Current Options and Future Directions in the Systemic Treatment of Metastatic Melanoma

This article has been adapted from an article originally published in The Journal of Supportive and Community Oncology (jcso-online.com). Schindler K, Postow M. Current options and future directions in the systemic treatment of metastatic melanoma. J Community Support Oncol. 2014;12(1):20-26.

The incidence of melanoma, a highly aggressive tumor arising from melanocytes, continues to rise by about 3% a year in the U.S. with about 76,000 patients being diagnosed every year and 9,000 patients dying of the disease.¹ Complete surgical resection is the standard for localized melanoma, with surgical excision margins depending on tumor thickness. For patients with involved sentinel lymph nodes, complete lymphadenectomy is typically recommended, although the benefits of completion lymphadenectomy are being evaluated in an ongoing randomized trial.^2,3

For patients with surgically resected, high-risk melanoma, the only approved adjuvant therapy is interferon-a (IFN-a).⁴ Use of IFN-a, however, remains controversial because of the associated adverse effects (AEs) and controversial effects on overall survival (OS).^5,6 Unfortunately, many patients with localized disease will ultimately experience a recurrence, and the prognosis of patients with metastatic disease is poor with a historical 5-year survival rate of 10%.⁷

Chemotherapy and interleukin 2

For more than 3 decades, conventional cytotoxic chemotherapy was used to treat metastatic melanoma. Typical agents included alkylating agents (dacarbazine, temozolomide, nitrosoureas), platinum analogs (cisplatin and carboplatin), and microtubular toxins (vinblastine and paclitaxel). Despite the clinical use and investigation of a number of these chemotherapies for patients with metastatic melanoma, the only treatment approved by the FDA is dacarbazine, which is administered intravenously every 3 to 4 weeks at a dose of 800 to 1,000 mg/m².

Monotherapy with dacarbazine is generally well tolerated with only mild AEs such as nausea, myelosuppression, and fatigue. In a pooled analysis, the overall response rate (RR) for dacarbazine was approximately 9%.⁸ Temozolomide, the oral analog of dacarbazine, penetrates into the central nervous system and has been compared with dacarbazine in randomized trials. These agents are believed to have similar efficacy, but temozolomide has been associated with a higher rate of lymphopenia.^9,10

Investigation of chemotherapy combinations such as cisplatin, vinblastine, and dacarbazine or carboplatin and paclitaxel have shown promising RRs but unfortunately no prolongation of OS compared with single-agent dacarbazine.^11-13 Despite its modest efficacy, chemotherapy still has a place in the palliative treatment for some patients.

In addition to dacarbazine, the immunotherapeutic strategy, high-dose recombinant interleukin-2 (IL-2), had also been a mainstay treatment for advanced melanoma for many years. IL-2 is administered as an IV infusion every 8 hours at a dose of 600,000 to 720,000  IU/kg on days 1 to 5 and days 15 to 19, with a maximum of 14 such biphasic cycles. Because of the significant acute toxicity profile, including capillary leak syndrome, cardiovascular complications, and seizures, IL-2 treatment requires hospitalization and is generally only performed at specialized centers for patients with good performance status. Though the overall RR in pooled analysis was low at 16%, the durability of responses in some responders that appeared to last many years led to the FDA approval of IL-2 in 1998.^14,15

IL-2 continues to be investigated. In a randomized trial, an improved RR and progression-free survival (PFS) were seen when IL-2 was combined with the glycoprotein 100 (gp100) peptide vaccine compared with IL-2 alone.¹⁶ Other approaches have sought to improve the safety of IL-2 by selectively delivering it to tumor sites. The fusion protein L19-IL2 couples IL-2 with the recombinant human vascular targeting antibody L19 and has preliminarily been shown to be safe in phase 1 evaluation and in combination with dacarbazine.^17,18

Antibodies that block immunologic checkpoints

Melanoma has long been recognized as an immunogenic malignancy but the efficacy of immunotherapeutic strategies has generally been modest. The precise etiology of why immunotherapy historically was not more successful is not completely understood, but it is possible that patients with advanced malignancy have predominant immune inhibitory circuits that prevent otherwise effective antitumor immune responses.

In recent years, research has illuminated some of these immunologic inhibitory elements, termed “immunologic checkpoints,” which include cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 (PD-1). Antibodies that target these checkpoints have resulted in durable responses in some patients and a unique pattern of immune-mediated AEs. Though an ongoing area of research, no pre- or on-treatment biomarkers have been sufficiently validated to enable specific patient selection for these therapies.

Antibodies Blocking CTLA-4

CTLA-4 is expressed on activated T cells and typically functions as a negative regulator of T-cell activity preserving normal immunologic homeostasis. Blocking CTLA-4 with therapeutic antibodies such as ipilimumab and tremelimumab prevents normal CTLA-4–mediated T-cell downregulation and thereby enhances the ability of T cells to exert their full antitumor immune effects (Figure 1). Ipilimumab was the first drug in the management of metastatic melanoma to show an improvement in OS in phase 3 studies, and although a phase 3 study of tremelimumab did not demonstrate an improvement in OS, durable responses were similarly seen.^19-21