Preclinical evaluation of targeted therapies for central nervous system metastases

Sep 21, 2026

Uploaded by Rowan

The central nervous system (CNS) can act as a sanctuary for metastatic tumors because many systemic treatments fail to penetrate intracranial lesions. Non-small cell lung cancer (NSCLC) frequently spreads to the brain, leaving substantial variability in outcomes across patients. Targeted therapies, including tyrosine kinase inhibitors, differ in CNS control due to pharmacokinetic properties such as blood–brain barrier permeability, efflux transporter interactions, and binding in plasma and brain tissue. This Review synthesizes preclinical evidence linking NSCLC-targeted therapy penetration with clinical efficacy, highlighting FDA-approved and in-development approaches.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Introduction

Clinical context of brain metastases in cancer patients

NSCLC frequency, prognosis, and treatment complexity

Local and systemic treatment approaches for CNS metastases

© 2024 . Published by The Company of Biologists Ltd | Disease Models & Mechanisms (2024) 17, dmm050836 . doi:10 . 1242/dmm.050836 REVIEW Preclinical evaluation of targeted therapies for central nervous system metastases Alexander J. Pfeil1,2, Joshua D. Hale2, Tiger S. Zhang2, Kentaro Wakayama3, Isao Miyazaki3, Igor Odintsov4 and Romel Somwar1,5,* ABSTRACT | The central nervous system (CNS) represents a site of sanctuary for many metastatic tumors when systemic therapies that control the primary tumor cannot effectively penetrate intracranial lesions. Nonsmall cell lung cancers (NSCLCs) are the most likely of all neoplasms to metastasize to the brain, with up to 60% of patients developing CNS metastases during the disease process. Targeted therapies such as tyrosine kinase inhibitors (TKIs) have helped reduce lung cancer mortality but vary considerably in their capacity to control CNS metastases. The ability of these therapies to effectively target lesions in the CNS depends on several of their pharmacokinetic properties, including blood–brain barrier permeability, affinity for efflux transporters, and binding affinity for both plasma and brain tissue. Despite the existence of numerous preclinical models with which to characterize these properties, many targeted therapies have not been rigorously tested for CNS penetration during the discovery process, whereas some made it through preclinical testing despite poor brain penetration kinetics. Several TKIs have now been engineered with the characteristics of CNS-penetrant drugs, with clinical trials proving these efforts fruitful. This Review outlines the extent and variability of preclinical evidence for the efficacy of NSCLC-targeted therapies, which have been approved by the US Food and Drug Administration (FDA) or are in development, for treating CNS metastases, and how these data correlate with clinical outcomes.
KEY WORDS: Targeted therapy, Non-small cell lung cancer, Central nervous system metastasis, Blood–brain barrier | | --- | | Introduction
Metastatic brain tumors are a significant cause of morbidity and mortality for patients with cancer. Patients with solid tumors have an estimated 10-40% chance of developing metastasis to the brain during the disease course, although the incidence of brain metastases varies greatly among different tumor types (Aizer et al., 2022) . For patients presenting with brain metastases at the time of diagnosis of their primary malignancy, prognosis and treatment will | 1Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. 2University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA. 3Taiho Pharmaceutical Co. Ltd. 3, Okubo, Tsukuba, Ibaraki 300-2611, Japan. 4Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 021105, USA. 5Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. *Author for correspondence ([somwarr@mskcc.org](somwarr@mskcc.org)) A.J. P. , 0000-0002-5159-019X; J. D. H. , 0009-0001-2683-6477; T.S.Z. , 0000- 0002-6669-8814; I. O. , 0000-0001-8073-8803; R.S. , 0000-0002-5282-6889 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0](https://creativecommons.org/licenses/by/4.0)), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. depend on the primary tumor type, performance status, disease extent and tumor-specific factors. Most of these patients will have a median overall survival (OS; see Glossary, Box 1) time of between 3 and 16 months (Lamba et al., 2021) . Primary neoplasms that have the highest propensity to spread to the central nervous system (CNS) are lung, breast, melanoma, renal cell and colorectal cancers (Lamba et al., 2021; Sacks and Rahman, 2020) . Lun

FAQs

Why do central nervous system metastases resist many systemic therapies?

The CNS provides a sanctuary site because systemic drugs often cannot effectively penetrate intracranial lesions. This limits treatment impact on brain metastases.

How do targeted therapies’ properties influence CNS efficacy?

Their ability to target CNS lesions depends on pharmacokinetic features such as blood–brain barrier permeability, interactions with efflux transporters, and binding affinity in plasma and brain tissue.

What treatment approaches are commonly used for NSCLC patients with brain metastases?

Care often combines local therapy (surgery and/or radiation) with systemic therapy. For impending herniation or solitary large lesions, neurosurgery or stereotactic radiosurgery (SRS) can be effective; for multiple lesions, whole-brain radiation therapy (WBRT) or SRS is considered.

Sep 21, 2026

Uploaded by Rowan