Clrm-11 alk tyrosine kinase inhibitor therapy and brain metastases in non-small cell lung cancer: impact on tumor size and distribution

Abstract Non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase rearrangement (ALK+) is known to have a high propensity to form brain metastases (BrM), with over 50% of ALK+ lung cancer patients developing BrM despite effective ALK tyrosine kinase inhibitor (TKI) therapy with central nervous system (CNS) activity. Pharmacokinetic (PK) data from other CNS-active lung cancer TKIs have suggested that there may be differences in drug concentration between white and gray matter in the brain, which may play a role in BrM formation patterns and response. In this study, we aimed to compare the size and distribution of ALK+ NSCLC BrMs at diagnosis in a TKI-naïve and TKI-exposed cohort. Brain MRI data from patients with ALK+ NSCLC were retrospectively reviewed, and each tumor was marked in a standard space brain model using 3D Slicer-4.11. FreeSurfer white-gray matter atlases were used to assess BrM distribution. We found that TKI-exposed patients had significantly smaller BrM diameters than TKI-naïve patients (6.1±3.8 vs. 10.2±5.5mm, p=0.02) and were more likely to have white matter-exclusive (3.5±4.4 vs. 1.4±2.0, p=0.05) and deep white matter metastases (3.2±4.3 vs. 1.3±2.0, p=0.06). The metastatic burden was similar between the groups, while the mean number of BrM per patient was numerically higher in the TKI-exposed group (10.6±11.9 vs. 6.2±9.5; p=0.22). These findings suggest that TKI therapy may result in smaller individual lesions that are more likely to be exclusive to the white matter, where drug concentrations may be significantly lower. This suboptimal CNS distribution of TKIs in the white matter may contribute to the progression of brain metastases in ALK+ patients despite TKI therapy. Further analyses are ongoing to evaluate ALK TKIs of varying CNS penetrance and later disease time points in more granular anatomic regions.