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

FIGURE 1. Shared biological mechanisms underlying cardiovascular toxicity of targeted therapies in NSCLC. Various therapeutic classes converge on common pathogenic pathways, including ion channel interference, mitochondrial dysfunction, oxidative stress, inflammatory activation, endothelial dysfunction, and metabolic dysregulation. These mechanisms contribute to overlapping cardiovascular phenotypes such as QT interval prolongation and arrhythmias, left ventricular dysfunction and heart failure, hemodynamic instability or shock, edema, ischemia and microvascular injury, and arterial hypertension. This mechanistic convergence supports a pathway-driven rather than drug-specific approach to cardiovascular risk assessment in NSCLC. ADC, antibody-drug conjugates; ALK, anaplastic lymphoma kinase; CRS, cytokine release syndrome; EGFR, epidermal growth factor receptor; LV, left ventricular. Created with Biorender.com.

FIGURE 2. EGFR/ErbB signaling in cancer cells and cardiomyocytes. Overlapping targeting of EGFR and HER2 signaling pathways in cancer cells and cardiomyocytes. EGFR tyrosine kinase inhibitors suppress oncogenic activity. EGFR signaling in tumor cells, but may also inhibit cardiomyocyte EGFR-mediated survival pathways. ADC, antibody-drug conjugates; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor 2; TKI, tyrosine kinase inhibitors. Created with Biorender.com.

FIGURE 3. Antitumor activity, cardiovascular, and metabolic effects of ALK/ROS1/NTRK TKIs. On-target antitumor and off-target cardiovascular and metabolic effects of ALK/ROS1/NTRK tyrosine kinase inhibitors. These agents inhibit oncogenic tyrosine kinase receptors in cancer cells, whereas off-target interactions in cardiomyocytes may impair cardiac repolarization by inhibiting the hERG potassium channel, leading to QT interval prolongation and arrhythmias. In parallel, lorlatinib exerts hepatic metabolic effects that disrupt lipid homeostasis, resulting in clinically relevant dyslipidemia. ALK, anaplastic lymphoma kinase; NTRK, neurotrophic tyrosine receptor kinase; TKI, tyrosine kinase inhibitors. Created with Biorender.com.

FIGURE 4. QTc prolongation management. The figure depicts a flowchart for the management of QTc prolongation in cancer patients receiving targeted therapy. *manually evaluated using Fridericia correction formula; †dizziness, near syncope, hypotension, chest pain, or palpitations. TdP, torsade de pointes.

FIGURE 5. Cardiac magnetic resonance in a patient treated with an EGFR tyrosine kinase inhibitor. Native T1 mapping demonstrates increased myocardial T1 values, consistent with expansion of the extracellular volume and suggestive of early myocardial fibrotic remodeling. The short-axis view is shown on the left, and the four-chamber view on the right.