed on regulatory T cells that inhibit excessive immune stimulation. CTLA-4 blockade was demonstrated in preclinical models to augment T-cell immune responses and induce major regressions and even cure of established tumors.[9,11,12] Another immune checkpoint axis under intense study is the programmed cell death protein (PD)-1:PD ligand (PDL)-1,2 axis. Engagement between PD-1 expressed on CD8+ T cells and its ligands (PD-L1 or PD-L2) expressed on cancer cells or APCs induces immune exhaustion; antibodies that bind to either PD-1 or its ligands interrupt this negative signal and result in enhanced T-cell number and function.[13-16] Monoclonal antibodies that bind CTLA-4 (eg, ipilimumab) or PD-1 (eg, pembrolizumab, nivolumab) have been associated with unprecedented clinical success in patients with metastatic melanoma and have also ushered in a therapeutic revolution in cancer immunotherapy in general.
CTLA-4 Blockade (Ipilimumab)
In two separate phase III trials, ipilimumab was associated with improved survival of patients with advanced melanoma.[3,17] The first pivotal phase III trial, which led to the FDA approval of ipilimumab for advanced melanoma in March 2011, demonstrated significantly improved OS with ipilimumab compared with gp100 vaccine therapy (median OS of 10 months vs 6.4 months, respectively) in patients who had received prior systemic therapy for unresectable stage III or IV melanoma. Ipilimumab was administered intravenously (IV) at a dose of 3 mg/kg every 3 weeks for up to four doses (induction) without any maintenance dosing; however, patients were eligible for re-induction therapy (with four more doses) at the time of progressive disease after initial benefit. The best ORR in the ipilimumab monotherapy group was 11% (CR = 1.5%; partial response [PR] = 9.5%). The disease control rate (DCR), defined as the proportion of patients with objective response or stable disease (SD), was 28%. Although the ORRs and CR rates were low, responses were mostly durable, with 60% of the responders maintaining their response beyond 2 years. While 60% of patients on ipilimumab monotherapy experienced immune-related adverse events (irAEs), severe (grade 3 or higher) irAEs were seen in only 15% of patients and included diarrhea/colitis (8%), endocrinopathy (2%), dermatologic toxicity (< 2%), and hepatic toxicity (< 1%). Most irAEs resolved by 6 to 8 weeks with appropriate immunosuppressive treatment (mostly glucocorticoids), although residual symptoms (eg, vitiligo, endocrinopathy symptoms, rectal pain) were sometimes present in long-term survivors. A second randomized phase III trial that compared ipilimumab (at 10 mg/kg) plus dacarbazine vs dacarbazine alone in patients with previously untreated metastatic melanoma also showed longer median OS with ipilimumab plus dacarbazine (11.2 mo) vs dacarbazine alone (9.1 mo), and higher 3-year survival (21% vs 12%, respectively).
A meta-analysis of pooled OS data from ipilimumab trials, which includes data from 1,861 melanoma patients, highlights the potential for long-term treatment-free survival in some patients. This meta-analysis listed a 3-year OS rate of 22%, with a plateau in the pooled Kaplan-Meier curve beginning at approximately 3 years after initiation of therapy, and extending through follow-up of as long as 10 years.
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