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

Abstract

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 34.8months. Although the overall toxicity rate of alectinib is acceptable, unexplained adverse events, including edema and bradycardia, may indicate potential cardiac toxicity. This study's aim was to investigate the cardiotoxicity profile and exposure-toxicity relationship of alectinib. 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, at6months and at 1 year at the cardio-oncology outpatients' clinic. Patients already receiving alectinib >6months underwent 1 cardiac evaluation. Bradycardia, edema, and severe alectinib toxicity (grade≥3 and grade≥2 adverse eventsleading to dose modifications) data were collected. Alectinib steady-state trough concentrations were used for exposure-toxicity analyses. 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 539ng/mL, SD=83ng/mL; 1-sided P=0.015). 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.