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

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. Prior presentation Some of the results from these analyses have been presented at the International Association for the Study of Lung Cancer (IASLC) 19th World Conference on Lung Cancer (WCLC), 23

Evaluation of the Effect of Lymph Node Status on the Survival of Non-Small Cell Lung Cancer Patients With Brain Metastases: Applications of a Novel Grade Prognostic Assessment Score Model Involving N Stage

“…Moreover, we attempted to evaluate the effect of the updated GPA index involving the N stage; hence, the original GPA index was verified equally, which showed that the original GPA could significantly identify the prognosis of NSCLC patients with BM, especially for selecting patients with the best or worst prognoses (Class A and Class D). However, it failed to stratify the difference between the 3 KPSm Karnofsky performance status; 4 size of BM, median diameter of the largest brain metastasis; 5 GPA, graded prognostic assessment; 6 Symptomatic treatment, reducing intracranial pressure treatment: Mannitol 125mg/time, twice every day, intravenous drip; 7 Conventional therapy, systemic chemotherapy plus local treatment; 8 TKIs therapy, first generation of tyrosine kinase inhibitors (TKIs): gefitinib or erlotinib.…”

“…Unfortunately, the median overall survival remains poor, at only eight months (3,4). Recently, the advent of targeted therapy and immunotherapy revolutionarily improve the survival of these patients depending on their molecular type and clinical characteristics (5)(6)(7). Therefore, it is vital to identify the factors affecting the prognosis of NSCLC.…”

Treatment Sequencing for Anaplastic Lymphoma Kinase-Rearranged Non-Small-Cell Lung Cancer

“…The third-generation ALK TKI lorlatinib was specifically designed to penetrate the blood-brain barrier and was proven to result in relevant drug concentrations in the cerebrospinal fluid [ 53 ]. Bauer et al reported the results regarding the intracranial activity of lorlatinib from the ongoing phase II trial discussed above [ 54 , 69 ]. 198 patients were evaluable, 59 only received previous crizotinib treatment and 139 received at least one second-generation TKI.…”

“…198 patients were evaluable, 59 only received previous crizotinib treatment and 139 received at least one second-generation TKI. The CIR of non-CNS-progression was consistently higher compared to the CIR of CNS-progression, indicating a potent and durable intracranial activity of lorlatinib in heavily pre-treated patients [ 69 ].…”

The Unique Pharmacometrics of Small Molecule Therapeutic Drug Tracer Imaging for Clinical Oncology

“…Biodistribution might identify compartments of poor drug penetration. PET isotopologues have been used to quantify the blood–brain barrier penetration of small molecule drugs in early-phase development [ 35 , 37 , 40 ], thereby predicting efficacy against brain metastases and encouraging further testing [ 34 ]. Clinical research with a temozolomide drug tracer, when temozolomide was an investigational therapeutic, demonstrated drug uptake in glioma brain tumors with scant drug retention by normal brain, predicting a favorable therapeutic index [ 17 ].…”