Abstract
: The advent of crizotinib, the first small molecule inhibitor against anaplastic lymphoma kinase (ALK), has led to impressive advances in the care of patients with advanced ALK-rearranged non-small cell lung cancer. The development of second-generation ALK inhibitors, starting with the recent U.S. Food and Drug Administration approval of ceritinib, promises to expand the therapeutic landscape for this cohort of patients. With increasing use of molecularly targeted therapy options, it has been observed that disease progression in patients receiving targeted agents has a heterogeneous biology, manifesting as either oligoprogressive or widely progressive disease, which may require development of innovative treatment strategies. This review discusses the first- and second-generation ALK inhibitors approved or in clinical development, as well as the novel challenges and approaches to disease progression in patients on targeted agents. IMPLICATIONS FOR PRACTICE: The identification of driver mutations in non-small cell lung cancer (NSCLC), most prominently epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), has expanded treatment options for a significant cohort of patients. However, the success of targeted agents has brought new challenges, particularly regarding management of progression. Progression manifests heterogeneously, and management of oligoprogression may differ from diffusely progressive disease. Multiple options for treatment at progression exist, and it is becoming evident that selecting the best avenue of care requires understanding the biology and potential drivers of disease progression. This review discusses the array of treatment options available for patients with ALK-positive NSCLC, as well as evaluation and treatment of progressive disease.