GlaxoSmithKline released results from two of its phase III melanoma studies: one evaluating single agent therapy with the targeted anti-cancer agents, dabrafenib and trametinib, in patients with BRAF V600 mutation positive metastatic melanoma; and one evaluating trametinib alone.

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, PFS) compared to those receiving chemotherapy. Additionally, patients in the METRIC study who received trametinib lived significantly longer (overall survival, OS) than those who received chemotherapy with dacarbazine. OS data are not yet mature in the BREAK3 trial.

"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, GSK. "We are planning regulatory submissions for dabrafenib and trametinib as single agent therapies and have recently started a phase III 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 common (³20%) adverse events 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 OS benefit was gained by the trametinib arm at the interim analysis (HR 0.54; p=0.0136). The most common (³20%) adverse events in the trametinib arm were rash (57%), diarrhea (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%).

In both studies, patients were selected for eligibility based on the BRAF mutation status of their cancer, performed by Response Genetics. 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 U.S. FDA pre-market approval of the test in the near future.