Journal
CLINICAL PHARMACOLOGY & THERAPEUTICS
Volume 109, Issue 2, Pages 394-402Publisher
WILEY
DOI: 10.1002/cpt.1989
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In NSCLC patients treated with crizotinib and alectinib, higher minimum plasma concentrations were associated with prolonged progression-free survival, suggesting the importance of therapeutic drug monitoring for these agents.
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.
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