Abstract 4483: Distinct spatial distribution patterns of ALK-inhibitor naïve versus ALK-inhibitor treated ALK-positive NSCLC brain metastases
Authors: Cheunkarndee Tia , Ganem Paola , Marrone Kristen A. , Murray Joseph C. , Feliciano Josephine L. , Hann Christine L. , Scott Susan C. , Ettinger David , Anagnostou Valsamo , Forde Patrick M. , Brahmer Julie R. , Levy Benjamin P. , Lam Vincent , Kamson David O. 
Published: April 2023

Abstract
Background: Non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase rearrangement (ALK+) has a high affinity to form brain metastases (BrM). The cumulative incidence of BrMs in ALK+ lung cancer is over 50%, despite highly effective ALK tyrosine kinase inhibitors (TKIs) with CNS activity. Pharmacokinetic (PK) data from other CNS-active lung cancer TKIs (e.g., osimertinib) have revealed major brain white vs. gray matter drug concentration differences, raising the possibility of a PK-driven effect on BrM formation and response. This study aims to compare the size and distribution of ALK+ NSCLC BrMs at diagnosis in a TKI-naïve and TKI-exposed cohort.
Methods: We retrospectively reviewed brain MRIs from the date of BrM diagnosis for patients with ALK+ NSCLC at Johns Hopkins. Demographic and clinical information were collected by chart review. Each tumor was marked in a standard space brain model in the corresponding anatomic location represented by a sphere of corresponding diameter using 3D Slicer 4.11. FreeSurfer white-gray matter atlases were used to assess BrM distribution. The data for patients who were on TKI vs TKI-naïve at the time of BrM diagnosis were then analyzed separately. T-tests were used to compare the metastatic burden (sum of BrM diameters), mean BrM diameter per patient, number of BM per patient, per individual mean of white matter exclusive (defined as no overlap with gray matter) and deep white matter (≥5mm away from gray matter) BrMs between patient groups.
Results: 429 BrMs were identified in 39 patients, with 25 patients being TKI-naïve at the time of BrM diagnosis while 14 patients were on TKI therapy. TKI-exposed patients had significantly smaller BrM diameters than those in the TKI-naïve group (6.1±3.8 vs 10.2±5.5mm, p=0.02). While metastatic burden was very similar between the groups, 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). Notably, patients in the TKI-exposed group also had higher numbers of 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) than those who were TKI-naïve.
Conclusion: Our data highlight the differences in BrM characteristics among ALK+ NSCLC exposed to ALK TKI. TKI therapy was associated with similar BrM burden but smaller individual lesions that were more likely to be exclusive to the white matter where drug concentrations might be significantly lower. These findings suggest that suboptimal drug CNS distribution in the white matter may underly brain progression of ALK+ NSCLC despite TKI therapy. Spatial analyses evaluating ALK TKIs of varying CNS penetrance and later disease time points in more granular anatomic regions are ongoing.
Citation Format: Tia Cheunkarndee, Paola Ganem, Kristen A. Marrone, Joseph C. Murray, Josephine L. Feliciano, Christine L. Hann, Susan C. Scott, David Ettinger, Valsamo Anagnostou, Patrick M. Forde, Julie R. Brahmer, Benjamin P. Levy, Vincent Lam, David O. Kamson. Distinct spatial distribution patterns of ALK-inhibitor naïve versus ALK-inhibitor treated ALK-positive NSCLC brain metastases. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4483.