ALK TKIs, particularly second- and third-generation ALK TKIs, have significantly improved progression-free survival (PFS) in patients with advanced ALK-positive non-small cell lung cancer (NSCLC). However, patients continue to face challenges related to drug resistance and disease progression; in the CROWN study, 40% of patients still experienced disease progression within five years. There are currently no standard treatment recommendations for this patient population. This study retrospectively evaluated the efficacy and safety of ensartinib combined with anlotinib as a second-line treatment in patients who had developed resistance to lorlatinib. The inclusion criteria for data collection were patients aged ≥18 years with histologically confirmed stage IIIB-IV ALK-positive NSCLC who had developed resistance to lorlatinib; prior to lorlatinib treatment, patients could have received up to two other ALK-TKIs, excluding ensartinib.