Cardiotoxicity Associated with Targeted Therapies in Lung Cancer: A Retrospective Cohort Study of 2,427 Patients at Renji Hospital

BackgroundTargeted therapies are central to lung cancer treatment, yet their cardiotoxic effects across drug classes remain inadequately characterized in real-world populations. The comparative burden of subclinical biomarker-defined injury, cycle-dependent risks, and post-marketing safety signals across therapeutic targets has not been fully evaluated. MethodsWe conducted a retrospective cohort study of 2,427 lung cancer patients treated with 82 targeted agents at Renji Hospital (2018-2024). Cardiotoxicity was defined as any new elevation in cardiac biomarkers according to the 2022 ESC cardio-oncology guideline criteria. Multivariable Cox models assessed cardiotoxicity risk across drug targets; restricted cubic splines modeled nonlinear associations between PD-1 inhibitor administration frequency and cardiotoxicity; and longitudinal biomarker trajectories were analyzed using generalized additive mixed models. To complement hospital-based findings, we performed independent pharmacovigilance analyses using 4,249 cardiac adverse event reports from the FDA Adverse Event Reporting System (FAERS). Disproportionality signals were quantified using proportional reporting ratios (PRRs). ResultsAmong 2,069 analyzable patients, 326 (15.8%) developed biomarker-defined cardiotoxicity. PD-1 inhibitors showed the highest adjusted risk (HR 1.81; 95% CI 1.43-2.28), followed by VEGF inhibitors (HR 1.33; 95% CI 1.06-1.67), whereas EGFR inhibitors were associated with lower incidence (HR 0.61; 95% CI 0.48-0.78). PD-1-related cardiotoxicity demonstrated a nonlinear exposure-response relationship, with risk rising steeply up to approximately four treatment cycles. Longitudinal analyses showed marked divergence in B-type natriuretic peptide (BNP) and creatine kinase-MB (CK-MB) trajectories among PD-1-treated patients, while troponin levels remained largely unchanged. FAERS analyses corroborated these findings: PD-1 inhibitors exhibited the strongest disproportionality signals for severe cardiac adverse events (PRR 1.84; 95% CI 1.68-2.02), including immune-mediated myocarditis (PRR 28.41) and autoimmune myocarditis (PRR 42.23). ConclusionsAcross both a real-world clinical cohort and a large post-marketing pharmacovigilance dataset, PD-1 inhibitors were consistently associated with the highest cardiotoxicity burden, characterized by an early cycle-dependent rise in risk and distinct elevations in BNP and CK-MB. Combined hospital-based and FAERS evidence supports target-specific cardiac surveillance strategies during lung cancer targeted therapy.