Novel Therapeutics for Melanoma

Nagashree Seetharamu; Patrick A Ott; Anna C Pavlick

Disclosures

Expert Rev Anticancer Ther. 2009;9(6):839-849. 

In This Article

Abstract and Introduction

Abstract

Advanced melanoma has the highest per-death loss of years of potential life expectancy except for adult leukemia. Standard therapy with agents such as dacarbazine, temozolomide and IL-2 is associated with notoriously low response rates. The identification of new active agents is, therefore, critical in this disease. In recent years, better understanding of melanoma biology, as well as cancer and immune biology in general has led to the development of a number of new potential therapeutic agents for advanced melanoma. While many of these compounds are being tested in clinical trials, there are more agents in various stages of preclinical development. These novel therapeutics offer hope for this aggressive and so far largely treatment-resistant disease. In this review we will discuss some of the most promising novel therapeutic agents for advanced melanoma.

Introduction

The incidence of melanoma is on the rise with an estimated 62,480 new cases and 8420 deaths in the USA in 2008.[1] Most early-stage melanomas (stage 0, stage I and stage II) are curable with optimal surgical excision. The likelihood of lymph node and/or systemic metastasis correlates with the thickness and depth of invasion of the primary lesion. Lymph node involvement (stage III disease) is associated with a much higher mortality (5-year survival of 24-69%[2]), largely due to the higher propensity for progression to systemic disease. Stage IV disease carries an even more dismal prognosis with 5-year survival ranging from 3 to 16%.[2] Currently available adjuvant treatment options and therapeutic agents for metastatic disease have not yet been proven to increase overall survival (OS). Conventional chemotherapy has limited efficacy in metastatic melanoma patients. Dacarbazine and its orally bioavailable derivative, temozolomide, have modest activity with response rates (RRs) in the range of 10-20% and median response duration of 6-8 months, but neither of these has demonstrated an effect on OS.[3,4,5,6] The other US FDA-approved drug for metastatic melanoma, IL-2, showed an overall RR of 16% in one meta-analysis[7] with a small proportion of durable responses, but has significant toxicity, thus limiting its use to patients with good performance status and preserved organ function. The immune-modulating agent IFN-α is currently the only drug approved by the FDA for the adjuvant treatment of high-risk melanoma. However, it is not generally accepted as a standard treatment in this setting, owing to its lack of impact on OS and an unfavorable toxicity profile.[8,9,10]

Investigators have looked at combinations of IL-2-based immunotherapy and cisplatin- and dacarbazine-based chemotherapy administered sequentially or concurrently (biochemotherapy) in patients with metastatic melanoma. After encouraging results from Phase II studies that also included maintenance biotherapy after successful biochemothrerapy,[11,12,13,14,15,16] a Phase III study comparing the efficacy of chemotherapy (cisplatin, vinblastine and dacarbazine [CVD]) with sequential biochemotherapy consisting of CVD plus IL-2 and IFN-α-2b was conducted and showed significantly higher RRs (48 vs 25%), time to progression and borderline significant median OS.[17] It was, however, associated with substantially more constitutional, hemodynamic and myelosuppressive toxic effects. Another recent Phase III trial compared concurrent biochemotherapy with CVD, IL-2, and IFN-α2b with CVD alone in patients with metastatic malignant melanoma (E3695), and showed no differences in the two groups with regards to OS or durable responses.[18] Along the same lines, a meta-analysis in more than 2500 patients who received either chemotherapy or biochemotherapy concluded that the complex biochemotherapy regimens consistently improved response rates, but not OS.[19] Hence, biochemotherapy cannot be considered a standard treatment for metastatic melanoma at this point.

Significant progress has been made in understanding the molecular biology of melanoma in recent years. Many novel agents targeting a wide spectrum of molecules and pathways have been identified and have been or are currently being evaluated in clinical trials. In this review we will provide an overview of the most promising novel therapeutics for advanced melanoma (Table 1).

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