NE Oncology Issue – September 2011

Chapman PB, et al. ASCO 2011: Abstract LBA4

Background

About 50% of melanomas have an activating V600E BRAF mutation, which suggests that inhibition of the mutated BRAF kinase may be of clinical benefit. Previous phase I and II trials with vemurafenib have shown impressive response rates in V600E BRAF-mutated metastatic melanoma patients.1

At ASCO 2011, Chapman and colleagues presented the results of BRIM-3 — a phase III randomized, openlabel, multicentre trial comparing vemurafenib with dacarbazine (DTIC) in previously untreated patients with V600E BRAF-mutated metastatic melanoma.2

Study design

  • Patients with previously untreated, unresectable stage IIIC or stage IV melanoma (ECOG performance status 0 or 1, with no active CNS metastases) who tested positive for V600E BRAF mutation by the cobas 4800 BRAF V600 Mutation Test were randomized in a one-to-one ratio to oral vemurafenib (960 mg, twice daily) or intravenous DTIC (1,000 mg/m2, three times weekly).
  • Cross-over was not permitted and the trial was a non-blinded randomization.
  • Co-primary endpoints were overall survival (OS) and progression-free survival (PFS) in the intent-to-treat (ITT) population.
  • Secondary endpoints included objective response rates (ORR) and safety.

Key findings

  • From January to December 2010, 675 patients were enrolled from 104 centres worldwide, and the cohorts were well-balanced.
    • Approximately two-thirds of patients in both arms had stage M1c disease, and 42% of patients had elevated LDH levels.
  • The data cut-off for this analysis was December 30, 2010.
  • At the pre-planned interim analysis (50% of deaths needed for final analysis), the hazard ratios (HR) for OS and PFS were 0.37 (95% CI 0.26–0.55; p <0.0001) and 0.26 (95% CI 0.20–0.33; p <0.0001), respectively, both in favour of vemurafenib. (Figures 1 and 2)
  • At six months, the estimated OS was 84% for vemurafenib, versus 64% for DTIC.
    • The median OS could not be analyzed at the time of this analysis.
    • Improvements in OS were seen for all sub-groups examined.
  • The median PFS was 5.3 months for vemurafenib, versus 1.6 months for DTIC, and was highly statistically significant in favour of vemurafenib.
    • All pre-specified subsets of patients showed clear benefits in PFS.
  • The ORR was 48.4% and 5.5% for vemurafenib and DTIC, respectively, among the 65% of patients evaluable for RR, to date.
  • As a result of the promising data, independent data monitoring committee (IDMC) recommended that the DTIC cohort has been allowed to cross over to vemurafenib.
  • At the time of analysis, 66% of vemurafenib patients and 25% of DTIC patients were still on treatment.
  • The most common toxicities associated with vemurafenib that required dose modifications were: arthralgia, rash, photosensitivity, fatigue, and increased liver function tests (LFTs). (Table 1)
  • Adverse events (AEs) of special interest were cutaneous squamous cell carcinoma (grade 3), keratoacanthoma, and skin papilloma (which are a function of vemurafenib and other drugs in this class).
  • For all AEs, grade 3 toxicities were fairly uncommon for both study arms, as was discontinuation.

Key conclusions

  • Vemurafenib is associated with statistically significantly improved OS and PFS compared to DTIC in patients with previously untreated, V600E BRAF-mutated metastatic melanoma.
  • Vemurafenib was associated with a 63% decrease in the hazard ratio of death (p <0.001) and a 74% decrease in the hazard of tumour progression (p <0.001).
  • The benefits of vemurafenib treatment were seen in all sub-groups, including poor prognosis patients.
  • Vemurafenib had a manageable safety profile, with few drug-related discontinuations.
  • This is the first single drug for melanoma to improve response rate, PFS and OS compared with standard chemotherapy.
  • Vemurafenib is a promising new therapy and a foundation upon which to build future combination therapies.

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. Chapman PB, Hauschild A, Robert C, et al. Vemurafenib: Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine (DTIC) in patients with V600E BRAF-mutated melanoma. J Clin Oncol (ASCO Annual Meeting Abstracts) 2011;29:LBA4.

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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.