BACKGROUND: Randomized trials have demonstrated that anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) can be safe and efficacious treatments for patients with ALK-positive advanced non-small-cell lung cancer (aNSCLC). However, their safety, tolerability, effectiveness, and patterns of use in real-world patients remain understudied. OBJECTIVE: We sought to assess the overall treatment pattern characteristics, safety, and effectiveness outcomes of real-world patients with ALK-positive aNSCLC receiving ALK TKIs. PATIENTS AND METHODS: This retrospective cohort study using electronic health record data included adult patients with ALK-positive aNSCLC receiving ALK TKIs between January 2012 and November 2021 at a large tertiary medical center, University of California, San Francisco (UCSF), with alectinib or crizotinib as the initial ALK TKI therapy. Our primary endpoints included the incidence of treatment changes (treatment dose adjustments, interruptions, and discontinuations) during the initial ALK TKI treatment, the count and type of subsequent treatments, rates of serious adverse events (sAEs), and major adverse events (mAEs) leading to any ALK TKI treatment changes. Secondary endpoints included the hazard ratios (HRs) for median mAE-free survival (mAEFS), real-world progression-free survival (rwPFS), and overall survival (OS) when comparing alectinib with crizotinib. RESULTS: The cohort consisted of 117 adult patients (70 alectinib and 47 crizotinib) with ALK-positive aNSCLC, with 24.8%, 17.9%, and 6.0% experiencing treatment dose adjustments, interruptions, and discontinuation, respectively. Of the 73 patients whose ALK TKI treatments were discontinued, 68 received subsequent treatments including newer generations of ALK TKIs, immune checkpoint inhibitors, and chemotherapies. The most common mAEs were rash (9.9%) and bradycardia (7.0%) for alectinib and liver toxicity (19.1%) for crizotinib. The most common sAEs were pericardial effusion (5.6%) and pleural effusion (5.6%) for alectinib and pulmonary embolism (6.4%) for crizotinib. Patients receiving alectinib versus crizotinib as their first ALK TKI treatment experienced significantly prolonged median rwPFS (29.3 versus 10.4 months) with an HR of 0.38 (95% CI 0.21-0.67), while prolonged median mAEFS (not reached versus 91.3 months) and OS (54.1 versus 45.8 months) were observed in patients receiving alectinib versus crizotinib but did not reach statistical significance. Yet, it is worth noting that there was a high degree of cross-over post-progression, which could significantly confound the overall survival measures. CONCLUSIONS: We found that ALK TKIs were highly tolerable, and alectinib was associated with favorable survival outcomes with longer time to adverse events (AE) requiring medical interventions, disease progression, and death, in the context of real-world use. Proactive monitoring for adverse events such as rash, bradycardia, and hepatotoxicity may help further promote the safe and optimal use of ALK TKIs in the treatment of patients with aNSCLC.