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Background and purpose <p>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.</p> Methods <p>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.</p> Results <p>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&#xa0;mm vs. 6.0 ± 7.2&#xa0;mm, <i>p</i> &lt; 0.001, and 5.6 ± 3.2&#xa0;mm, <i>p</i> = 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], <i>p</i> = 0.008 and 3.3 [CI 95% 1.52–7.25], <i>p</i> = 0.002, respectively).</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年7月16日

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  • Tia Cheunkarndee,
  • Zsombor Ritter,
  • Max Saint-Germain,
  • Paola Ghanem,
  • Kristen A. Marrone,
  • Joseph C. Murray,
  • Josephine L. Feliciano,
  • Christine L. Hann,
  • Jordina Rincon Torroella,
  • Solmaz Sahebjam,
  • Susan C. Scott,
  • David S. Ettinger,
  • Valsamo Anagnostou,
  • Patrick M. Forde,
  • Julie R. Brahmer,
  • Benjamin P. Levy,
  • Vincent K. Lam,
  • David O. Kamson

摘要

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.