How I treat ALK-positive non-small cell lung cancer

Since the discovery of anaplastic lymphocyte kinase (ALK) rearrangement in non-small cell lung cancer (NSCLC) and subsequent development of increasingly effective and central nervous system (CNS)-penetrant first-generation, second-generation and third-generation ALK tyrosine kinase inhibitors (TKIs), the landscape of resistance mechanisms and treatment decisions has become increasingly complex. Tissue and/or plasma-based molecular tests can identify not only the rearrangement proper but also common resistance mechanisms to guide decision-making for further lines of treatment. However, frequently encountered questions exist regarding how to diagnosis ALK rearrangement, how to select a first-line ALK TKI, how to diagnose and manage ALK TKI resistance, how to control CNS disease and how to handle failure of ALK inhibition. Herein, we attempt to answer these questions through the evidence-based interpretation of studies on ALK-rearranged NSCLC combined with experience gained from our institution. The authors also propose a therapeutic algorithm for the management of this complex and highly treatable disease to assist clinicians globally in the treatment of patients with ALK-positive NSCLC. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, any changes made are indicated, and the use is non-commercial.