Exposure-response analyses of anaplastic lymphoma kinase inhibitors crizotinib and alectinib in non-small-cell lung cancer patients


Clin Pharmacol Ther. 2020 Jul 19. doi: 10.1002/cpt.1989. Online ahead of print.


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 were included who were treated with crizotinib or alectinib and of whom pharmacokinetic samples were collected in routine care. 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%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 reached (95%CI 19.8-NA) for patients with Cmin < 435 ng/mL (37%) and ≥ 435 ng/mL, respectively (p=0.04). Multivariable analysis resulted in a 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.