Brain Metastases from NSCLC: Radiation Therapy in the Era of Targeted Therapies

Abstract

Brain metastases (BMs) will develop in a large proportion of patients with NSCLC throughout the course of their disease. Among patients with NSCLC with oncogenic drivers, mainly EGFR activating mutations and anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangements, the presence of BM is a common secondary localization of disease both at the time of diagnosis and at relapse. Because of the limited penetration of a wide range of drugs across the blood-brain barrier, radiotherapy is considered the cornerstone of treatment of BMs. However, evidence of dramatic intracranial response rates has been reported in recent years with targeted therapies such as tyrosine kinase inhibitors and has been supported by new insights into pharmacokinetics to increase rates of tyrosine kinase inhibitors' penetration of the cerebrospinal fluid (CSF). In this context, the combination of brain radiotherapy and targeted therapies seems relevant, and there is a strong radiobiological rationale to harness the radiosentizing effect of the drugs. Nevertheless, to date, there is a paucity of high-level clinical evidence supporting the combination of brain radiotherapy and targeted therapies in patients with NSCLC and BMs, and there are often methodological biases in reported studies, such as the lack of stratification by mutation status. Moreover, among asymptomatic patients not suitable for ablative treatment, this strategy is challenged by the promising results associated with the administration of targeted therapies alone. Herein, we review the biological rationale to combine targeted therapies and brain radiotherapy for patients with NSCLC and BMs, report the clinical data available to date, and discuss future directions to improve outcome in this group of patients.

Detection of ROS1 rearrangement in non-small cell lung cancer: current and future perspectives

“…As seen for the mentioned oncogene-addicted NSCLC, mutations occurring in ROS1 kinase domains preclude crizotinib activity. Since their first report,56 a few of them have been reported to be clinically meaningful 57. Given the homology in their respective kinase domains, ALK and ROS1 share a spectrum of active inhibitors beyond crizotinib (e.g., ceritinib, lorlatinib, entrectinib), developed in order to overcome the resistance to the first-generation molecule.…”

Efficacy of EGFR‐TKIs with or without upfront brain radiotherapy for EGFR‐mutant NSCLC patients with central nervous system metastases

“…26,27 Moreover, WBRT or focal RT can cause early and delayed blood brain barrier disruption, which presumably leads to an increase in TKI permeability. 28 In addition, EGFR-TKIs could enhance the radiation response at several levels, including cell cycle arrest, apoptosis induction, accelerated cellular repopulation, and DNA damage repair. 29 Based on these biological rationales, radiation and EGFR-TKI are expected to provide good combinational therapy.…”

Current progress and outcomes of clinical trials on using epidermal growth factor receptor‐tyrosine kinase inhibitor therapy in non‐small cell lung cancer patients with brain metastases

“…Currently, the majority of researchers believed that local radiotherapy or WBRT will result in increased permeability of the BBB, 46 , 47 , 48 , 49 and TKIs are known to decrease the resistance of wild-type EGFR NSCLC cells to radiotherapy and increase the sensitivity of EGFR -mutant cells to radiotherapy. 50 Gow et al 51 conducted a study on 63 lung adenocarcinoma patients with brain metastases who had undergone WBRT and found that EGFR mutations [odds ratio ( OR) = 4.46, P = 0.029] and use of TKIs ( OR = 3.8, P = 0.034) are independent factors affecting WBRT response rates, which were higher in patients with EGFR mutations than those with wild-type EGFR (54% vs. 24%, P = 0.045). Patients who simultaneously used EGFR-TKI had a higher WBRT response rates than those who did not (67% vs. 39%, P = 0.038).…”