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 ALKpositive 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.

Enteral administration of alectinib for ALK-positive non-small cell lung cancer in an elderly patient

“…Therefore, therapeutic drug monitoring should be part of routine clinical management for these agents. [ 8 ] However, there are indirect arguments against underdosing in the present case. Indeed, our patient presented side effects (hepatic cytolysis) as well as the rapid therapeutic response objectified on the chest X-ray.…”

Physiologically‐based pharmacokinetic model for alectinib, ruxolitinib, and panobinostat in the presence of cancer, renal impairment, and hepatic impairment

“…Therefore, the observed changes in alectinib PK can be attributed to changes in hepatic intrinsic clearance. Despite that no dose‐toxicity could be established in the published literature for alectinib, patients treated with alectinib were shown before to benefit from higher exposure (Groenland, 2020).…”

“…Moderate to severe HIP causes a 2.25–2.34‐fold increase in alectinib exposure that warrants dose reduction to 300 mg (Morcos, 2018). However, no dose–toxicity relationship could be established in the published literature till now for alectinib (Groenland, 2020). Alectinib (Table 1) is a Biopharmaceutical Classification System class II (BCS II) drug (Parrott, 2016).…”

The Right Dose: From Phase I to Clinical Practice

“…The interindividual variability in apparent oral clearance of many oral targeted therapies is high; coefficients of variation typically range between 40% and 70%. 5,[7][8][9] As illustrated in Fig. 1, many factors contribute to this high variability.…”