CNS Metastasis: A Common Site of Progression in ALK+ NSCLC1

Many patients with ALK+ NSCLC will progress in the CNS2,3

  • In up to 46% of ALK+ NSCLC patients, the CNS is the first site of progression while receiving an ALK-directed therapy3
  • Smaller aggregates of metastatic tumor cells, or "micrometastases," are able to cross the blood-brain barrier with minimal disruption, allowing them to continue to grow and reach a clinically significant size4
  • Since conventional scans can only detect lesions that have reached a size within specific resolution capacity, micrometastases may go undetected5

The blood-brain barrier removes small molecules from the CNS through efflux activity4

  • The blood-brain barrier forms a CNS sanctuary for metastatic disease4
  • The blood-barrier is reinforced by P-gp, a drug-efflux-transporter protein, which actively removes a broad range of P-gp substrates from the endothelial cell cytoplasm before they cross into the CNS4

Certain transporter proteins may prevent small molecules from crossing the blood-brain barrier6,7

ALK blood-brain barrier diagram showing transporter proteins

Reprinted from NeuroRx, Vol 2/edition 1, Löscher W, Potschka H, Blood-brain barrier active efflux transporters: ATP-binding cassette gene family, 86-98, Copyright 2005, with permission from Elsevier.

Significant morbidity is associated with CNS metastasis8

  • Significant neurological signs and symptoms related to the location and extent of brain involvement occur in most patients

ALK=anaplastic lymphoma kinase; BCRP=breast cancer resistance protein; CNS=central nervous system; MRP=multidrug resistance protein; NSCLC=non-small cell lung cancer; P-gp=p-glycoprotein.


  1. Otterson GA, Riely GJ, Shaw AT, et al. Clinical characteristics of ALK+ NSCLC patients (pts) treated with crizotinib beyond disease progression (PD): potential implications for management [abstract]. J Clin Oncol. 2012;30(suppl). Abstract 7600.
  2. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med. 2012;4:120ra17. doi:10.1126/scitranslmed.3003316. PMID: 22277784
  3. Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol. 2012;7:1807-1814. PMID: 23154552
  4. Deeken JF, Löscher W. The blood-brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res. 2007;13:1663-1674. PMID: 17363519
  5. Silvestri GA, Gould MK, Margolis ML, et al. Noninvasive staging of non-small cell lung cancer: AACP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132(suppl 3):178S-201S. PMID: 17873168
  6. Löscher W, Potschka H. Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx. 2005;2:86-98. PMID: 15717060
  7. Schinkel AH, Jonker JW. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv Drug Deliv Rev. 2003;55:3-29. PMID: 12535572
  8. Chi A, Komaki R. Treatment of brain metastasis from lung cancer. Cancers (Basel). 2010;2:2100-2137. PMID: 24281220