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: [email protected] 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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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: [email protected] Copyright © 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/13/0812-e112
e112
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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