GSK presents positive results for investigational BRAF and MEK inhibitors dabrafenib and trametinib at ASCO

Phase III studies of single agent therapy in metastatic melanoma with BRAF V600 mutations meet primary endpoints

Findings from GlaxoSmithKline (GSK) plc’s Phase III clinical study programme evaluating single agent therapy with the targeted anti cancer agents, dabrafenib and 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.

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 III programme 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 (³20%) 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 (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%).

Additional results from early phase studies of both investigational medicines were presented at this meeting including a Phase II study of dabrafenib in patients with BRAF V600 mutation positive metastatic melanoma with concurrent metastases to the brain and a Phase I/II study of the combination of dabrafenib and trametinib 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 tumour samples and aim to submit for US FDA Pre-Market Approval of the test in the near future.

What is BREAK3?

BREAK3 is a Phase III, randomised, open-label study comparing the efficacy, safety, and tolerability of dabrafenib to dacarbazine in patients with advanced (Stage III) or metastatic (Stage IV) melanoma who harbour a BRAF V600E mutation. The primary endpoint of the study was progression free survival. Patients randomised to dacarbazine and whose disease progressed were allowed to crossover and receive dabrafenib. The study enrolled 250 patients from around the world, including the United States, Australia, Canada, and Europe.

What is METRIC?

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

About dabrafenib

Dabrafenib is an investigational, orally bioavailable inhibitor of the BRAF protein. Dabrafenib was discovered and developed at GSK.

About trametinib

Trametinib is an investigational, orally bioavailable inhibitor of the MEK protein. Trametinib was discovered by Japan Tobacco and in-licensed by GSK in 2006.