Wednesday, August 8, 2012

Kinase Inhibitor Trials Show Melanoma Benefits | News | Drug Discovery and Development Magazine

Findings from GlaxoSmithKline (GSK) plc’s Phase 3 clinical study program evaluating single agent therapy with the targeted anti-cancer agents, dabrafenib (below left structure) and trametinib (below right structure), in patients with BRAF V600 mutation positive metastatic melanoma have been released. 
Both the BREAK3 study of dabrafenib (BRAF inhibitor) and 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. OS data are not yet mature in the BREAK3 trial.

“The results from the clinical studies of dabrafenib and trametinib presented at this meeting represent important progress towards understanding how these investigational agents could benefit patients with advanced and metastatic melanoma. Importantly, trametinib is the first MEK inhibitor to demonstrate clinical benefit in a late phase melanoma trial.” said Dr. Rafael Amado, Head of Oncology R&D for GlaxoSmithKline. “We are planning regulatory submissions for dabrafenib and trametinib as single agent therapies and have recently started a Phase 3 program to further investigate the effect of the combination in this disease.”

The BREAK3 study enrolled patients with previously untreated BRAF V600E mutation positive metastatic melanoma and compared dabrafenib to dacarbazine. In this study, dabrafenib treatment reduced the risk of disease progression or death by 70% (Hazard Ratio (HR) 0.30; p<0.0001) compared to chemotherapy. The median PFS was 5.1 months in the dabrafenib arm compared with 2.7 months in the dacarbazine arm. The most commonly reported (20%) adverse events (AEs) in the dabrafenib arm were hyperkeratosis (37%), headache (32%), pyrexia (25% Grade 1/2; 3% Grade 3), arthralgia (27%), skin papilloma (24%), alopecia (22%) and palmar-plantar erythrodysaesthesia syndrome (20%).  Other skin-related toxicities of interest included photosensitivity (3%) and Grade 3 squamous cell carcinoma/keratoacanthoma (5%).

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 (20%) 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%).
Additional results from early phase studies of both investigational medicines were presented at this meeting including a Phase 2 study of dabrafenib in patients with BRAF V600 mutation positive metastatic melanoma with concurrent metastases to the brain and a Phase 1/2 study of the combination of dabrafenib (see structure) and trametinib (see structure below) in patients with BRAF V600 mutation positive metastatic melanoma.
In all of these studies, 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 tumor samples and aim to submit for US FDA Pre-Market Approval of the test in the near future.

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