Association between lorlatinib blood concentration and adverse events and clinical impact of dose modification

• Published in: Lung cancer (Amsterdam, Netherlands) Netherlands), 2024-10, Vol.196, p.107954, Article 107954
• Main Authors: Shimoda Igawa, Yukiko, Yoshida, Tatsuya, Makihara, Reiko, Torasawa, Masahiro, Tateishi, Akiko, Matsumoto, Yuji, Shinno, Yuki, Okuma, Yusuke, Goto, Yasushi, Horinouchi, Hidehito, Yamamoto, Noboru, Ohe, Yuichiro
• Format: Article
• Language: English
• Subjects: Adult; Adverse events; Aged; Aminopyridines - administration & dosage; Aminopyridines - adverse effects; Anaplastic lymphoma kinase; Anaplastic Lymphoma Kinase - antagonists & inhibitors; Anaplastic Lymphoma Kinase - genetics; Blood concentration; Carcinoma, Non-Small-Cell Lung - drug therapy; Female; Humans; Lactams - adverse effects; Lactams, Macrocyclic - administration & dosage; Lorlatinib; Lung Neoplasms - drug therapy; Male; Middle Aged; Non-small cell lung cancer; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - therapeutic use; Pyrazoles - administration & dosage; Pyrazoles - adverse effects; Pyrazoles - pharmacokinetics; Pyrazoles - therapeutic use; Retrospective Studies; Tyrosine kinase inhibitors; Young Adult
• ISSN: 0169-5002; 1872-8332; 1872-8332
• DOI: 10.1016/j.lungcan.2024.107954

•We conducted an analysis using serial samples from patients with available serum.•Lorlatinib blood concentration was high in patients with grade ≥ 3 adverse events.•Adverse events improved as lorlatinib blood concentrations decreased.•Treatment with lorlatinib is suggested to be conducted under dose monitoring. Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) inhibitor, causes distinct adverse events (AEs), including hyperlipidemia and central nervous system (CNS) disorders. Although dose modifications are recommended to manage these AEs, whether dose modifications can achieve optimal blood lorlatinib concentrations and reduce the incidence of lorlatinib-induced AEs remains unclear. Therefore, we investigated the association between lorlatinib exposure and AEs in each patient. We retrospectively reviewed patients with advanced ALK-rearranged non-small cell lung cancer treated with lorlatinib between November 2018 and July 2022. Serum lorlatinib concentrations were assessed using high-performance liquid chromatography–tandem mass spectrometry. All AEs were evaluated using the Common Terminology Criteria for Adverse Events version 5.0. The median age of the 55 eligible patients was 59 years (range: 23–79 years). All patients were administered lorlatinib after first line ALK-tyrosine kinase inhibitor failure. Grade ≥ 3 AEs occurred in 25 patients (25/55, 45 %), including hyperlipidemia in 17 (17/55, 31 %), CNS disorders in 7 (7/55, 13 %), and edema in 6 (6/55, 11 %). Dose modification was required in 23 patients (23/55, 42 %). Among the 36 patients with available data on serum lorlatinib levels at day 28 (±14) and no drug dose modifications, lorlatinib serum concentrations were significantly higher in patients with grade ≥ 3 AEs than in those without AEs (median: 462 ng/mL vs. 177 ng/mL, p