Effectiveness of targeted therapy with dabrafenib and trametinib

Trametinib (Trametinib) is a reversible inhibitor of MEK1 and MEK2 activation and MEK1 and MEK2 kinase activity. MEK protein is an upstream regulator of the ERK pathway and can promote cell proliferation. The BRAF V600E mutation results in constitutive activation of the BRAF pathway, including MEK1 and MEK2. Trametinib inhibits the growth of BRAF V600 mutation-positive melanoma cells in vitro and in vivo. Trametinib was approved by the FDA in 2013 as a single agent for the treatment of BRAF V600E or BRAF V600K mutation-positive unresectable or metastatic melanoma.

Some mutations in the BRAF gene, including those leading to BRAF V600E, can lead to constitutively activated BRAF kinase, thereby stimulating tumor cell growth. Dabrafenib inhibits the growth of BRAF V600 mutation-positive melanoma cells in vitro and in vivo. Dabrafenib was approved by the FDA in 2013 as a single agent for the treatment of BRAF V600E mutation-positive unresectable or metastatic melanoma.

Compared with chemotherapy,targeted inhibition of the MAPK pathway using the BRAF inhibitor dabrafenib can improve progression-free survival (PFS) and overall survival (OS) in patients with BRAF V600-mutated metastatic melanoma. However, acquired resistance to BRAF inhibitor monotherapy often occurs through reactivation of the MAPK pathway, resulting in a median PFS of 6 to 8 months. In addition, the use of BRAF inhibitor monotherapy may lead to the development of secondary skin tumors. Derived from paradoxical activation of the MAPK pathway in cells without BRAF mutations.

Single-agent trametinib improves OS compared with chemotherapyIn patients with BRAF V600 mutation-positive metastatic melanoma, it is not associated with paradoxical activation. Combining the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib solves the limitations of single-agent BRAF inhibitors, significantly delays the emergence of drug resistance, has a longer median PFS than dabrafenib alone, and reduces the incidence of BRAF inhibitor-induced skin tumors.

The original drug of Trametinib has been launched in China and is included in the scope of medical insurance. Only patients who meet the indications can choose to reimburse. The price of 2 mg*30 tablets is more than RMB 10,000. The original drug of Trametinib sold overseas is priced at more than RMB 7,000 (the price may fluctuate due to the exchange rate). There are also generic trametinib drugs produced in other countries overseas, and their pharmaceutical ingredients are basically the same as those of the original drugs sold domestically and abroad. For example, the price of 2mg*30 tablets produced by a Laos pharmaceutical factory is more than 2,000 yuan (the price may fluctuate due to the exchange rate), and the price is relatively cheap.