FDA Approves Trametinib in Combination with Dabrafenib for Advanced Melanoma

The combination therapy is approved under the agency’s accelerated approval programme

On 10 January 2014 the US Food and Drug Administration (FDA) announced approval of trametinib (Mekinist) in combination with dabrafenib (Tafinlar) to treat patients with unresectable or metastatic melanoma. They are specifically indicated as a combination therapy for patients with melanoma whose tumours express gene mutations BRAF V600E and V600K.

In May 2013, the FDA approved both drugs as single agents to treat patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. These mutations must be detected by an FDA-approved test. Trametinib and dabrafenib are used to block signaling in different sites of the same molecular pathway that promotes cancer cell growth. The BRAF protein is involved in the regulation of normal cell growth, but it is mutated in approximately half of melanomas arising from the skin.

Trametinib and dabrafenib are the first drugs approved for combination treatment of melanoma. According to Dr Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, the study of their combination is based on the strong understanding of the biological pathways of melanoma and the approval illustrates the value of studying drugs in combination.

The safety and effectiveness of trametinib in combination with dabrafenib were demonstrated in a randomised phase II part of a phase I/II open-label clinical trial of 162 participants with unresectable or metastatic melanoma with the BRAF V600E or V600K mutation, most of whom had not received prior therapy. Participants received either trametinib in combination with dabrafenib or dabrafenib as a single agent until disease progression or side effects became intolerable.

Results showed that 76% of participants treated with trametinib in combination with dabrafenib had objective response that lasted an average of 10.5 months. In contrast, 54% of participants treated with dabrafenib as a single agent experienced objective responses that lasted an average of 5.6 months. Clinical trials are ongoing to determine whether trametinib in combination with dabrafenib improves survival.

The most common side effects reported in participants receiving trametinib in combination with dabrafenib included fever, chills, tiredness, rash, nausea, vomiting, diarrhoea, abdominal pain, peripheral oedema, cough, headache, joint pain, night sweats, decreased appetite, constipation and muscle pain. During clinical testing, the incidence and severity of fever increased when trametinib was used in combination with dabrafenib.

Serious side effects included bleeding, venous thromboembolism, cardiomyopathy, skin and occular toxicity. One of the serious side effects of dabrafenib – the development of a new squamous cell carcinoma of the skin — was reduced when the drug was used in combination with trametinib; this is consistent with the biology of the effects of these two drugs on the targeted molecular pathway. The incidence of squamous cell carcinoma of the skin in this trial was 7% with the combination compared to 19% with single agent dabrafenib. Other clinically significant side effects include renal failure.

Patients should be also advised that trametinib and dabrafenib can cause embryofetal defects and that treatment may cause infertility.

The FDA approved the combination of trametinib and dabrafenib under the agency’s Accelerated Approval programme, which allows the FDA to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. This programme provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials. The FDA also reviewed this combination of drugs under the agency’s priority review because they demonstrated the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition.
 
Mekinist and Tafinlar are marketed by GlaxoSmithKline.