Effectiveness of ALK inhibitors in treatment of CNS metastases in NSCLC patients

Abstract

Metastases to the central nervous system (CNS) in patients with non-small cell lung cancer constitute an extremely difficult clinical problem, and their occurrence is associated with a poor prognosis. Due to the existence of the blood-brain barrier (BBB) and the action of proteins responsible for the transport of drugs, e.g. P-glycoprotein (P-gp), the penetration of drugs into the CNS is insufficient. Until recently, the only method of CNS metastases treatment was radiotherapy and neurosurgery. The advancement of molecular biology allowed discover targets for molecularly targeted therapies. One of targets is abnormal anaplastic lymphoma kinase, which results from the rearrangement of the ALK gene in patients with non-small cell lung cancer (NSCLC). ALK rearrangement occurs in only about 4.5% of NSCLC patients, but its presence favors brain metastases. The ALK inhibitors (ALKi) were modified to obtain molecules with high ability to penetrate into the CNS. This was achieved by modifying the structure of individual molecules, which became, inter alia, less substrates for P-gp. These modifications caused that less than 10% of patients experience progression in CNS during new ALK inhibitors treatment. This review summarizes the knowledge about the action of BBB, the pharmacodynamics and pharmacokinetics of ALKi, with particular emphasis on their ability to penetrate the CNS and the intracranial activity of individual drugs from different generations of ALK inhibitors.

Evaluation of Immunohistochemical Expression of ALK-1 in Gliomas, WHO Grade 4 and Its Correlation with IDH1-R132H Mutation Status

“…Despite the positive outcomes observed in pre-clinical and in vivo studies conducted on GB when ALK inhibitors were applied, there have been no clinical trials demonstrating a significant impact on the survival of GB patients with the use of ALK inhibitors, likely due to their limited ability to penetrate the blood-brain barrier and the challenges in achieving therapeutic concentrations in the brain [ 8 , 11 ]. However, the second and third-generation ALK inhibitors have exhibited notable effectiveness in treating CNS metastases in ALK-rearranged non-small cell lung cancers (NSCLC), indicating their ability to penetrate the brain effectively [ 10 , 15 ].…”

Clinical and Molecular Traits of a Novel SPECC1L-ALK Fusion in a Patient with Advanced Non-Small Cell Lung Cancer

“…Many ALK-TKIs have been validated since the first EML4-ALK fusion in NSCLC was discovered, and their use in clinical practice has significantly improved PFS and OS in patients with metastatic ALK-positive NSCLC [22]. Nonetheless, there is heterogeneity in the clinical response between various ALK fusion subtypes, as well as ALK fusion variants [23].…”

Sustained Improvement in the Management of Patients with Non-Small-Cell Lung Cancer (NSCLC) Harboring ALK Translocation: Where Are We Running?

“…The new ALK-Is have been modified to obtain molecules with a high ability to penetrate into the central nervous system (CNS). This was achieved by changing the structures of individual molecules, which became substrates for P-gp [45] (Figure 3).…”