NE Oncology Issue – September 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.

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Canadian Perspectives

Silvy Lachance, MD, FRCPC, CSPQ
Dr. Silvy Lachance is currently a hematologist, clinical researcher, and Director of the Stem Cell Transplant Program at the MaisonneuveRosement Hospital in Montreal, Quebec, and Professor of Medicine and Director of the Fellowship Program in Stem Cell Transplantation at the University of Montreal. In 1995, Dr. Lachance established the first Stem Cell Transplant Unit at the University Health Centre (CUSE) in Sherbrooke, Quebec. She joined the Hematology and Oncology Division of the Montreal General Hospital as a transplant physician in 1997 and became an Associate Professor of Medicine at McGill University in 2005, holding both positions until 2006. Dr. Lachance has served as chair of the Continuing Medical Education Committee of the Quebec Association of Hematologists and Oncologists, and is currently treasurer of the executive committee. She has also served as chair of the jury for the hematology specialty exam board of the Collège des Médecins du Québec (CMQ). Her research interests include stem cell transplant, graft-versus-host-disease, and lymphoproliferative disorders.

Teresa Petrella, BSc, MD, MSc, FRCPC
Teresa Petrella is a Medical Oncologist at the Odette Cancer Centre (OCC) in Toronto, Canada and an Assistant Professor at the University of Toronto. Dr. Petrella has a BSc in Molecular Biology from the University of Western Ontario and she completed her MD at Queen’s University. Her Internal Medicine and Medical Oncology training was at McMaster University. She subsequently completed a fellowship in Melanoma and Breast Cancer at the Toronto Sunnybrook Regional Cancer Centre along with a Masters degree in Health Research Methodology at McMaster University. She was the recipient of a CIHR/CAMO award for her research in vaccine therapy in combination with interferon for melanoma patients. Dr. Petrella joined the staff at OCC in 2002 and became the head of the Melanoma Site Group. She also chairs the Provincial Guidelines Melanoma Disease Site Group Program in Evidence Based Care the National Cancer Institute of Canada (NCIC) Melanoma Clinical Trials Group. Her research interests are in melanoma and breast cancer and she is currently the Principal Investigator for several multicentre trials investigating novel therapies in melanoma.