September 2011 ASCO 2011

Metastatic Melanoma

Melanoma has historically been refractory to most standard systemic therapy. Metastatic melanoma has a poor prognosis, with the median survival for patients with stage IV disease ranging from eight to 18 months after diagnosis, depending on the substage.1 Two approved treatments, dacarbazine (DTIC) and interleukin- 2 (IL-2), have not demonstrated an impact on overall survival (OS) in randomized trials.2

However, new agents and treatment strategies are changing the landscape of the management of melanoma, aided by a greater understanding of the genetic abnormalities that catalyze the development and progression of the disease. The discovery of activating mutations in BRAF, for example, was followed by the discovery of other mutations, which allowed melanoma to be classified into a group of diseases. This also created the opportunity to develop therapies that target the activating molecules and their pathways.3

New research is ongoing to explore novel agents and therapy combinations, identify additional prognostic biomarkers that may result in personalized therapy, and improve current treatment options.

At ASCO 2011, various studies were presented that highlighted the ongoing clinical advances in melanoma. This article reports on eight of these studies.

  • An open-label pilot study of vemurafenib in previously treated metastatic melanoma patients with brain metastases provides early efficacy signals and demonstrated that vemurafenib is well tolerated in symptomatic patients with melanoma metastatic to the brain.
  • The BRIM-2 trial — a pivotal phase II study of vemurafenib in previously treated patients with BRAF V600E mutation-positive metastatic melanoma — confirmed that vemurafenib is an active agent in patients with BRAF mutation-positive melanoma who have completed prior systemic therapy.
  • BRIM-3 — a phase III randomized, open-label, multicentre trial comparing vemurafenib with DTIC in patients with V600E BRAF-mutated melanoma — showed that vemurafenib improves overall response rates (ORR), progression-free survival (PFS), and OS compared with DTIC in patients with previously untreated, V600E BRAF-mutated metastatic melanoma.
  • Molecular testing with an investigational polymerase chain reaction (PCR) assay (the cobas 4800 BRAF V600 mutation test) has a higher sensitivity than Sanger sequencing and is robust, rapid and accurate. This test may have clinical utility in assessing the activity of vemurafenib for BRAF V600 mutations, as demonstrated in the BRIM-2 trial.
  • A claims-based analysis assessed the burden of metastatic melanoma, including treatment patterns, healthcare use, and costs, and found that resource utilization and cost increased considerably after the development of metastases in patients with melanoma. Furthermore, targeted therapies are needed to improve outcomes and reduce the burden of disease.
  • A phase III randomized study of ipilimumab plus DTIC versus DTIC alone as first-line treatment in patients with advanced melanoma demonstrated that combination therapy significantly improved OS. Furthermore, adverse events were similar to those seen in previous studies of ipilimumab alone.
  • A phase I trial of ipilimumab plus bevacizumab in patients with advanced melanoma — the first combination study to investigate potential synergies of these agents — suggests that the combination can be safely administered.
  • The first in-human phase I study of the oral RAF inhibitor RAF265 in advanced cutaneous melanoma defined the maximum tolerated dose (MTD) of this agent, and showed that clinical activity was observed at multiple dose cohorts in patients with BRAF mutant and wild type melanoma.

References: 1. Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009;27:6199–6206. 2. O’Day SJ, Atkins MB, Boasberg P, et al. Phase II multicenter trial of maintenance biotherapy after induction concurrent biochemotherapy for patients with metastatic melanoma. J Clin Oncol 2009;27(36):6207–6212. 3. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417(6892):949–954.