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

Clin Pharmacol Ther. 2021 Feb;109(2):394-402. doi: 10.1002/cpt.1989. Epub 2020 Aug 19.

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 = 0.009). For alectinib, mPFS was 12.6 months vs. not estimable (95% CI, 19.8-not estimable) for patients with Cmin < 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 Cmin ≥ 235 ng/mL and 435 ng/mL, respectively. Therefore, therapeutic drug monitoring should be part of routine clinical management for these agents.

Publication types

  • Observational Study

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Anaplastic Lymphoma Kinase / antagonists & inhibitors*
  • Carbazoles / therapeutic use*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Crizotinib / therapeutic use*
  • Female
  • Humans
  • Lung Neoplasms / drug therapy*
  • Male
  • Middle Aged
  • Piperidines / therapeutic use*
  • Progression-Free Survival
  • Protein Kinase Inhibitors / therapeutic use*
  • Retrospective Studies
  • Young Adult

Substances

  • Carbazoles
  • Piperidines
  • Protein Kinase Inhibitors
  • Crizotinib
  • Anaplastic Lymphoma Kinase
  • alectinib