Pharmacokinetics of Lorlatinib After Single and Multiple Dosing in Patients with Anaplastic Lymphoma Kinase (ALK)-Positive Non-Small Cell Lung Cancer: Results from a Global Phase I/II Study

Abstract

Background Lorlatinib demonstrated efficacy (including intracranial activity) in patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) in a phase I/II study (NCT01970865). Background and Objective This analysis describes the pharmacokinetics (PK) of lorlatinib following single and multiple dosing. Methods This ongoing, multicenter, open-label, single-arm, phase I/II trial enrolled patients with ALK-positive or c-ros oncogene 1 (ROS1)-positive advanced NSCLC. In phase I, patients received escalating doses of lorlatinib (10-200 mg orally once daily) and twice-daily doses of 35, 75, and 100 mg in continuous 21-day cycles. In phase II, lorlatinib was administered at a starting dose of 100 mg once daily in continuous 21-day cycles. Parameters investigated included the potential for lorlatinib to inhibit/induce cytochrome P450 (CYP) 3A; the absorption/metabolism of lorlatinib and its major metabolite PF-06895751; and differences in these parameters between Asian and non-Asian patients. Results Data were available for 54 patients from phase I and 275 patients from phase II. Lorlatinib plasma exposure increased dose proportionally after single doses of 10-200 mg, and slightly less than dose proportionally after multiple doses. Lorlatinib clearance increased following multiple dosing compared with single dosing, indicating autoinduction. The area under the concentration-time curve from time zero to time τ (the dosing interval; AUC τ ) of PF-06895751 was approximately 80% higher than that of lorlatinib after multiple dosing. Lorlatinib exhibited brain penetration. Furthermore, no overt differences in single-and multiple-dose PK parameters between the Asian and non-Asian patients were observed. Conclusions Lorlatinib is highly brain penetrant and exhibits autoinduction after multiple dosing. There appears to be no inherent differences in lorlatinib PK between healthy subjects and cancer patients, or between Asian and non-Asian patients. ClinicalTrials.gov NCT01970865.Lee P. James, Karen J. Klamerus and Ganesh Mugundu at the time this research was conducted.

Immunotherapy in Non-Small Cell Lung Cancer With Actionable Mutations Other Than EGFR

“…ALK fusions are seen in 3-5% of NSCLC patients and are more common among the following groups: no prior smoking history, adenocarcinoma histology, younger age, female gender, and tumors with wild type EGFR and KRAS (16,(19)(20)(21). Several ALK inhibitors have been approved by the FDA for metastatic NSCLC, including crizotinib, brigatinib, alectinib, lorlatinib and ceritinib (22)(23)(24)(25)(26)(27)(28)(29). The data on the efficacy of ICIs in the ALK fusion positive NSCLC has been scarce.…”

Evaluation of Lorlatinib Cerebrospinal Fluid Concentrations in Relation to Target Concentrations for Anaplastic Lymphoma Kinase (ALK) Inhibition

“…The CSF/free plasma ratios observed in this analysis (range: 0.61–0.96) were much higher than the CSF/plasma ratios observed with the first‐generation ALK/ROS1 TKI crizotinib (range: 0.0006–0.026) 9–11 and the second‐generation ALK TKI alectinib (0.002–0.005) 8 . Lorlatinib PK at single dose and at steady state are largely dose proportional 30 . Lorlatinib has a plasma elimination half‐life of approximately 24 hours after a single dose 34…”

“…Plasma samples for lorlatinib PK were also collected from all other patients and analyzed according to methods previously published. 30 For ALK molecular profiling, the extraction and analysis of cell-free DNA (cfDNA) was performed using a validated, commercially available 73-gene cfDNA next-generation sequencing (NGS) assay (Guardant360, panel version 2.10, bioinformatics pipeline version 3.0; Guardant Health, Inc., Redwood City, California), as previously described. 31,32 Statistical Analysis For an evaluation of the relationship between unbound plasma concentrations and CSF concentrations of lorlatinib, a linear regression model via the generalized linear models function in R version 3.5.1 (R Foundation for Statistical Computing, Vienna, Austria) was applied.…”

“…Post hoc population PK model estimates of average lorlatinib steady-state plasma concentration (C ss,avg ) were used to derive the average steady-state unbound plasma concentration (C ss,avg,u ) based on the known lorlatinib human protein binding (fraction unbound of 0.34). 30,33,34 The CSF concentration in each patient was then estimated as the product of plasma C ss,avg,u and the study-specific CSF to unbound plasma concentration ratio derived earlier by linear regression. The known minimum efficacy concentrations (C eff ) for wild-type ALK and the L1196M and G1202R ALK resistance mutations were multiplied by the fraction of unbound value (0.34) to derive the effective C eff in the CNS.…”

“…The known minimum efficacy concentrations (C eff ) for wild-type ALK and the L1196M and G1202R ALK resistance mutations were multiplied by the fraction of unbound value (0.34) to derive the effective C eff in the CNS. 16,30 The projected CSF concentrations were compared with the CNS C eff to evaluate the ratio of patients achieving coverage of these mutations. 16…”