Precision drug development in ROS1-positive lung cancer

Introduction: The treatment paradigm of non-small cell lung cancer (NSCLC) continues to evolve with the advent of broadened molecularly-targeted approaches. Similar to activating EGFR mutations and ALK rearrangements, ROS1 translocations define a distinct molecular subtype of NSCLC. ROS1 forms fusion products with a series of partners, leading to oncogenesis. Areas covered: This review will discuss key ROS1-fusion related downstream pathways and diagnostic techniques for detection of ROS1 rearrangements. Crizotinib, an inhibitor of MET/ALK/ROS1, has been approved as a targeted treatment for ROS1 positive lung cancer. Moreover, we will address the main resistance mechanisms to crizotinib, including development of secondary ROS1 mutations (such as G2032R and L2026M), activation of bypass signaling pathways (including EGFR and KRAS) and limitations in central nervous system penetrance. We will also review emerging therapies in ROS1 positive NSCLC, including cabozantinib, lorlatinib, entrectinib, and ceritinib. Expert commentary: Targeted therapy in ROS1 positive NSCLC has resulted in improved clinical outcomes compared with traditional chemotherapy. Thus, it is essential to screen for ROS1 fusions in NSCLC patients. Continued investigations should focus on improving understanding and identification of resistance mechanisms upon disease progression via repeat tissue or liquid biopsy, with the ultimate goal to tailor subsequent treatment to specific aberrations.