Date: 2012-06-04
Type of information:
phase: 3
Announcement: results and online publication of phase III data in the New England Journal of Medicine
[Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma. Keith T. Flaherty, M.D., Caroline Robert, M.D., Ph.D., Peter Hersey, M.D., Ph.D., Paul Nathan, M.D., Ph.D., Claus Garbe, M.D., Mohammed Milhem, M.B., Lev V. Demidov, M.D., Jessica C. Hassel, M.D., Piotr Rutkowski, M.D., Ph.D., Peter Mohr, M.D., Reinhard Dummer, M.D., Uwe Trefzer, M.D., James M.G. Larkin, M.D., Jochen Utikal, M.D., Brigitte Dreno, M.D., Marta Nyakas, M.D., Mark R. Middleton, Ph.D., Jürgen C. Becker, M.D., Ph.D., Michelle Casey, Ph.D., Laurie J. Sherman, R.N., Frank S. Wu, M.D., Ph.D., Daniele Ouellet, Ph.D., Anne-Marie Martin, Ph.D., Kiran Patel, M.D., and Dirk Schadendorf, M.D. for the METRIC Study Group. June 4, 2012 (10.1056/NEJMoa1203421)]
Company: GSK (UK)
Product: trametinib
Action mechanism: Trametinib is an investigational, orally bioavailable inhibitor of the MEK protein. It was discovered by Japan tobacco and in-licensed by GSK in 2006.
Disease: metastatic melanoma with BRAF V600 mutations
Therapeutic area: Cancer - Oncology
Country: Austria, Belgium,Czech Republic, France, Germany, Greece, Italy, Norway, Poland, Russia, Sweden, Switzerland, Ukraine, UK), North America (USA, Canada), Argentina, Australia, and New Zealand
Trial details: The METRIC Phase III study of trametinib, a MEK inhibitor, in patients with advanced/metastatic melanoma enrolled 322 patients with BRAF V600E or K mutation who had no more than one prior regimen of chemotherapy and no prior BRAF inhibitor treatment. The primary endpoint of the study was progression free survival. Patients randomised to the chemotherapy cohort were allowed to crossover to receive trametinib therapy upon independent confirmation of documented disease progressed. The study was conducted in Europe (Austria, Belgium,Czech Republic, France, Germany, Greece, Italy, Norway, Poland, Russia, Sweden, Switzerland, Ukraine, United Kingdom), North America (US, Canada), Argentina, Australia, and New Zealand.
Latest
news: GSK has presented positive results for investigational MEK inhibitor trametinib at ASCO. Findings from GSK’s Phase III clinical study programme evaluating single agent therapy with the targeted anti cancer agent trametinib, in patients with BRAF V600 mutation positive metastatic melanoma were presented today at the Annual Meeting of the American Society of Clinical Oncology in Chicago. The Phase III data for trametinib were also published online today in the New England Journal of Medicine. In this study, patients were selected for eligibility based on the BRAF mutation status of their cancer. Testing was performed centrally by Response Genetics Inc (RGI). The important role of companion diagnostics to precisely identify patients who may derive benefit from these drugs is highlighted by the results of these studies. GSK and bioMerieux have collaborated to develop a companion diagnostic assay that specifically identifies BRAF V600 (V600E and V600K) mutations in tumour samples and aim to submit for US FDA Pre-Market Approval of the test in the near future.
The METRIC study of trametinib (MEK inhibitor) demonstrated a statistically significant benefit in the length of time patients with BRAF V600 mutation positive advanced or metastatic melanoma lived without progression of their disease or death (Progression Free Survival or PFS) compared to those receiving chemotherapy. Additionally, patients in the METRIC study who received trametinib lived significantly longer (Overall Survival or OS) than those who received chemotherapy with dacarbazine.
The METRIC study enrolled patients with BRAF V600E or K mutation positive metastatic melanoma, and included patients who had one prior regimen of chemotherapy. The median PFS of 4.8 months in the trametinib arm was significantly greater than the 1.5 month median PFS in the chemotherapy arm with a 55% reduction in risk of disease progression or death (HR 0.45; p<0.0001) in the trametinib arm. Additionally, a significant Overall Survival benefit was gained by the trametinib arm at the interim analysis (HR 0.54;p=0.0136). The most commonly reported (³20%) AEs in the trametinib arm were rash (57%), diarrhoea (43%), fatigue (26%), and peripheral oedema (26%). Other adverse events associated with trametinib in this study include hypertension (15%), chorioretinopathy (< 1%) and decrease in ejection fraction/ventricular dysfunction (7%).
GSK is now planning regulatory submissions for trametinib as single agent therapies and has also recently started a Phase III programme to further investigate the effect of the combination of trametinib and dabrafenib in this disease.
