Exposure-Response Analyses of Anaplastic Lymphoma Kinase Inhibitors Crizotinib and Alectinib in Non-Small Cell Lung Cancer Patients.

Clinical Pharmacology and Therapeutics
Stefanie L GroenlandNeeltje Steeghs

Abstract

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 (Cmin ) 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 Cmin 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 Cmin  < 235 ng/mL (48%) and ≥ 235 ng/mL, respectively (P = 0.08). In multivariable analysis, Cmin  < 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 ...Continue Reading

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Citations

Nov 10, 2020·European Journal of Clinical Pharmacology·Anna Mueller-SchoellCharlotte Kloft
May 20, 2021·American Society of Clinical Oncology Educational Book·Stefanie L GroenlandVarsha Gandhi

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