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

doi:10.1016/j.jaccao.2022.09.006

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

JACC CardioOncol. 2023 Jan 17;5(1):102-113. doi: 10.1016/j.jaccao.2022.09.006. eCollection 2023 Feb.

Authors

Melinda A Pruis^{1

2}, G D Marijn Veerman¹, H Carlijne Hassing³, Daan A C Lanser¹, Marthe S Paats², Ron H N van Schaik⁴, Ron H J Mathijssen¹, Olivier Manintveld³, Anne-Marie C Dingemans²

Affiliations

¹ Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Centre, Rotterdam, the Netherlands.
² Department of Pulmonary Medicine, Erasmus MC Cancer Institute, University Medical Centre, Rotterdam, the Netherlands.
³ Department of Cardiology, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands.
⁴ Department of Clinical Chemistry, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands.

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 C_trough (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.

Keywords: AE, adverse event; ALK, anaplastic lymphoma kinase; CV, cardiovascular; ECG, electrocardiogram; IVC, inferior vena cava; LVEF, left ventricular ejection fraction; MET, mesenchymal epithelial transition; NSCLC, non-small cell lung cancer; OV, outpatient visit; PK, pharmacokinetic; TKI, tyrosine kinase inhibitor; alectinib; anaplastic lymphoma kinase; bradycardia; cardio-oncology; non-small cell lung cancer.