Cardiac Toxicity of Alectinib in Patients With ALK+ Lung Cancer: Outcomes of Cardio-Oncology Follow-Up

Melinda A. Pruis, G. D.Marijn Veerman, H. Carlijne Hassing, Daan A.C. Lanser, Marthe S. Paats, Ron H.N. van Schaik, Ron H.J. Mathijssen, Olivier Manintveld, Anne Marie C. Dingemans*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)
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Abstract

Background: Anaplastic lymphoma kinase (ALK) translocations in metastatic non-small cell lung cancer (3% to 7%) predict for response to ALK-inhibitors (eg, alectinib, first line), resulting in a 5-year survival rate of ∼60% and median progression-free survival of 34.8 months. Although the overall toxicity rate of alectinib is acceptable, unexplained adverse events, including edema and bradycardia, may indicate potential cardiac toxicity. Objectives: This study's aim was to investigate the cardiotoxicity profile and exposure–toxicity relationship of alectinib. Methods: Between April 2020 and September 2021, 53 patients with ALK-positive non-small cell lung cancer treated with alectinib were included. Patients starting with alectinib after April 2020 underwent a cardiac work-up at start, at 6 months and at 1 year at the cardio-oncology outpatients' clinic. Patients already receiving alectinib >6 months underwent 1 cardiac evaluation. Bradycardia, edema, and severe alectinib toxicity (grade ≥3 and grade ≥2 adverse events leading to dose modifications) data were collected. Alectinib steady-state trough concentrations were used for exposure–toxicity analyses. Results: Left ventricular ejection fraction remained stable in all patients who underwent an on-treatment cardiac evaluation (n = 34; median 62%; IQR: 58%-64%). Twenty-two patients (42%) developed alectinib-related bradycardia (6 symptomatic bradycardia). One patient underwent a pacemaker implantation for severe symptomatic bradycardia. Severe toxicity was significantly associated with a 35% higher alectinib mean Ctrough (728 vs 539 ng/mL, SD = 83 ng/mL; 1-sided P = 0.015). Conclusions: No patients showed signs of a diminished left ventricular ejection fraction. Alectinib caused more bradycardia than previously reported (42%) with some instances of severe symptomatic bradycardia. Patients with severe toxicity generally had an elevated exposure above the therapeutic threshold.

Original languageEnglish
Pages (from-to)102-113
Number of pages12
JournalJACC: CardioOncology
Volume5
Issue number1
DOIs
Publication statusPublished - Feb 2023

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