Dabrafenib

Drug from the group of serine-threonine kinase inhibitors (protein kinase inhibitor), which inhibits the function of the protein BRAF Dabrafenib is used in adult patients to treat metastatic malignant melanoma. BRAF gene mutations can be detected in 40-60% of malignant melanomas. Of these, 90% result in an exchange of valine (V, in position 600) for glutamate (E) (B-RAF V600 mutation), which leads to over- and long-term activation of the mutated kinase.

Such "activating" mutations in the BRAF gene lead to sustained activation of the MAPK (mitogen-activated protein kinase) pathway with consecutive excessive cell growth. As a kinase inhibitor (serine-threonine kinase), dabrafenib inhibits the signaling pathway of the mutated BRAF protein and thus inhibits the growth of the mutated (melanoma) cells.

Dabrafenib is metabolised in the liver via cytochrome P450 3A4 (CYP3A4) and cytochrome P450 2C8. It produces hydroxy-dabrafenib metabolite, which is oxidized via CYP3A4. The oxidized product "carboxy-dabrafenib" is eliminated either via the liver or the kidney.

More than 70% of patients do not respond after chronic BRAF inhibitor therapy. A reactivation of the MAPK signaling pathway is possible. Furthermore, therapy of BRAF wild-type cells with RAS mutation can cause a paradoxical activation of the MAPK pathway with an increased risk of squamous cell carcinoma

Hyperkeratosis, pyrexia, headache, dizziness, arthralgia, hair loss, papilloma and hand-foot syndrome.

Tafinlar®

The drug dabrafenib was approved by the European Commission for use throughout the EU in August 2013. The combination of dabrafenib with the MEK inhibitor trametinib was approved in the USA in January 2014 and in the EU in September 2015. In the pivotal Phase III study (BREAK-3), monotherapy with the oral BRAF inhibitor dabrafenib was associated with a significant extension of progression-free survival in patients with distant metastatic melanoma (n=187) compared to DTIC monochemotherapy (6.9 months vs. 2.7 months).

Combination therapy (dabrafenib + trametinib): the combined use of the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib (COMB-d/COMB-v studies) showed a clear survival benefit (overall and progression-free survival) (side effects: fever, chills, fatigue, rash, hyperparalysis, headache, arthralgia, diarrhoea).

1. Huang M et al (2013) B-Raf and the inhibitors: from bench to bedside. In: Journal of Hematology Oncology 6: 30
2. Schadendorf D (2016) Darafenib in combination with trametinib. Thieme Drug Report 1: 1-12