Targeted therapies in non–small cell lung cancer and their cardiovascular impact: mechanisms, clinical profiles, and strategies of management

The therapeutic landscape of non-small cell lung cancer (NSCLC) has been profoundly transformed by the widespread adoption of molecular profiling and the development of targeted therapies, like tyrosine kinase inhibitors (TKIs), antibody-drug conjugates (ADCs), and bispecific antibodies (BsAbs). These agents have significantly improved survival and quality of life in molecularly selected subgroups, potentially converting NSCLC into a chronic disease requiring prolonged treatment exposure. However, extended survival has led to increasing recognition of cancer treatment-related cardiovascular (CV) disease as a clinically relevant and sometimes dose-limiting complication. Unlike conventional chemotherapy, CV toxicities associated with targeted therapies frequently arise from on-target or off-target interference with signaling pathways that are essential for myocardial survival, endothelial function, vascular regulation, and the cardiac conduction system. From common pathophysiological mechanisms, a broad spectrum of clinical manifestations arises, ranging from asymptomatic electrocardiographic changes to arterial hypertension, dyslipidemia, venous thromboembolism, arrhythmias, and heart failure. This review provides a comprehensive overview of CV toxicities associated with targeted therapies in NSCLC, integrating mechanistic insights with clinical evidence. We summarize class-specific CV risk profiles across EGFR, ALK/ROS1, RET, MET, NTRK, BRAF, and KRAS-G12C inhibitors, as well as ADCs and BsAbs, highlighting both shared and distinct patterns of cardiotoxicity. As targeted therapies continue to expand across disease stages and treatment lines, CV toxicity is expected to play an increasingly important role in therapeutic decision-making. Integrating CV considerations into oncologic care is therefore essential to preserve treatment continuity, optimize long-term outcomes, and maximize the benefits of modern targeted therapies in NSCLC.