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Time for a New Paradigm in the Treatment of Metastatic Melanoma

Published Online: June 25th 2012 Oncology & Hematology Review (US), 2012;8(2):100-5 DOI: https://doi.org/10.17925/OHR.2012.08.2.100
Authors: Jennifer Wargo, Rene Gonzalez, Rodabe Amaria
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Abstract:
Overview

Metastatic melanoma is a very common disease with an increasing incidence worldwide and is notoriously difficult to treat. The long-established treatments including dacarbazine and interleukin-2 have shown limited response rates and are associated with significant toxicities. More recently, treatments have been developed that decrease inhibition of T-cell action against melanomas. Among these, ipilimumab was recently approved for use in metastatic melanoma and has shown improved overall survival (OS) and progression-free survival rates (PFS). Another such treatment currently in development is the monoclonal antibody, anti-PD-1. This blocks PD-1 inhibition of T-cells and has shown promising response rates in early clinical trials. Another treatment approach is to use targeted therapies in patients with mutations in BRAF or CKIT signaling pathways and it is vital that the mutational status of these genes be determined in patients with metastatic melanoma to best determine effective therapeutic options. Vemurafenib was recently approved for metastatic melanoma and targets the BRAF V600E mutation which occurrs in about 50 % of cutaneous melanomas. Recent results from the ongoing Phase III BRIM-3 study comparing vemurafenib with dacarbazine showed that median 12-month OS rates and the risk of death were reduced with vemurafenib. Other BRAF inhibitors such as dabrafenib and MEK inhibitors such as trametinib are also in development. New treatments in ongoing clinical trials coupled with an improved biologic understanding are likely to improve responses and outcomes for patients with metastatic melanoma.

Keywords

Metastatic melanoma, targeted treatments, BRAF-, MEK-, CKIT-inhibitors, PD-1, PD-1ligand, anti-PD-1

Article:

The incidence of melanoma is high and is the sixth most common cancer in US men and eighth most common cancer type in US women.1,2 Moreover, the incidence of metastatic melanoma has been increasing worldwide at a rate faster than any other solid malignancy.3 There were an estimated 76,250 new cases of melanoma and 9,180 deaths from the disease in the US alone this year.4 Melanoma has been shown to affect a large number of younger patients and thus it is one of the leading cancers in terms of patient years-of-life lost.5

The prognosis for patients with metastatic disease has traditionally been poor with a median survival of approximately 6–9 months due to lack of effective therapeutic options.6,7 Indeed, no therapy had ever shown a survival advantage for patients with advanced melanoma until 2011. Survival for patients with stage III disease is quite varied as patients with low tumor burden (stage IIIa) do much better than those with multiple lymph node metastases or in-transit metastases (stage IIIb/IIIc disease).8

While melanoma has been resistant to chemotherapy, it does express tumor-specific antigens that have made immunotherapy a viable treatment option. Key research in determining gene mutations that drive melanoma growth have been instrumental in helping to develop targeted therapies that show great promise in treating patients with advanced disease. Two new agents, ipilimumab and vemurafenib, have recently received approval based on clinical evidence that they impart a statistically significant survival advantage over control patients receiving vaccine or chemotherapy. Appropriate combination and sequencing of old and new agents holds the promise of increasing the number of complete durable responses.

The paradigm shift for melanoma will be to consider long-term durable responses and a potential cure of the disease as the goal of future therapeutic trials, rather than simply palliation. This article provides an overview of traditional and emerging management approaches as well as reviews strategies for combining and sequencing available treatments to optimize outcomes.

Challenges in Treating Metastatic Melanoma
Melanoma is a particularly difficult disease to manage for several reasons. Firstly, it has a high metastatic potential with a tendency to disseminate to distant sites, often including the brain, via hematogenous and lymphatic channels leading to poor prognosis.9 It is the only cancer where millimeters (not centimeters) of tumor are used in the staging system, with a 4 mm melanoma imparting as much risk as a 10 cm lung tumor. Furthermore, melanomas can downregulate patients’ own intrinsic immune system pathways creating both a local and systemic immune-depleted state.10

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Disclosure

Rene Gonzalez has received research funding from Roche/Genentech, GSK, Prometheus, consultancy fees from Roche/Genentech, GSK, Prometheus, and speaking fees from Roche/Genentech and Prometheus. The other authors have no conflicts of interest to declare.

Correspondence

Rene Gonzalez, MD, FACP, Professor of Medicine, Director, Melanoma Research Clinics, University of Colorado Anschutz Medical Campus, Division of Medical Oncology, Mail Stop F703, 1665 Aurora Court, Aurora, CO 80045, US. E: Rene.Gonzalez@ucdenver.edu

Received

2012-08-20T00:00:00

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