Dramatic Response to Sequential BRAF Inhibition in BRAFV600E–Mutant Metastatic Lung Adenocarcinoma

Lung cancer is the leading cause of cancer-related death. Targeted therapy directed toward molecular pathways that drive non–small-cell lung cancer (NSCLC) has dramatically improved treatment options. Some of the oncogenic drivers identified in lung adenocarcinoma involve the RAS-RAF-mitogen-activated protein kinase (MAPK) kinase (MEK)-extracellular regulated kinase (ERK) pathway (MAPK-ERK pathway). BRAF is a key protein in MAPK-ERK signaling.

Mutations in BRAF are present in 1% to 3% of NSCLC and lead to constitutive activation of the MAPK-ERK pathway, promoting cancer cell proliferation and survival.

Substitution of valine with glutamic acid at codon 600 of exon 15 (V600E) is the most common BRAF mutation (approximately 50%) in NSCLC. Several other mutations of BRAF have been identified and are grouped as non-V600E mutations.

Patients with NSCLC harboring BRAF V600E mutations are sensitive to BRAF inhibitors (BRAFis) alone or in combination with MEK inhibitors (MEKis). After initial response, patients typically experience relapse as a result of various resistance mechanisms. Treatment after progression is not well defined.

In this report, we present a case of a patient who achieved a significant response with dabrafenib and trametinib after initial progression on vemurafenib.