NE Oncology Issue – September 2011

Dummer R, et al. ASCO 2011: Abstract 8548

Background

Melanoma is a common cause of cerebral metastases, and indicates a poor prognosis. In phase I and II studies, vemurafenib has shown dramatic activity in metastatic melanoma harbouring V600-mutated BRAF.1,2 However, these studies excluded patients with active brain metastases and thus to date the activity of vemurafenib — an orally available inhibitor of oncogenic BRAF kinase — for brain metastases has remained unknown.

At ASCO 2011, Dummer and colleagues presented their early findings from an open-label pilot study of vemurafenib in previously treated metastatic melanoma patients with brain metastases.3

Study design

  • The study was an open-label, single-arm trial of vemurafenib designed to evaluate the safety and efficacy of this agent in patients with metastatic melanoma and non-resectable brain metastases.
  • Patients had BRAF V600 mutations (determined by the cobas 4800 BRAF V600 Mutation Test).
  • Patients with an ECOG performance status of 0–2 had to have been pretreated with radiotherapy and/or chemotherapy and were on stable or decreasing doses of steroids, and had brain metastases-related symptoms.
  • Vemurafenib was administered continuously at a dose of 960 mg twice daily, until progressive disease (PD) or toxicity.
  • Staging by magnetic resonance imaging (MRI) brain and computed tomography (CT) of the thorax/abdomen was scheduled every four weeks in the first two months, and then every eight weeks thereafter.
  • Overall survival (OS) was determined, as well as measurements of improvements in physical symptoms.
  • Patients’ serum S100 levels were also determined.
  • Adverse events (AEs), including serious adverse events (SAEs), were assessed.

Key findings

  • Seven patients were enrolled in the study:
    • Median age was 47 years (range 24–50 years);
    • Median number of nine brain metastases in each patient (range: 3–18);
    • All patients had metastases at other organ sites;
    • Patients had an ECOG performance status of 0–2;
    • All patients were on dexamethasone.
  • As of March 2011, patients have received treatment with vemurafenib for one to four months, with one patient on treatment for four months; one patient for three months; three patients for two months; and the remaining two patients for one month.
  • Six patients reported 38 treatment-emergent AEs.
    • All AEs were grade 1 or 2.
    • There were no grade 3 or higher AEs reported.
  • Of the 38 treatment-emergent AEs, 18 were reported by four patients as being possibly drug-related. (Table 1)
    • Four SAEs were reported by two patients, but were not treatment-related.
  • Preliminary evaluation showed that vemurafenib induced tumour regression in brain metastases with similar kinetics to other sites of involvement.
  • Five patients’ staging reports are currently available:
    • Patient 1 presented with a confirmed partial response in brain and body (as assessed by Response Evaluation Criteria in Solid Tumors [RECIST]) associated with a reduction of S100 from 141.6 μg/L (pretreatment) to 4.4 μg/L (day 43). (Figure 1) Dexamethasone and morphine doses were reduced.
  • Partial response was confirmed by brain MRI.
    • Patient 2 showed a minor response in brain and body at week 4 associated with a reduction of S100 from 35.6 μg/L (day 1) to 3.26 μg/L (day 15). (Figure 1)
    • As of March 2011, all other evaluable patients presented stable disease.
    • Serum S100 levels are shown in Figure 1 for Patients 1, 2 and 3.

Key conclusions

  • To date, vemurafenib has been well tolerated in symptomatic patients with melanoma metastatic to the brain.
  • This study provides early, strong results suggesting activity of vemurafenib in brain metastases.

References: 1. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010;363:809–819. 2. Ribas A, Kim KB, Schuchter LM, et al. BRIM-2: an open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAFV600E mutationpositive melanoma. J Clin Oncol (ASCO Annual Meeting Abstracts) 2011;29:8509. 3. Dummer R, Rinderknecht J, Goldinger SM, et al. An open-label pilot study of vemurafenib in previously treated metastatic melanoma patients with brain metastases. J Clin Oncol (ASCO Annual Meeting Abstracts) 2011;29:8548.

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Canadian Perspectives

dr-lachance
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.

dr-petrella
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.