Emerging therapeutics and evolving assessment criteria for intracranial metastases in patients with oncogene-driven non-small-cell lung cancer

Abstract

The improved survival outcomes of patients with non-small-cell lung cancer (NSCLC), largely owing to the improved control of systemic disease provided by immune-checkpoint inhibitors and novel targeted therapies, have highlighted the challenges posed by central nervous system (CNS) metastases as a devastating yet common complication, with up to 50% of patients developing such lesions during the course of the disease. Early-generation tyrosine-kinase inhibitors (TKIs) often provide robust systemic disease control in patients with oncogene-driven NSCLCs, although these agents are usually unable to accumulate to therapeutically relevant concentrations in the CNS owing to an inability to cross the blood-brain barrier. However, the past few years have seen a paradigm shift with the emergence of several novel or later-generation TKIs with improved CNS penetrance. Such agents have promising levels of activity against brain metastases, as demonstrated by data from preclinical and clinical studies. In this Review, we describe current preclinical and clinical evidence of the intracranial activity of TKIs targeting various oncogenic drivers in patients with NSCLC, with a focus on newer agents with enhanced CNS penetration, leptomeningeal disease and the need for intrathecal treatment options. We also discuss evolving assessment criteria and regulatory considerations for future clinical investigations.

Figure 1.. Schematic illustration of the (A) blood–brain barrier and (B) the blood–tumour barrier.

(A) The BBB consists of endothelial cells lining cerebral capillaries that are connected by tight junctions and interact with astrocytes, pericytes and microganglia. Transport proteins on the endothelial cells enable the selective transport of various substrates. Active transport takes place by efflux via transporters such as P-glycoprotein. (B) In the case of brain metastases, the protective BBB becomes disrupted and transforms into a blood–tumour barrier (BTB) with increased permeability due to a modified basement membrane and loss of tight junctions (as a result of tumor-secreted VEGF and angiopoietin-2). Pericytes and astrocytes are often also lost, and transcytosis components are downregulated

Figure 2.. MRI brain images (axial view, T1 sequence, post-contrast) demonstrating

(A) diffuse LMD with enhancement within the cerebral sulci (B) normal brain without metastases or LMD

Figure 3.. Intrathecal chemotherapy can be delivered through two different methods

A) Direct injection into the CSF in the lower lumbar spinal column or B) Injection into an Ommaya reservoir (intraventricular implant that is surgically placed beneath the scalp)