The Incidence of Brain Metastases in Stage IV ROS1-Rearranged Non-Small Cell Lung Cancer and Rate of Central Nervous System Progression on Crizotinib

J Thorac Oncol. 2018 Nov;13(11):1717-1726. doi: 10.1016/j.jtho.2018.07.001. Epub 2018 Jul 5.


Introduction: Central nervous system (CNS) metastases in lung cancer are a frequent cause of morbidity and mortality. There are conflicting data on the incidence of CNS metastases in stage IV ROS1-positive NSCLC and the rate of CNS progression during crizotinib therapy.

Methods: A retrospective review of 579 patients with stage IV NSCLC between June 2008 and December 2017 was performed. Brain metastases and oncogene status (ROS1, ALK receptor tyrosine kinase gene [ALK], EGFR, KRAS, BRAF, and others) were recorded. We measured progression-free survival and time to CNS progression in ROS1-positive and ALK-positive patients who were taking crizotinib.

Results: We identified 33 ROS1-positive and 115 ALK-positive patients with stage IV NSCLC. The incidences of brain metastases for treatment-naive, stage IV ROS1-positive and ALK-positive NSCLC were 36% (12 of 33) and 34% (39 of 115), respectively. There were no statistically significant differences in incidence of brain metastases across ROS1, ALK, EGFR, KRAS, BRAF, or other mutations. Complete survival data were available for 19 ROS1-positive and 83 ALK-positive patients. The median progression-free survival times for ROS1-positive and ALK-positive patients were 11 and 8 months, respectively (p = 0.304). The CNS was the first and sole site of progression in 47% of ROS1-positive (nine of 19) and 33% of ALK-positive (28 of 83) patients, with no statistically significant differences between these groups (p = 0.610).

Conclusions: Brain metastases are common in treatment-naive stage IV ROS1-positive NSCLC, though the incidence does not differ from that in other oncogene cohorts. The CNS is a common first site of progression in ROS1-positive patients who are taking crizotinib. This study reinforces the importance of developing CNS-penetrant tyrosine kinase inhibitors for patients with ROS1-positive NSCLC.

Keywords: Brain metastasis; Crizotinib; Non–small cell lung cancer; ROS1.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / therapeutic use
  • Brain Neoplasms / enzymology
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / pathology
  • Brain Neoplasms / secondary*
  • Carcinoma, Non-Small-Cell Lung / enzymology
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Crizotinib / therapeutic use*
  • Disease Progression
  • Female
  • Gene Rearrangement
  • Humans
  • Incidence
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology*
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Protein-Tyrosine Kinases / genetics*
  • Proto-Oncogene Proteins / genetics*
  • Retrospective Studies
  • Young Adult


  • Antineoplastic Agents
  • Proto-Oncogene Proteins
  • Crizotinib
  • Protein-Tyrosine Kinases
  • ROS1 protein, human