Dabrafenib Therapy and Genotype

Dabrafenib (brand name Tafinlar) is a kinase inhibitor used in the treatment of individuals with unresectable or metastatic melanoma, metastatic non-small cell lung cancer (NSCLC), locally advanced or metastatic anaplastic thyroid cancer (ATC), pediatric low-grade glioma (LGG), and other unresectable or metastatic solid tumors with specific variants. Dabrafenib can be used as a single agent to treat melanoma with the valine 600 to glutamic acid (V600E) variant or in combination with the MEK inhibitor trametinib to treat multiple tumor types with V600E or V600K variants. (1) The BRAF protein is an intracellular kinase in the mitogen-activated protein kinases (MAPK) pathway. Functionally, BRAF regulates essential cell processes such as cell growth, division, differentiation, and apoptosis. The gene is also a proto-oncogene—when mutated, it transforms normal cells into cancerous cells. Variation in the kinase domain of BRAF is associated with various cancers. The most common variant, V600E, constitutively activates the kinase and causes cell proliferation in the absence of growth factors that would usually be needed. The V600E variant is detected in approximately 50% of melanomas, 25% of ATC, 2% of NSCLC, and 20% of pediatric LGGs (2, 3, 4, 5, 6, 7, 8). The FDA-approved label for dabrafenib states that the presence of mutation in tumor specimens (V600E for dabrafenib monotherapy; V600E or V600K for dabrafenib plus trametinib) should be confirmed using an FDA-approved test before starting treatment with dabrafenib. Dabrafenib is not indicated for the treatment of individuals with wild-type tumors, or the treatment of colorectal cancer due to intrinsic resistance to inhibitor monotherapy. (1) The label also states that individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency should be monitored for signs of hemolytic anemia while taking dabrafenib (1). However, it is important to note that an independent literature review by the Clinical Pharmacogenetics Implementation Consortium found no publications to support or refute this risk and thus issued no guidance for G6PD deficiency and dabrafenib therapy (9).