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Exposure–Response Analyses of Anaplastic Lymphoma Kinase Inhibitors Crizotinib and Alectinib in Non‐Small Cell Lung Cancer Patients
Author(s) -
Groenland Stefanie L.,
Geel Dieuwertje R.,
Janssen Julie M.,
Vries Niels,
Rosing Hilde,
Beijnen Jos H.,
Burgers Jacobus A.,
Smit Egbert F.,
Huitema Alwin D.R.,
Steeghs Neeltje
Publication year - 2021
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1989
Subject(s) - alectinib , crizotinib , anaplastic lymphoma kinase , lung cancer , medicine , hazard ratio , oncology , confidence interval , pharmacology , gastroenterology , malignant pleural effusion
Crizotinib and alectinib are anaplastic lymphoma kinase (ALK)‐inhibitors indicated for the treatment of ALK‐positive metastatic non‐small cell lung cancer (NSCLC). At the currently used fixed doses, interindividual variability in exposure is high. The aim of this study was to investigate whether minimum plasma concentrations (C min ) of crizotinib and alectinib are related to efficacy and toxicity. An observational study was performed, in which ALK‐positive NSCLC patients who were treated with crizotinib and alectinib and from whom pharmacokinetic samples were collected in routine care, were included in the study. Exposure–response analyses were explored using previously proposed C min thresholds of 235 ng/mL for crizotinib and 435 ng/mL for alectinib. Forty‐eight crizotinib and 52 alectinib patients were included. For crizotinib, median progression‐free survival (mPFS) was 5.7 vs. 17.4 months for patients with C min < 235 ng/mL (48%) and ≥ 235 ng/mL, respectively ( P = 0.08). In multivariable analysis, C min < 235 ng/mL resulted in a hazard ratio (HR) of 1.79 (95% confidence interval (CI), 0.90–3.59, P = 0.100). In a pooled analysis of all crizotinib patients (not only ALK‐positive, n = 79), the HR was 2.15 (95% CI, 1.21–3.84, P = 0.009). For alectinib, mPFS was 12.6 months vs. not estimable (95% CI, 19.8–not estimable) for patients with C min < 435 ng/mL (37%) and ≥ 435 ng/mL, respectively ( P = 0.04). Multivariable analysis resulted in an HR of 4.29 (95% CI, 1.33–13.90, P = 0.015). In conclusion, PFS of crizotinib and alectinib treated NSCLC patients is prolonged in patients with C min ≥ 235 ng/mL and 435 ng/mL, respectively. Therefore, therapeutic drug monitoring should be part of routine clinical management for these agents.