Effective Crizotinib Schedule for Brain Metastases in ALK Rearrangement Metastatic Non–Small-Cell Lung Cancer
Authors: Nir Peled, Leor Zach, Ori Liran, Maya Ilouze, Paul A. Bunn, Fred R. Hirsch
Journal: Journal of Thoracic Oncology (2013)

The echinoderm microtubule–associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) gene fusion occurs in 2% to 7% of non–small-cell lung cancer cases.1Kwak EL Bang YJ Camidge DR et al.Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.N Engl J Med. 2010; 363: 1693-1703Crossref PubMed Scopus (3812) Google Scholar Tumors expressing this fusion respond to treatment with crizotinib, an ALK tyrosine kinase inhibitor. However, brain metastases frequently occur, even in the presence of systemic response to therapy.2Chun SG Choe KS Iyengar P Yordy JS Timmerman RD Isolated central nervous system progression on Crizotinib: an Achilles heel of non-small cell lung cancer with EML4-ALK translocation?.Cancer Biol Ther. 2012; 13: 1376-1383Crossref PubMed Scopus (90) Google Scholar A 45-year-old never-smoker man who was previously reported in this journal,3Peled N Palmer G Hirsch FR et al.Next-generation sequencing identifies and immunohistochemistry confirms a novel crizotinib-sensitive ALK rearrangement in a patient with metastatic non-small-cell lung cancer.J Thorac Oncol. 2012; 7: e14-e16Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar is presented here again for a dramatic response to brain metastases. Previously, he was presented for having abnormality in RNA editing for ALK gene and a complete response to crizotinib 250 mg twice daily therapy. He was diagnosed as harboring EML4-ALK rearrangement through abnormal ALK immunohistochemistry staining and breakpoints in ALK intron 19, detected by next-generation sequence. ALK fluorescence in situ hybridization result was falsely negative. After a follow-up of 20 months, the patient developed asymptomatic milliary spread of brain metastases without any other evidence for active disease and he was treated by whole-brain radiotherapy (WBRT; 30 Gy). Crizotinib was stopped for the radiation period and readministered thereafter in the previous standard schedule of 250 mg twice daily. A follow-up magnetic resonance imaging 3 months later showed lack of response and new brain lesions. Aiming to increase crizotinib brain penetration, we rescheduled crizotinib therapy to a single-day administration of 500 mg every day (morning). Brain magnetic resonance imaging in 2 months showed a dramatic response and elimination of 90% of the brain lesions (Fig. 1). Positron emission tomography computed tomography showed no evidence of active disease elsewhere. Brain metastases are the Achilles' heel of non–small-cell lung cancer with EML4-ALK translocation.2Chun SG Choe KS Iyengar P Yordy JS Timmerman RD Isolated central nervous system progression on Crizotinib: an Achilles heel of non-small cell lung cancer with EML4-ALK translocation?.Cancer Biol Ther. 2012; 13: 1376-1383Crossref PubMed Scopus (90) Google Scholar However, there is growing data supporting a therapeutic benefit of crizotinib also in cases of brain metastases.4Kaneda H Okamoto I Nakagawa K Rapid response of brain metastasis to crizotinib in a patient with ALK rearrangement-positive non-small-cell lung cancer.J Thorac Oncol. 2013; 8: e32-e33Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar In this case report, the brain metastases were developed under crizotinib therapy and have further shown resistance to WBRT, whereas it responded well to a different treatment schedule of crizotinib. Interestingly enough, Kaneda et al. have also shown a response to crizotinib therapy (standard dose) after a resistance to radiation.4Kaneda H Okamoto I Nakagawa K Rapid response of brain metastasis to crizotinib in a patient with ALK rearrangement-positive non-small-cell lung cancer.J Thorac Oncol. 2013; 8: e32-e33Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar Other reports did not show a response to standard dose crizotinib specifically after WBRT.5Kim YH Ozasa H Nagai H et al.High-dose crizotinib for brain metastases refractory to standard-dose crizotinib.J Thorac Oncol. 2013; 8: e85-e86Crossref PubMed Scopus (35) Google Scholar Therefore we hypothesize that the drug penetration might not increase sufficiently on standard crizotinib schedule after WBRT and that increasing in the Cmax, without increasing the daily dose of 500 mg/day could be beneficial. A previous report demonstrated brain response after dose escalation up to 1000 mg/day, however, producing asymptomatic bradycardia of 39 beats per minute.5Kim YH Ozasa H Nagai H et al.High-dose crizotinib for brain metastases refractory to standard-dose crizotinib.J Thorac Oncol. 2013; 8: e85-e86Crossref PubMed Scopus (35) Google Scholar It is important to emphasize that the response might be a late benefit of WBRT and/or related to the increased permeability of the blood–brain barrier to crizotinib secondary to the WBRT. Further studies measuring crizotinib level in the cerebrospinal fluid are required to investigate this effect. In summary, this case report suggests increasing crizotinib schedule to a single administration of the standard daily dose (500 mg/day) for brain metastases may be an option when they have developed under crizotinib therapy, after conventional radiotherapy. This approach would warrant further evaluation, potentially delaying the need for second-generation inhibitors or other new therapies. The authors thank Dr. Shani Shilo for her assistance with this case report.