Med Oncol (2015) 32:3 DOI 10.1007/s12032-014-0477-7
LETTER TO THE EDITOR
Rapid response of brain metastases to alectinib in a patient with non-small-cell lung cancer resistant to crizotinib Hitomi Ajimizu • Young Hak Kim Michiaki Mishima
•
Received: 17 December 2014 / Accepted: 19 December 2014 Ó Springer Science+Business Media New York 2015
Abstract Crizotinib is a potent and specific small-molecule inhibitor of both anaplastic lymphoma kinase (ALK) and c-MET tyrosine kinases, and patients with ALK rearrangement tumor benefit from crizotinib treatment; however, its penetration into calculated cerebrospinal fluid (CSF) is considered to be poor. Alectinib is a highly selective, next-generation ALK inhibitor, and both preclinical and clinical studies have indicated that alectinib is also effective in crizotinib-resistant tumors. A recent in vitro study demonstrated significant antitumor activity of alectinib for brain metastases using mouse models of ALKpositive non-small-cell lung cancer. In this paper, we report a first case alectinib was highly effective against brain metastases refractory to crizotinib. Further investigation of alectinib in this setting would be particularly valuable. Keywords Alectinib Crizotinib EML4-ALK Brain metastases NSCLC
No adjuvant chemotherapy was given due to the patient’s refusal. She then started to receive regular follow-up; however, she developed brain metastases 8 months after surgery (Fig. 1a). The administration of crizotinib, 250 mg twice daily, was initiated based on the results of molecular analysis that demonstrated an echinoderm microtubuleassociated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) rearrangement. Brain CT taken after 4 weeks showed marked response (Fig. 1b) at the cost of diarrhea (grade 1), esophageal pain (grade 1), skin rash (grade 1), and flashing lights (grade 1); however, the tumor size increased a bit after 8 weeks and it was obvious after 12 weeks (Fig. 1c), but there were no neurological symptoms. We therefore abandoned crizotinib and started alectinib, 300 mg twice daily. We initially planned to start radiotherapy if the brain tumors did not decrease in size after 2 weeks, but her brain metastases completely disappeared on a brain CT (Fig. 1d). She is continuing to receive alectinib treatment without any adverse events.
Case presentation Discussion A 47-year-old woman, a never smoker, was referred to Kyoto University Hospital because of an abnormal chest shadow detected at an annual medical checkup. A computed tomography (CT) scan revealed a lung nodule in the right lower lobe and lymph node metastases in the right hilum. She underwent right lower lobe resection and was diagnosed with lung cancer (adenocarcinoma, T2aN2M0).
H. Ajimizu Y. H. Kim (&) M. Mishima Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan e-mail: [email protected]
Maillet et al. [1] reported two cases of non-small-cell lung cancer (NSCLC) with ALK rearrangement in which crizotinib was effective for extracranial disease but ineffective for intracranial metastases. It has been reported that crizotinib penetrates poorly into the blood–brain barrier, and the calculated cerebrospinal fluid (CSF)-to-plasma ratio of crizotinib is only 0.0026 [2]. This poor penetration into CNS makes a brain sanctuary site for metastases in ALKpositive NSCLC patients treated with crizotinib. We previously reported a case of ALK-positive NSCLC in which high-dose crizotinib was effective for brain metastases refractory to standard-dose crizotinib; however, the patient
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Med Oncol (2015) 32:3
Fig. 1 Brain computed tomography a before crizotinib and b after 1 month showed a marked response of brain metastases, but c brain metastases regrew after 3 months of crizotinib. d Alectinib demonstrated rapid and complete response of brain metastases in 2 weeks
developed bradycardia, and the response duration was quite short [3]. Alectinib is a highly selective, next-generation ALK inhibitor. Both preclinical and clinical studies have indicated that alectinib is also effective in crizotinibresistant tumors, and currently, a randomized study comparing alectinib and crizotinib in ALK-positive NSCLC is underway. Recently, Kodama et al. [4] demonstrated significant antitumor activity of alectinib for brain metastases using mouse models of ALK-positive NSCLC. A dosefinding study of alectinib conducted in the United States also showed the effectiveness of alectinib for brain metastases [5]. To our knowledge, however, this is the first case report that demonstrates alectinib is highly effective against brain metastases refractory to crizotinib. Further investigation of alectinib in this setting would be particularly valuable. Acknowledgments
No funding source for this work was provided.
Conflict of interest The authors have no conflict of interest to declare.
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References 1. Maillet D, Martel-Lafay I, Arpin D, et al. Ineffectiveness of crizotinib on brain metastases in two cases of lung adenocarcinoma with EML4-ALK rearrangement. J Thorac Oncol. 2013;8: e30–1. 2. Costa DB, Kobayashi S, Pandya SS, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol. 2011;29:e443–5. 3. Kim YH, Ozasa H, Nagai H, et al. High-dose crizotinib for brain metastases refractory to standard-dose crizotinib. J Thorac Oncol. 2013;8:e85–6. 4. Kodama T, Hasegawa M, Takanashi K, et al. Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases. Cancer Chemother Pharmacol. 2014;74:1023–8. 5. Gadgeel SM, Gandhi L, Riely GJ, et al. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study. Lancet Oncol. 2014;15:1119–28.
LETTER TO THE EDITOR
Rapid response of brain metastases to alectinib in a patient with non-small-cell lung cancer resistant to crizotinib Hitomi Ajimizu • Young Hak Kim Michiaki Mishima
•
Received: 17 December 2014 / Accepted: 19 December 2014 Ó Springer Science+Business Media New York 2015
Abstract Crizotinib is a potent and specific small-molecule inhibitor of both anaplastic lymphoma kinase (ALK) and c-MET tyrosine kinases, and patients with ALK rearrangement tumor benefit from crizotinib treatment; however, its penetration into calculated cerebrospinal fluid (CSF) is considered to be poor. Alectinib is a highly selective, next-generation ALK inhibitor, and both preclinical and clinical studies have indicated that alectinib is also effective in crizotinib-resistant tumors. A recent in vitro study demonstrated significant antitumor activity of alectinib for brain metastases using mouse models of ALKpositive non-small-cell lung cancer. In this paper, we report a first case alectinib was highly effective against brain metastases refractory to crizotinib. Further investigation of alectinib in this setting would be particularly valuable. Keywords Alectinib Crizotinib EML4-ALK Brain metastases NSCLC
No adjuvant chemotherapy was given due to the patient’s refusal. She then started to receive regular follow-up; however, she developed brain metastases 8 months after surgery (Fig. 1a). The administration of crizotinib, 250 mg twice daily, was initiated based on the results of molecular analysis that demonstrated an echinoderm microtubuleassociated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) rearrangement. Brain CT taken after 4 weeks showed marked response (Fig. 1b) at the cost of diarrhea (grade 1), esophageal pain (grade 1), skin rash (grade 1), and flashing lights (grade 1); however, the tumor size increased a bit after 8 weeks and it was obvious after 12 weeks (Fig. 1c), but there were no neurological symptoms. We therefore abandoned crizotinib and started alectinib, 300 mg twice daily. We initially planned to start radiotherapy if the brain tumors did not decrease in size after 2 weeks, but her brain metastases completely disappeared on a brain CT (Fig. 1d). She is continuing to receive alectinib treatment without any adverse events.
Case presentation Discussion A 47-year-old woman, a never smoker, was referred to Kyoto University Hospital because of an abnormal chest shadow detected at an annual medical checkup. A computed tomography (CT) scan revealed a lung nodule in the right lower lobe and lymph node metastases in the right hilum. She underwent right lower lobe resection and was diagnosed with lung cancer (adenocarcinoma, T2aN2M0).
H. Ajimizu Y. H. Kim (&) M. Mishima Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan e-mail: [email protected]
Maillet et al. [1] reported two cases of non-small-cell lung cancer (NSCLC) with ALK rearrangement in which crizotinib was effective for extracranial disease but ineffective for intracranial metastases. It has been reported that crizotinib penetrates poorly into the blood–brain barrier, and the calculated cerebrospinal fluid (CSF)-to-plasma ratio of crizotinib is only 0.0026 [2]. This poor penetration into CNS makes a brain sanctuary site for metastases in ALKpositive NSCLC patients treated with crizotinib. We previously reported a case of ALK-positive NSCLC in which high-dose crizotinib was effective for brain metastases refractory to standard-dose crizotinib; however, the patient
123
3
Page 2 of 2
Med Oncol (2015) 32:3
Fig. 1 Brain computed tomography a before crizotinib and b after 1 month showed a marked response of brain metastases, but c brain metastases regrew after 3 months of crizotinib. d Alectinib demonstrated rapid and complete response of brain metastases in 2 weeks
developed bradycardia, and the response duration was quite short [3]. Alectinib is a highly selective, next-generation ALK inhibitor. Both preclinical and clinical studies have indicated that alectinib is also effective in crizotinibresistant tumors, and currently, a randomized study comparing alectinib and crizotinib in ALK-positive NSCLC is underway. Recently, Kodama et al. [4] demonstrated significant antitumor activity of alectinib for brain metastases using mouse models of ALK-positive NSCLC. A dosefinding study of alectinib conducted in the United States also showed the effectiveness of alectinib for brain metastases [5]. To our knowledge, however, this is the first case report that demonstrates alectinib is highly effective against brain metastases refractory to crizotinib. Further investigation of alectinib in this setting would be particularly valuable. Acknowledgments
No funding source for this work was provided.
Conflict of interest The authors have no conflict of interest to declare.
123
References 1. Maillet D, Martel-Lafay I, Arpin D, et al. Ineffectiveness of crizotinib on brain metastases in two cases of lung adenocarcinoma with EML4-ALK rearrangement. J Thorac Oncol. 2013;8: e30–1. 2. Costa DB, Kobayashi S, Pandya SS, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol. 2011;29:e443–5. 3. Kim YH, Ozasa H, Nagai H, et al. High-dose crizotinib for brain metastases refractory to standard-dose crizotinib. J Thorac Oncol. 2013;8:e85–6. 4. Kodama T, Hasegawa M, Takanashi K, et al. Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases. Cancer Chemother Pharmacol. 2014;74:1023–8. 5. Gadgeel SM, Gandhi L, Riely GJ, et al. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study. Lancet Oncol. 2014;15:1119–28.
