Phase III human trials of single agent therapy using dabrafenib and trametinib for patients with BRAF V600 mutation positive metastatic melanoma met their primary endpoints, GSK (GlaxoSmithKline) reported at the Annual Meeting of ASCo (American Society of Clinical Oncology), Chicago, Illinois, today. The trial results were also published today in NEJM (New England Journal of Medicine).

The researchers explained that in both studies, the BREAK3 which tested the BRAF inhibitor (dabrafenib), and the METRIC study which evaluated the MEK inhibitor (trametinib) showed statistically significant benefits for patients with BRAF V600 mutation positive advanced or metastatic melanoma, regarding how long they survived without disease progression (PFS or Progression Free Survival). In both studies, the active ingredients were compared to patients receiving chemotherapy.

The METRIC study showed that those on trametinib lived considerably longer than patients receiving chemotherapy alongside dacarbazine. It is too early to report on OS (Overall Survival) in the BREAK3 study.

Dr. Rafael Amado, Head of Oncology R&D for GlaxoSmithKline, said:

"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.

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 - a Phase III, randomized, open-label study which compared the tolerability, safety and efficacy of dabrafenib to dacarbazine in individuals with Sage III (advanced) or Stage IV (metastatic) melanoma. The patients carry a BRAF V600 mutation. The primary endpoind was progression free survival. The study included 250 participants from the USA, Europe, Canada and Australia. Individuals with BRAF V600E mutation positive metastatic melanoma, who had been previously untreated were given dabrafenib. They were compared to those on dacarbazine.
  • Those on dabrafenib had a 70% lower risk of disease progression or death (Hazard Ratio (HR) 0.30; p<0.0001) compared patients on chemotherapy.

  • In the dabrafenib arm, progression free survival was 5.1 months, compared to 2.7 months in the dacarbazine arm.

  • In the dabrafenib arm, the following adverse events were reported: 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%).
The METRIC Study - a Phase III trial of the MEK inhibitor, trametinib, in advanced/metastatic melanoma patients with with BRAF V600E or K mutation. They had had at least one previous regimen of chemotherapy, but no previous BRAF inhibitor treatment. The primary endpoint was progression free survival. The study involved 322 patients in the USA, Canada, Europe, Australia, New Zealand, and Argentina.
  • Patients with BRAF V600E or K mutation positive metastatic melanoma were enrolled, some of them had been previously treated with chemotherapy.

  • Those in the trametinib arm had a median progression free survival of 4.8 months, compared to 1.5 months in the chemotherapy arm

  • This in the trametinib arm had a 55% lower risk of disease progression or death, compared to the patients in the chemotherapy arm.

  • Overall survival benefit was significantly higher for those in the trametinib arm at the interim analysis.

  • The most commonly reported adverse events for those on trametinib were rash (57%), diarrhea (43%), fatigue (26%), and peripheral edema (26%). A much lower percentage reported hypertension, chorioretinopathy, and a drop in ejection fraction/ventricular dysfunction.
Written by Christian Nordqvist