Distinct size and spatial distribution patterns of ALK-inhibitor-naïve versus ALK-inhibitor exposed ALK-positive NSCLC brain metastases.

Background and purpose: Non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase rearrangement (ALK+) has a high affinity to form brain metastases (BMs). The cumulative incidence of BMs 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 have raised the possibility of a PK-driven effect on BMs formation and response. This study aims to compare the size and distribution of ALK + NSCLC BMs at diagnosis in a TKI-naïve and TKI-exposed cohort.

Methods: We retrospectively reviewed brain MRIs from the date of initial BMs detection for patients diagnosed with ALK + NSCLC at Johns Hopkins between 2007 and 2022. 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. The data for patients who were TKI-naïve, had current or prior treatment with crizotinib, or had current or prior treatment with second-generation TKIs at the time of BMs diagnosis were then analyzed separately to compare the size and localization of BMs between the groups.

Results: 405 BMs were identified in 48 patients, of which 30 patients TKI-naïve, 11 were crizotinib-treated, and 7 were second-generation TKI-treated. TKI-naïve BMs were significantly larger in diameter than both crizotinib-treated and second-generation TKI-treated BMs (mean diameter 8.78 ± 6.0 mm vs. 6.0 ± 7.2 mm, p < 0.001, and 5.6 ± 3.2 mm, p = 0.003, respectively). Patients in the crizotinib-treated group also had significantly more BMs exclusively in the white matter compared to the other two groups (OR = 1.9 [CI 95%: 1.17-2.99], p = 0.008 and 3.3 [CI 95% 1.52-7.25], p = 0.002, respectively).

Conclusion: Our data highlight differences in size and distribution among TKI-naïve, crizotinib-treated, and second-generation TKI-treated BMs in ALK + NSCLC. These findings suggest that suboptimal drug CNS distribution in the white matter may underlie brain progression of ALK + NSCLC despite TKI therapy and raise the possibility of a spatially-mediated resistance mechanism.