Background The discovery of driver mutations has transformed advanced non–small cell lung cancer treatment, with ALK (anaplastic lymphoma kinase)–rearranged patients achieving longest overall survival. However, the risk of cancer therapy–related cardiovascular diseases (CTRCVDs) is underrecognized, particularly comparing second‐generation ALK–tyrosine kinase inhibitors alectinib and brigatinib to the third‐generation tyrosine kinase inhibitor lorlatinib, which offers the longest progression‐free survival. We aimed to compare CTRCVDs risks among patients with lung cancer receiving ALK‐tyrosine kinase inhibitor, assess incidence trends, and identify clinical risk factors associated with ALK‐tyrosine kinase inhibitor‐related CTRCVDs. Methods This retrospective cohort study of 946 848 adults with lung cancer (2010–2024) using TriNetX compared CTRCVDs risk in ALK‐mutated patients treated with lorlatinib versus brigatinib/alectinib. After excluding ROS1‐mutated cases and 1:1 propensity score matching, 744 patients per group were analyzed. CTRCVDs, defined as myocardial infarction, stroke, arterial embolism, or heart failure, were evaluated with Kaplan–Meier analysis and Cox proportional hazards models over 2 years. Results Lorlatinib treatment was associated with a significantly increased risk of CTRCVDs (hazard ratio HR, 3.00 95% CI, 1.65–5.45; P <0.001). Incidence rose from 2.2% at 6 months to 6.6% at 3 years, versus 1.7% and 2.2% in the brigatinib/alectinib cohort. Multivariable analysis identified advanced age (HR, 1.02 95% CI, 1.00–1.04; P =0.04), atrial fibrillation/flutter history (HR, 2.39 95% CI, 1.13–5.07; P =0.002), and lorlatinib use (HR, 2.42 95% CI, 1.57–3.72; P <0.001) as independent predictors. Conclusion These findings underscore the importance of routine cardiovascular monitoring, particularly in older patients and those with atrial arrhythmias.
Lin et al. (Thu,) studied this question.