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

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.