Novel Targets in the Treatment of Advanced Melanoma

New First-Line Treatment Options

Kathryn A Culos, Sandra Cuellar

Disclosures

The Annals of Pharmacotherapy. 2013;47(4):519-526. 

In This Article

Abstract and Introduction

Abstract

Objective: To discuss the clinical efficacy and safety of ipilimumab, vemurafenib, and investigational agents for the treatment of unresectable stage III and stage IV melanoma and define current strategies of first-line treatment selection.

Data sources: Literature was accessed through MEDLINE and International Pharmaceutical Abstracts (1970-November 2012) using the terms melanoma, metastatic melanoma, ipilimumab, vemurafenib, dabrafenib, and trametinib. In addition, reference citations from publications identified were reviewed.

Dtudy selection and data extraction: All articles published in English identified from the data sources were evaluated. Studies and abstracts including more than 10 adult patients were included in the review.

Data synthesis: Treatment options for unresectable stage III and IV melanoma are poor and have remained largely unchanged for the past 40 years. Two randomized Phase 3 clinical trials have demonstrated a significant survival benefit with the use of ipilimumab compared to a melanoma vaccine (10.1 vs 6.4 months; p = 0.003) and compared to dacarbazine (11.2 months, 95% CI 9.4–13.6 vs 9.1 months, 95% CI 7.8–10.5). Additionally, long-term follow-up has revealed cases of durable responses of greater than 3 years. Response rates of 50% and greater have been described in vemurafenib-treated patients (1 Phase 1, 1 Phase 2, and 1 Phase 3 randomized trial), although duration of response has not been fully determined. Both new agents possess unique toxicity profiles including immune-related adverse events with ipilimumab and secondary cutaneous cancers reported with vemurafenib use.

Conclusions: Treatment strategies have changed for patients with advanced melanoma with the use of ipilimumab and vemurafenib as first-line agents. Increased clinical experience and further published data with these and investigational agents will guide the development of treatment algorithms outlining optimal drug selection and sequencing as well as improve management of their novel adverse events.

Introduction

Melanoma is a challenging malignancy to treat and, with its increasing incidence, is currently the fifth and seventh most commonly diagnosed cancer in men and women, respectively.[1,2] Of the 75,000 new diagnoses estimated to occur in 2012, nearly 15% will have unresectable stage III or IV disease, with a 5-year survival rate of 15%.[2] Treatment recommendations for these patients have remained nearly unchanged for the past 40 years.[3] However, in 2011, two agents, ipilimumab and vemurafenib, were approved by the Food and Drug Administration (FDA) based on data demonstrating improved survival and response rates (RRs) superior to the standard of care.

For this review article we accessed MEDLINE and International Pharmaceutical Abstracts (1970-November 2012) using the key words metastatic melanoma, ipilimumab, vemurafenib, dabrafenib, and trametinib. Included studies and abstracts with more than 10 adult patients were used to evaluate the benefits and risks of these new agents with the historical standard of care.

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