BRAF p.V600E Mutation as Acquired Resistance Mechanism of Lorlatinib in a ROS1 Rearrangement Lung Adenocarcinoma Patient with Primary Ceritinib Resistance

Both crizotinib and ceritinib are recommended as first-line theray for NSCLC with ROS1 rearrangements, with the latter having stronger infiltration ability across blood-brain barrier. Here we report for the first time that a brain metastatic adenocarcinoma patient with CD74-ROS1 rearrangement was sensitive to crizotinib but resistant to ceritinib. Intracranial progression happened after 7 months of crizotinib, and sencond-line lorlatinib resulted in partial response and a PFS of 8 months. Upon lorlatinib resistance, repeated NGS detection of ctDNA from peripheral blood showed BRAF p.V600E, CD74-ROS1 and ROS1 pG2032R. Then, Trametinib, dabrafenib, and cabozantinib was administered to the patient. However, disease progressed very quickly and the patient passed away only one month later, with a overall survival of months. The last ctDNA test, one week before death of the patient, found that BRAF p.V600E disappeared, leaving only CD74-ROS1and ROS1 pG2032R,with a very high frequency. To our knowledge, this is the first case report of a ROS-1 rearrangement lung cancer patient that is sensitive to crizotinib but resistant to ceritinib, and BRAF p.V600E as resistant mechanism for lorlatinib.