Brain Penetration of Lorlatinib: Cumulative Incidences of CNS and Non-CNS Progression with Lorlatinib in Patients with Previously Treated ALK-Positive Non-Small-Cell Lung Cancer
Open Access
- 14 February 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Targeted Oncology
- Vol. 15 (1), 55-65
- https://doi.org/10.1007/s11523-020-00702-4
Abstract
Background Lorlatinib is a potent, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) designed to penetrate the blood–brain barrier. Objective We report the cumulative incidence of central nervous system (CNS) and non-CNS progression with lorlatinib in patients with ALK-positive non-small-cell lung cancer (NSCLC) previously treated with ALK TKIs. Patients and methods In an ongoing phase II study (NCT01970865), 198 patients with ALK-positive NSCLC with ≥ 1 prior ALK TKI were enrolled into expansion cohorts (EXP) based on treatment history. Patients received lorlatinib 100 mg once daily. Patients were analyzed for progressive disease, categorized as CNS or non-CNS progression, by independent central review. Cumulative incidence probabilities were calculated adopting a competing risks approach. Results Fifty-nine patients received crizotinib as their only prior ALK TKI (EXP2–3A); cumulative incidence rates (CIRs) of CNS and non-CNS progression were both 22% at 12 months in patients with baseline CNS metastases (n = 37), and CIR of non-CNS progression at 12 months was higher versus that for CNS progression in patients without baseline CNS metastases [43% vs. 9% (n = 22)]. In patients who received ≥ 1 prior second-generation ALK TKI [EXP3B–5 (n = 139)], CIR of non-CNS progression at 12 months was higher versus that for CNS progression in patients both with and without baseline CNS metastases (35% vs. 23% (n = 94) and 55% vs. 12% (n = 45), respectively). Conclusions Lorlatinib showed substantial intracranial activity in patients with pretreated ALK-positive NSCLC, with or without baseline CNS metastases, whose disease progressed on crizotinib or second-generation ALK TKIs. ClinicalTrials.gov identifier NCT01970865.Keywords
Funding Information
- Pfizer Inc.
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