The discovery of driving genes and the advent of targeted drugs have brought non-small cell lung cancer (NSCLC) into the era of precision medicine and personalized treatment. Over the past decade, with the continuous development of biomedicine, the non-small cell lung cancer driver genes that have been identified include EGFR, ALK, ROS1, BRAF and so on.
Small molecule tyrosine kinase inhibitors (TKIs), or molecularly targeted therapeutic drugs, that target these driver genes, have gradually transitioned from the clinical trial stage to the real world. The "precision" properties of these drugs, their combined efficacy and safety, open up new treatment options for patients with advanced non-small cell lung cancer (Table 1).
Table 1. NSCLC common driver genes and targeted drugs
The evaluation of a drug generally starts from two dimensions: efficacy and safety. More people usually pay more attention to the anti-tumor effect of drugs, especially new targeted therapy drugs. Secondly, we will pay attention to the relatively common toxic reactions of these targeted drugs, such as rashes, gastrointestinal reactions, liver function damage and so on. Relatively rare safety concerns, such as the cardiotoxicity of targeted therapies, are often overlooked.
Cardiotoxicity reported in clinical studies, including arrhythmias, heart failure, etc., should be paid attention to in the process of treatment. In addition, since most patients are elderly, and some of them have underlying cardiovascular diseases, the cardiovascular risks posed by these drugs are of even greater concern.
Recently, a research paper published in the Journal of Thoracic Oncology summarized and reported on cardiac toxicity data such as heart failure, QT interval prolongation, supraventricular tachycardia, and ventricular arrhythmias caused by common targeted therapies for non-small cell lung cancer using the WHO adverse drug reaction database VigiBase.
ALK/ROS1 inhibitors are more likely to cause heart block
Overall, ALK/ROS1 inhibitors have a higher rate of cardiac conduction disorders,including long QT syndrome,' than targeted drugs targeting other driver genes (EGFR, BRAF, and MEK) (Figure 1). In ALK/ROS1 inhibitors, the proportion of heart block with crizotinib is higher than that of other drugs, of which the occurrence time is about 1 month (30 days) when receiving treatment, and 9 becomes a severe case.
In addition to ALK/ROS1-TKI, the proportion of developing long QT syndrome after treatment with other inhibitors is also higher than the overall database average (Figure 1).
Figure 1. Comparison of cardiotoxicity between targeted drug classes targeting different driver genes
Treatment with three-generation EGFR-TKI osimertinib predisposes multiple cardiotoxic events
Compared with other EGFR inhibitors or other driver gene inhibitors, the proportion of long QT syndromes developed by osiminib is significantly increased, generally occurring at a median treatment time of 29 days (Figure 2). In addition, the proportion of supraventricular tachycardia after receiving treatment with this drug is also higher than that of other drugs, with the median occurrence occurring 21 days after treatment, and 90% of cases are serious events. The incidence of heart failure was also significantly higher than with other drugs, with a median incidence of about 3 months (85 days) after treatment.
Figure 2. Occurrence of long QT intervals after treatment with EGFR inhibitors
A higher proportion of heart failure occurs after treatment with BRAF and MEK inhibitors
In addition to osimertinib, the proportion of up-ventricular rates occurring after treatment with the BRAF inhibitor daratinib was also higher than with other targeted therapy drugs, with a median time of about 2 months (61.5 days) after treatment. In addition, treatment with dalatinib and kras/MEK inhibitor Trametinib is more likely to develop heart failure than other drugs, with median occurrence times of 116 days and 87 days, respectively (Figure 3).
Figure 3. Occurrence of heart failure after treatment with BRAF and MEK inhibitors
brief summary
ALK/ROS1 inhibitors are prone to heart block, and EGFR inhibitors are prone to a variety of cardiotoxic events after treatment with osiminib, which should be of concern to us. Other drugs, while causing less than these drugs, are at risk of developing cardiotoxic events.
Therefore, in the follow-up after targeted therapy, do not only focus on the efficacy, safety is equally important. The most common means of monitoring cardiotoxic events is electrocardiogram, which is also a very convenient method for finding various arrhythmias, and should not be ignored at each follow-up visit. In addition, if there are clinical manifestations of heart failure such as dyspnea and edema during treatment, it should also be treated in time to exclude the influence of targeted therapy factors.
The principle of "safety first" must be followed in the process of targeted therapy, because safety is an important guarantee for long-lasting efficacy. Safe and good efficacy is the real "double harvest" of targeted therapy.
参考文献：Sarah Waliany, et al. Pharmacovigilance Analysis of Cardiac Toxicities Associated With Targeted Therapies for Metastatic NSCLC. Journal of Thoracic Oncology. 2021; 16(12): 2029-2039.