REVIEW article
Front. Pharmacol.
Sec. Cardiovascular and Smooth Muscle Pharmacology
Targeted therapies in non–small cell lung cancer and their cardiovascular impact: mechanisms, clinical profiles, and strategies of management
Simone Nardin 1,2
Francesca Vezzoli 1,3
Gianluca Cognolato 1,3
Rocco Mollace 4,5
Beatrice Ramella Pollone 2,6
Federica Biello 1
Davide Cao 4,7
Marco Tagliamento 2,6
Matteo Sarocchi 6
Matteo Pagnesi 8
Monica Verdoia 9
Benedetta Conte 3,1
Salvatore Grisanti 8,10
Carlo Genova 6,2
Alessandra Gennari 1,3
Matteo Nardin 11
1. Azienda Ospedaliero Universitaria Maggiore della Carita, Novara, Italy
2. Universita degli Studi di Genova, Genoa, Italy
3. Universita degli Studi del Piemonte Orientale Amedeo Avogadro Scuola di Medicina, Novara, Italy
4. Cliniche Gavazzeni SpA, Bergamo, Italy
5. Universita degli Studi di Roma Tor Vergata, Rome, Italy
6. IRCCS Ospedale Policlinico San Martino, Genoa, Italy
7. Humanitas University, Pieve Emanuele, Italy
8. Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Brescia, Italy
9. Nuovo Ospedale degli Infermi, Ponderano, Italy
10. Universita degli Studi di Brescia, Brescia, Italy
11. Dipartimento di Medicina, Asst degli Spedali Civili di Brescia, Brescia, Italy
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Abstract
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.
Summary
Keywords
Cardiotoxcity, cardiovascular, cardiovascular diseae, lung cancer, NSCLC, targeted therapy
Received
19 January 2026
Accepted
19 February 2026
Copyright
© 2026 Nardin, Vezzoli, Cognolato, Mollace, Ramella Pollone, Biello, Cao, Tagliamento, Sarocchi, Pagnesi, Verdoia, Conte, Grisanti, Genova, Gennari and Nardin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Matteo Nardin
Disclaimer
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