BRAF V600E Mediates Crizotinib Resistance and Responds to Dabrafenib and Trametinib in a ROS1-Rearranged Non-Small Cell Lung Cancer: A Case Report

Abstract

Crizotinib, a multitargeted MET/ALK/ROS1 tyrosine kinase inhibitor, has been approved for the treatment of ROS1 fusion–positive non-small cell lung cancers (NSCLCs). However, “on-target” or “off-target” resistance alterations often emerge that confer the drug resistance. Patients with ROS1-rearranged NSCLC who develop crizotinib resistance, especially those acquiring “off-target” resistance mutations, still lack effective therapeutic options for after crizotinib treatment. Herein, we reported a patient with stage IVb lung adenocarcinoma harboring ROS1 fusion, who acquired a BRAF V600E and lost the ROS1 fusion after progression on crizotinib. It was deduced that the V600E may originate from a subclone with an extremely low fraction that was independent of ROS1 fusion–positive cells. The patient was subsequently treated with dabrafenib and trametinib combination and achieved a partial response lasting for more than 6 months. Our study revealed that BRAF V600E can confer the crizotinib resistance in ROS1 fusion–positive NSCLC and presented the first case showing that the treatment with dabrafenib and trametinib can serve as an effective option for later-line treatment for this molecular-defined subgroup. Key Points: Patients with ROS1-rearranged non-small cell lung cancer (NSCLC) who acquire “off-target” resistance mutations to crizotinib still lack effective therapeutic options for after crizotinib treatment. This report describes the case of a patient with ROS1-rearranged NSCLC who acquired a BRAF V600E and lost the ROS1 fusion after crizotinib failure. The case was subsequently treated with dabrafenib and trametinib combination and achieved a partial response lasting for more than 6 months. This is the first article reporting that treatment with dabrafenib and trametinib may serve as an effective option for later-line treatment for patients harboring resistant BRAF V600E.