ASCEND-2: a canary in a coal mine for descending to second-line treatment for ALK-rearranged non-small cell lung cancer

The discovery of oncogenic driver mutations has revolutionized the management of non-small cell lung cancer (NSCLC) for the past decade. The prevalence of anaplastic lymphoma kinase (ALK) rearrangement in NSCLC is estimated to be 2–7% (1). Crizotinib, a tyrosine kinase inhibitor (TKI), which targets ALK as well as ROS1 and c-MET, was approved by the U.S. Food and Drug Administration (FDA) in 2011 for the treatment of metastatic ALK-rearranged NSCLC. Several studies have demonstrated a median progression-free survival (PFS) of approximately 8 to 11 months and response rates of 65% to 75% (2,3). However, as with other targeted therapies, patients eventually progress due to the emergence of acquired resistance via the activation or inhibition of alternative signaling pathways, secondary ALK mutations, or amplification of the ALKfusion gene.