Brain Metastases in Lung Cancers with Emerging Targetable Fusion Drivers

Abstract

The management of non-small cell lung cancer (NSCLC) has transformed with the discovery of therapeutically tractable oncogenic drivers. In addition to activating driver mutations, gene fusions or rearrangements form a unique sub-class, with anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) targeted agents approved as the standard of care in the first-line setting for advanced disease. There are a number of emerging fusion drivers, however, including neurotrophin kinase (NTRK), rearrangement during transfection (RET), and neuregulin 1 (NRG1) for which there are evolving high-impact systemic treatment options. Brain metastases are highly prevalent in NSCLC patients, with molecularly selected populations such as epidermal growth factor receptor (EGFR) mutant and ALK-rearranged tumors particularly brain tropic. Accordingly, there exists a substantial body of research pertaining to the understanding of brain metastases in such populations. Little is known, however, on the molecular mechanisms of brain metastases in those with other targetable fusion drivers in NSCLC. This review encompasses key areas including the biological underpinnings of brain metastases in fusion-driven lung cancers, the intracranial efficacy of novel systemic therapies, and future directions required to optimize the control and prevention of brain metastases.

Prognostic impacts of extracranial metastasis on non‐small cell lung cancer with brain metastasis: A retrospective study based on surveillance, epidemiology, and end results database

“…Similarly, a previous study based on SEER database demonstrated that more than half of patients showed bone metastasis within metastatic NSCLC patients 27 . Remarkably, we found that different subtypes showed difference among diverse ECM sites, which is probably because different subtypes have different genetic variation propensities, such as EGFR, ALK, and MET were seen more mutated in AD, while FGFR1 and FGFR3 mutation were more frequent in SCC 28–32 . Indeed, different mutational profiles being prone to distinctive metastatic patterns in lung cancer have been elucidated.…”

Diagnostics, therapeutics and RET inhibitor resistance for RET fusion–positive non-small cell lung cancers and future perspectives

“…Future clinical trials of the existing selective drugs should aim to differentiate histologies, earlier testing and initiation of treatment during the disease course might increase the number of eligible patients [95]. Moreover, as discussed in the previous section, further clinical trials of drugs, registries and collaborative studies are encouraged to study the efficacy of combinations of RET inhibitors with other targeted agents are advocated to include baseline and serial brain imaging in patients to characterize baseline intracranial disease, response to therapy, and patterns of disease progression [52,96]. We are on the threshold of a new era in targeting RET fusion-positive NSCLCs.…”

Comparative Efficacy and Safety of Lorlatinib and Alectinib for ALK-Rearrangement Positive Advanced Non-Small Cell Lung Cancer in Asian and Non-Asian Patients: A Systematic Review and Network Meta-Analysis

“…Lung cancer is associated with a high rate of central nervous system (CNS) metastases [15][16][17]. ALK rearrangement-positive (ALK-p) NSCLC has been reported to exhibit a high frequency of CNS metastases, which is associated with worse prognosis and reduced quality of life (QOL) [17,18].…”

“…A remarkable feature of lorlatinib is that it is designed to cross the blood-brain barrier. This makes it highly effective for the treatment of ALK-p advanced NSCLCs, even those with CNS metastases [16,[28][29][30]. Several in vivo studies have reported that lorlatinib reduces the size of NSCLC brain metastases in mouse models in a concentration-dependent manner [31,32].…”

“…A remarkable feature of lorlatinib is that it is designed to cross the blood-brain barrier. This makes it highly effective for the treatment of ALK-p advanced NSCLCs, even those with CNS metastases [16,[28][29][30]. Several in vivo studies have Figure 1.…”