Nir Peled, Leor Zach, Ori Liran, Maya Ilouze, Paul A. Bunn Jr, Fred R

Case Report
Effective Crizotinib Schedule for Brain Metastases in ALK
Rearrangement Metastatic Non–Small-Cell Lung Cancer
Nir Peled, MD, PhD,* Leor Zach, MD,† Ori Liran, MSc,* Maya Ilouze, PhD,* Paul A. Bunn Jr., MD,‡
and Fred R. Hirsch, MD, PhD‡
T
he 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.1 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.2
CASE PRESENTATION
A 45-year-old never-smoker man who was previously
reported in this journal,3 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 wholebrain 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 followup 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
*The Thoracic Cancer Research and Detection Center, †The Radiation
Institute, Sheba Medical Center, Tel Aviv University, Tel-Aviv, Israel; and
‡University of Colorado Cancer Center, Division of Medical Oncology,
University of Colorado Denver, Aurora, Colorado.
Disclosure: Dr. Hirsch is a (compensated) consultant (on the advisory board)
for Pfizer and has a research agreement through University of Colorado
with Ventana/Roche. The remaining authors declare no conflict of interest.
Address for correspondence: Nir Peled, MD, PhD, FCCP, Head, The Thoracic
Cancer Research and Detection Center, Sheba Medical Center, Tel Aviv
University, Ramat-Gan 52621, Israel. E-mail: nirp@post.tau.ac.il
Copyright © 2013 by the International Association for the Study of Lung
Cancer
ISSN: 1556-0864/13/0812-e112
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tomography computed tomography showed no evidence of
active disease elsewhere.
DISCUSSION
Brain metastases are the Achilles’ heel of non–small-cell
lung cancer with EML4-ALK translocation.2 However, there
is growing data supporting a therapeutic benefit of crizotinib
also in cases of brain metastases.4 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.4 Other
reports did not show a response to standard dose crizotinib
specifically after WBRT.5 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.5
It is important to emphasize that the response might
be a late benefit of WBRT and/or related to the increased
FIGURE 1. Brain MRIs (axial t1 with contrast images) in
February, May, and July 2013. Brain metastases were diagnosed after 20 months of crizotinib therapy (250 mg twice
daily). Whole-brain radiotherapy (3000 cGy/10fr) was
administered while crizotinib was continued in standard dose
(except for the radiation period). Follow-up MRI (May 2013)
showed lack of response. Then, crizotinib was rescheduled
for 500 mg X1/day, with a dramatic response 2 months later.
MRI, magnetic resonance imaging.
Journal of Thoracic Oncology ® • Volume 8, Number 12, December 2013
Journal of Thoracic Oncology ® • Volume 8, Number 12, December 2013CrizotinibScheduleforBrainMetastasesinALKRearrangementMetastaticNSCLC
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.
ACKNOWLEDGMENT
The authors thank Dr. Shani Shilo for her assistance
with this case report.
REFERENCES
1.Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma
kinase inhibition in non-small-cell lung cancer. N Engl J Med
2010;363:1693–1703.
2.Chun SG, Choe KS, Iyengar P, Yordy JS, Timmerman RD. Isolated central nervous system progression on Crizotinib: an Achilles heel of nonsmall cell lung cancer with EML4-ALK translocation? Cancer Biol Ther
2012;13:1376–1383.
3.Peled 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–e16.
4.Kaneda 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–e33.
5.Kim YH, Ozasa H, Nagai H, et al. High-dose crizotinib for brain
metastases refractory to standard-dose crizotinib. J Thorac Oncol
2013;8:e85–e86.
Copyright © 2013 by the International Association for the Study of Lung Cancer
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