Increased Cardiovascular Risk With Lorlatinib in Patients With ALK-Mutated Lung Cancer: A Real-World Comparative
Chien-Yu Lin1,2, Po-Lan Su2,3, Chin-Wei Kuo1,2
1Institute of Clinical Medicine, College of Medicine National Cheng Kung University Tainan Taiwan.
Background:
The discovery of driver mutations has transformed advanced non-small cell lung cancer treatment, with ALK (anaplastic lymphoma kinase)-rearranged patients achieving longest overall survival. However, the risk of cancer therapy-related cardiovascular diseases (CTRCVDs) is underrecognized, particularly comparing second-generation ALK-tyrosine kinase inhibitors alectinib and brigatinib to the third-generation tyrosine kinase inhibitor lorlatinib, which offers the longest progression-free survival. We aimed to compare CTRCVDs risks among patients with lung cancer receiving ALK-tyrosine kinase inhibitor, assess incidence trends, and identify clinical risk factors associated with ALK-tyrosine kinase inhibitor-related CTRCVDs.
Methods:
This retrospective cohort study of 946 848 adults with lung cancer (2010-2024) using TriNetX compared CTRCVDs risk in ALK-mutated patients treated with lorlatinib versus brigatinib/alectinib. After excluding ROS1-mutated cases and 1:1 propensity score matching, 744 patients per group were analyzed. CTRCVDs, defined as myocardial infarction, stroke, arterial embolism, or heart failure, were evaluated with Kaplan-Meier analysis and Cox proportional hazards models over 2 years.
Results:
Lorlatinib treatment was associated with a significantly increased risk of CTRCVDs (hazard ratio [HR], 3.00 [95% CI, 1.65-5.45]; P<0.001). Incidence rose from 2.2% at 6 months to 6.6% at 3 years, versus 1.7% and 2.2% in the brigatinib/alectinib cohort. Multivariable analysis identified advanced age (HR, 1.02 [95% CI, 1.00-1.04]; P=0.04), atrial fibrillation/flutter history (HR, 2.39 [95% CI, 1.13-5.07]; P=0.002), and lorlatinib use (HR, 2.42 [95% CI, 1.57-3.72]; P<0.001) as independent predictors.
Conclusion:
These findings underscore the importance of routine cardiovascular monitoring, particularly in older patients and those with atrial arrhythmias.
Insights
Lorlatinib increases cancer therapy-related cardiovascular disease risk in ALK-positive lung cancer patients. Routine monitoring is crucial, especially for older individuals and those with arrhythmias.
Area of Science:
- Oncology
- Cardiology
- Pharmacology
Background:
- Anaplastic lymphoma kinase (ALK) rearrangements define a subset of advanced non-small cell lung cancer (NSCLC) patients who benefit from targeted therapies.
- While ALK inhibitors improve survival, cancer therapy-related cardiovascular diseases (CTRCVDs) risk is a significant concern.
- Third-generation ALK inhibitors like lorlatinib offer superior progression-free survival but require careful cardiovascular risk assessment compared to second-generation agents (alectinib, brigatinib).
Purpose of the Study:
- To compare the CTRCVDs risk between lorlatinib and brigatinib/alectinib in ALK-mutated NSCLC patients.
- To assess incidence trends of CTRCVDs in patients receiving ALK tyrosine kinase inhibitors.
- To identify clinical risk factors associated with ALK tyrosine kinase inhibitor-related CTRCVDs.
Main Methods:
- Retrospective cohort study of 946,848 adult lung cancer patients (2010-2024) using the TriNetX database.
- Comparison of CTRCVDs risk (myocardial infarction, stroke, arterial embolism, heart failure) between lorlatinib and brigatinib/alectinib in 744 propensity score-matched ALK-mutated patients.
- Kaplan-Meier analysis and Cox proportional hazards models were used to evaluate outcomes over 2 years.
Main Results:
- Lorlatinib use was associated with a significantly increased risk of CTRCVDs (HR, 3.00; P<0.001) compared to brigatinib/alectinib.
- CTRCVDs incidence increased from 2.2% at 6 months to 6.6% at 3 years with lorlatinib, versus 1.7% and 2.2% with brigatinib/alectinib.
- Independent predictors for CTRCVDs included advanced age (HR, 1.02; P=0.04), history of atrial fibrillation/flutter (HR, 2.39; P=0.002), and lorlatinib use (HR, 2.42; P<0.001).
Conclusions:
- Lorlatinib treatment significantly elevates CTRCVDs risk in ALK-positive NSCLC patients.
- Advanced age and pre-existing atrial arrhythmias are key risk factors for developing CTRCVDs.
- Routine cardiovascular monitoring is essential for patients on ALK tyrosine kinase inhibitors, particularly older individuals and those with arrhythmias.
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