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Alectinib Induces a Durable (>15 Months) Complete Response in an ALK-Positive Non-Small Cell Lung Cancer Patient Who Progressed on Crizotinib With Diffuse Leptomeningeal Carcinomatosis

Alectinib Induces a Durable (>15 Months) Complete Response in an ALK-Positive Non-Small Cell Lung... Downloaded from https://academic.oup.com/oncolo/article/20/2/224/6399029 by DeepDyve user on 01 February 2022 Brief Communications Station, NJ, http://www.merck.com) 6 mg three times a day with Alectinib Induces a Durable (>15 Months) resolution of her symptoms while crizotinib was continued. Complete Response in an ALK-Positive She was urgently referred to a phase I/II trial of alectinib (RO5424802/CH5424802) (AF-002JG, NCT01588028), a second- Non-Small Cell Lung Cancer Patient Who generation ALK inhibitor, for crizotinib-resistant patients but ProgressedonCrizotinibWithDiffuse was ineligible due to lack of measurable disease by repeated Leptomeningeal Carcinomatosis computed tomography (CT) scan of the chest, abdomen, and pelvis and steroid dependency. The AF-002JG protocol requires patient to be free of neurological symptoms while Introduction off steroids for at least 14 days prior to enrollment. She could Crizotinib, a multitargeted anaplastic lymphoma kinase (ALK) not receive more cranial radiation because of previous whole- inhibitor, has demonstrated significantly improved progression- brain radiation. With permission from F. Hoffmann-La Roche free survival over chemotherapy in patients with advanced ALK- and approval by the U.S. Food and Drug Administration and rearranged non-small cell lung cancer (NSCLC) [1, 2]. However, the institutional review board (IRB) of the University of prolonged survival also seems to lead to eventual relapse in the California Irvine (UCI) Medical Center, she received alectinib sanctuary sites,presentingasleptomeningealcarcinomatosisor 600 mg orally twice daily under an emergency (bypassing the intramedullary metastasis, both of which have extremely poor mandatory 30-day waiting period) single-patient investigational prognoses [3]. In this paper, we described one patient who new drug (IND) application in early August 2013 after signing developed diffuse leptomeningeal carcinomatosis as the only an informed consent approved by the UCI IRB. Crizotinib was “site”ofprogressionafteraprolongedresponsetocrizotiniband discontinued the day before initiation of alectinib. Pre- who is being treated successfully with a second-generation ALK treatment lumbar puncture on the same day before starting inhibitor alectinib (CH5424802/RO5424802; F. Hoffmann-La alectinib demonstrated increased monocytes, and the cere- Roche AG, Basel, Switzerland, http://www.roche.com) alone. bral spinal fluid (CSF) cytology was positive for malignant That treatment has been ongoing for.15 months. adenocarcinoma (Fig. 1). However, tumor material was insuf- Case Presentation ficient to perform immunohistochemistry for ALK, fluorescence The patient is a 29-year-old Persian never-smoker woman who in situ hybridization for ALK break-apart analysis, or reverse was diagnosed with stage IIIA NSCLC at age 22. She received transcription polymerase chain reaction to detect potential curative surgical resection and adjuvant cisplatin and Navelbine acquired resistant ALK mutations. Pretreatment MRI also (GlaxoSmithKline, Research Triangle Park, NC, http://www.gsk. revealed diffuse enhancement of the meninges (Fig. 2A, 2C). com) chemotherapy. She remained free of disease for the next 3 By the time of alectinib initiation, the patient had years but then developed malignant pleural effusion and spinal experienced significant side effects from the high dose of metastasis. She received thoracic spine radiation and completed steroids, including oral thrush and vaginal candidiasis, despite six cycles of carboplatin, paclitaxel, and bevacizumab chemo- oral fluconazole treatment; weight gain; truncal obesity; fluid therapy with partial response.Three months later she was found retention; and insomnia. She was able to taper off Decadron to have at least 10 small brain lesions and received whole-brain after 10 days on alectinib. A lumbar puncture 14 days after radiation. Her tumor tested positive for rearrangement of the startingalectinib revealed significantlydecreased but persistent anaplastic lymphoma kinase (ALK) gene, and she was enrolled malignant cells. Her dysarthria symptoms returned briefly while into the randomized phase III trial comparing docetaxel and off steroids; the dose of alectinib was increased to 750 mg twice pemetrexed with crizotinib (PROFILE1007, NCT00932893). She daily, and steroids at 2 mg twice daily were reinitiated. Her was randomized to the chemotherapy arm (docetaxel) and leptomeningeal carcinomatosis symptoms resolved and never achieved stable disease after four cycles of docetaxel, which was recurred. A repeated lumbar puncture 4 weeks after initiation stopped because of patient intolerance. Six months later she of alectinib revealed clearance of malignant cells. A 6-week relapsed with osseous metastasis including the pelvis and follow-up MRI of the brain and entire spine showed resolu- received radiation to the pelvis. She then crossed over to tion of the meningeal enhancement (Fig. 2B, 2D). The patient crizotinib 250 mg twice daily in November 2011, and crizotinib was eventually weaned off all steroids within 2 months of was reduced to 200 mg twice daily after 2 months because of alectinib and has remained asymptomatic ongoing for .15 neutropenia. She achieved a complete response systematically. months. A repeated CTscan of the chest, abdomen, and pelvis Eighteen months into her crizotinib treatment she developed in November 2014 revealed continual systemic control with transient double vision, but magnetic resonance imaging no evidence of visceral disease and stable bone metastasis. (MRI) performed at that time did not reveal any abnormality. Approximately 1 month later she developed right hand Discussion paresthesia, right facial numbness, and dysarthria and, with Alectinib is a second-generation ALK inhibitor that has demon- repeated MRI, was found to have leptomeningeal carcinoma- strated clinical activity against brainmetastasis inpatientswith tosis diffusely involving the cerebellum and cervical spinal cord. ALK-rearranged NSCLC who were ALK inhibitor na¨ ıve [4] or She was started on Decadron (Merck & Co., Inc., Whitehouse resistant to crizotinib [5]. From the report of the dose-finding The Oncologist 2015;20:224–226 www.TheOncologist.com ©AlphaMed Press 2015 Downloaded from https://academic.oup.com/oncolo/article/20/2/224/6399029 by DeepDyve user on 01 February 2022 Ou, Sommers, Azada et al. 225 alectinib in the CSF and in the serum, with a ratio of ∼0.75 indicating a very high degree of penetration of alectinib into the CNS [5]. Consequently, when the rapid steroid taper within 2 weeks of initiating alectinib treatment did not completely eliminate the leptomeningeal carcinomatosis symptoms of our patient, we increased the dose of alectinib to 750 mg twice daily and restarted steroid treatment, followed by a prolonged but successfulsteroidtaper(2months).Indeed,750mgtwicedailywas welltoleratedbythepatientwithoutanylaboratoryabnormalities, in concordance with the phase I results of the U.S. alectinib trial. However, given the potentially higher level of alectinib that is achievable in the CSF with a 750-mg twice-dailydose,the excellent leptomeningeal carcinomatosis control with alectinib in our patient may not be translatable at the 600-mg twice-daily dose, although a recent publication after submission of this case report Figure 1. Malignant cells in the cerebral spinal fluid before showed that alectinib at 600 mg twice daily also had significant alectinib treatment. activity against leptomeningeal carcinomatosis in ALK-positive NSCLC patients who failed crizotinib and ceritinib [6]. Given that the patient is not on protocol treatment, no paired alectinib plasma/CSF ratio was determined. Crizotinib has been shown to achieve a very low CSF/plasma level based on one case report of a patient with ALK rearrange- ment whoalsoprogressed oncrizotinibwithisolatedleptomen- ingeal carinomatosis [7]. Progression in the central nervous system (CNS) is a leading cause of crizotinib failure [8]. Several approaches have been tried to treat leptomeningeal carcinoma- tosisinpatientswith ALK-rearranged NSCLC. Ahn and colleagues havecombined crizotinib and intrathecal(IT)methotrexate(MTX) in treating two crizotinib-na¨ ıve patients with ALK-rearranged NSCLC [9]. Both patients were able to receive IT MTX for 5 months before one had symptomatic deterioration and the other developed necrotizing leukoencephalopathy from IT MTX [9]. Ceritinib, a second-generation ALK inhibitor, had been shown to be effective under compassionate use for.5 months at the time ofthe reportinacrizotinib-resistant patientswithALK-rearranged NSCLC who developed carcinomatosis meningitis [10]. Another second-generation ALK inhibitor, AP26113, has also shown consistent CNS activity in crizotinib-resistant ALK-rearranged patients [11], but to date there is no report of single-agent AP26113 activity against leptomeningeal carcinomatosis arising in crizotinib-resistant patients with ALK-rearranged NSCLC. Other strategies that have been used to treat brain metastasis in pa- tients with ALK-rearrangedNSCLC,suchascrizotinibwithhigh- dose systemic chemotherapy [12], once-daily dosing instead of twice daily [13], or high-dose cirizotinib [14], have not been reported in patients with leptomeningeal carcinomatosis. Leptomeningeal carcinomatosis seemed to be a late pre- Figure 2. Images of the cerebellum before and after 6 weeks of sentation of advanced stage IV NSCLC [3, 15]. Overall survival of alectinib treatment, showing resolution of the meningeal enhance- ment. (A, B): Axial magnetic resonance imaging (MRI). (C, D): Coronal NSCLC patients with leptomeningeal carcinomatosis remains MRI images of the cerebellum before and after 6 weeks of alectinib poor. Consequently, leptomeningeal carcinomatosis is usually treatment showing resolution of the meningeal enhancement. an exclusion criterion in the vast majority of NSCLC clinical trials. Even when leptomeningeal carcinomatosis is allowed, as in the portion of the alectinib phase I/II trial conducted in the U.S. (AF- AF-002JGtrial,patientswithleptomeningealcarcinomatosishave 002JG, NCT01588028), an initial objective response rate of 52% in to be asymptomatic off all steroids for at least 2 weeks, and that brain metastasis was observed with alectinib [4]. The recom- is quite difficulty to achieve without any concurrent treatment mended phase II dose for alectinib was determined to be 600 mg because leptomeningeal carcinomatosis is usually diagnosed when patients become symptomatic. Furthermore, leptomenin- orally twice daily, although there was no significant difference in the serum pharmacokinectics of alectinib at 600 mg or 750 mg geal carcinomatosis is considered nonmeasurable by Response twice daily [5]. However, a linear correlation seems to exist Evaluation Criteria in Solid Tumors, making assessment of re- between the concentrations of free (non-albumin-bound) sponse to treatment in a clinical trial difficult.With the advent of www.TheOncologist.com ©AlphaMed Press 2015 Downloaded from https://academic.oup.com/oncolo/article/20/2/224/6399029 by DeepDyve user on 01 February 2022 226 Alectinib for Leptomeningeal Carcinomatosis 2. Shaw AT, Kim DW, Nakagawa K et al. Crizotinib versus chemotherapy in second-generation ALK inhibitors that have demonstrated CNS advanced ALK-positive lung cancer. N Engl J Med 2013;368:2385–2394. activity, the activity of these ALK inhibitors in brain metastasis 3. Gainor JF, Ou SH, Logan J et al.The central nervous system as a sanctuary including leptomeningeal carcinomatosis are being investigated site in ALK-positive non-small-cell lung cancer. J Thorac Oncol 2013;8: systemically [16]. Meanwhile, case reports such as our current 1570–1573. patient case and the patient case by Arrondeau et al. [10] are 4. Seto T, Kiura K, Nishio M et al. CH5424802 (RO5424802) for patients how we can communicate the efficacy of second-generation with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP ALK inhibitors in leptomeningeal carcinomatosis in patients study): A single-arm, open-label, phase 1-2 study. Lancet Oncol 2013;14: with ALK-rearranged NSCLC. 590–598. 5. Gadgeel SM, Gandhi L, Riely GJ et al. Safety and activity of alectinib Acknowledgments against systemic disease and brain metastases in patients with crizotinib- We thank Jared D. Grace at Hoffmann-La Roche Inc. and Gina resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): Results from M. Davis and Dr. Patricia Keegan, Division of Oncology the dose-finding portion of a phase 1/2 study. Lancet Oncol 2014;15: 1119–1128. Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, for rapid permission and approval of 6. Gainor JF, Sherman AS, Willoughby K et al. Alectinib salvages CNS metastases in ALK-positive lung cancer patients previously treated with the emergency single-patient investigational new drug crizotinib and ceritinib. J Thorac Oncol 2014 [Epub ahead of print]. application allowing the use of alectinib for our patient. 7. Costa DB, Kobayashi S, Pandya SS et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol 2011;29: Author Contributions e443–e445. Conception/Design: Sai-Hong Ignatius Ou Provision of study material or patients: Sai-Hong Ignatius Ou, Michele C. 8. Ou SHI, Janne ¨ PA, Bartlett CH et al. Clinical benefit of continuing ALK Azada, Edward B. Garon inhibition with crizotinib beyond initial disease progression in patients with Collection and/or assembly of data: Sai-Hong Ignatius Ou, Karen R. Sommers, advanced ALK-positive NSCLC. Ann Oncol 2014;25:415–422. Michele C. Azada, Edward B. Garon Data analysis and interpretation: Sai-Hong Ignatius Ou, Karen R. Sommers, 9. Ahn HK, Han B, Lee SJ et al. ALK inhibitor crizotinib combined with Michele C. Azada, Edward B. Garon intrathecal methotrexate treatment for non-small cell lung cancer with Manuscript writing: Sai-Hong Ignatius Ou, Michele C. Azada, Edward B. Garon leptomeningeal carcinomatosis. Lung Cancer 2012;76:253–254. Final approval of manuscript: Sai-Hong Ignatius Ou, Karen R. Sommers, 10. Arrondeau J, Ammari S, Besse B et al. LDK378 compassionate use for Michele C. Azada, Edward B. Garon treating carcinomatous meningitis in an ALK translocated non-small-cell lung SAI-HONG IGNATIUS OU cancer. J Thorac Oncol 2014;9:e62–e63. KAREN R. SOMMERS 11. Gettinger SN, Bazhenova L, Salgia R et al. Updated efficacy and safety of MICHELE C. AZADA the ALK inhibitor AP26113 in patients (pts) with advanced malignancies, Chao Family Comprehensive Cancer Center, Department of including ALK1 non-small cell lung cancer (NSCLC). J Clin Oncol 2014;32(suppl): 8047a. Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange, California, USA 12. Gandhi L, Drappatz J, Ramaiya NH et al. High-dose pemetrexed in combination with high-dose crizotinib for the treatment of refractory CNS EDWARD B. GARON metastases in ALK-rearranged non-small-cell lung cancer. J Thorac Oncol 2013; Jonsson Comprehensive Cancer Center, Department of Medicine, 8:e3–e5. Division of Hematology-Oncology, University of California Los 13. Peled N, Zach L, Liran O et al. Effective crizotinib schedule for brain Angeles School of Medicine, Los Angeles, California, USA metastases in ALK rearrangement metastatic non-small-cell lung cancer. J Thorac Oncol 2013;8:e112–e113. Disclosures 14. Kim YH, Ozasa H, Nagai H et al. High-dose crizotinib for brain metastases Sai-Hong Ignatius Ou: Roche/Genentech (RF, H); Edward B. Garon: Merck, refractory to standard-dose crizotinib. J Thorac Oncol 2013;8:e85–e86. Bristol-Myers Squib (C/A); Merck, Genentech, AstraZeneca, Pfizer, 15. Lee SJ, Lee JI, Nam DH et al. Leptomeningeal carcinomatosis in non- Novartis, Puma (RF).The other authors indicated no financial relationship. (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert small-cell lung cancer patients: Impact on survival and correlated prognostic testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/ factors. J Thorac Oncol 2013;8:185–191. inventor/patent holder; (SAB) Scientific advisory board 16. Awad MM, Shaw AT. ALK inhibitors in non-small cell lung cancer: Crizotinib and beyond. Clin Adv Hematol Oncol 2014;12:429–439. REFERENCES 1. Solomon BJ, Mok T, Kim DW et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Eng J Med 2014;371:2167–2177. http://dx.doi.org/10.1634/theoncologist.2014-0309 The ©AlphaMed Press 2015 Oncologist http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Oncologist Oxford University Press

Alectinib Induces a Durable (>15 Months) Complete Response in an ALK-Positive Non-Small Cell Lung Cancer Patient Who Progressed on Crizotinib With Diffuse Leptomeningeal Carcinomatosis

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Oxford University Press
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Copyright © 2022 Oxford University Press
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1083-7159
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1549-490X
DOI
10.1634/theoncologist.2014-0309
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Abstract

Downloaded from https://academic.oup.com/oncolo/article/20/2/224/6399029 by DeepDyve user on 01 February 2022 Brief Communications Station, NJ, http://www.merck.com) 6 mg three times a day with Alectinib Induces a Durable (>15 Months) resolution of her symptoms while crizotinib was continued. Complete Response in an ALK-Positive She was urgently referred to a phase I/II trial of alectinib (RO5424802/CH5424802) (AF-002JG, NCT01588028), a second- Non-Small Cell Lung Cancer Patient Who generation ALK inhibitor, for crizotinib-resistant patients but ProgressedonCrizotinibWithDiffuse was ineligible due to lack of measurable disease by repeated Leptomeningeal Carcinomatosis computed tomography (CT) scan of the chest, abdomen, and pelvis and steroid dependency. The AF-002JG protocol requires patient to be free of neurological symptoms while Introduction off steroids for at least 14 days prior to enrollment. She could Crizotinib, a multitargeted anaplastic lymphoma kinase (ALK) not receive more cranial radiation because of previous whole- inhibitor, has demonstrated significantly improved progression- brain radiation. With permission from F. Hoffmann-La Roche free survival over chemotherapy in patients with advanced ALK- and approval by the U.S. Food and Drug Administration and rearranged non-small cell lung cancer (NSCLC) [1, 2]. However, the institutional review board (IRB) of the University of prolonged survival also seems to lead to eventual relapse in the California Irvine (UCI) Medical Center, she received alectinib sanctuary sites,presentingasleptomeningealcarcinomatosisor 600 mg orally twice daily under an emergency (bypassing the intramedullary metastasis, both of which have extremely poor mandatory 30-day waiting period) single-patient investigational prognoses [3]. In this paper, we described one patient who new drug (IND) application in early August 2013 after signing developed diffuse leptomeningeal carcinomatosis as the only an informed consent approved by the UCI IRB. Crizotinib was “site”ofprogressionafteraprolongedresponsetocrizotiniband discontinued the day before initiation of alectinib. Pre- who is being treated successfully with a second-generation ALK treatment lumbar puncture on the same day before starting inhibitor alectinib (CH5424802/RO5424802; F. Hoffmann-La alectinib demonstrated increased monocytes, and the cere- Roche AG, Basel, Switzerland, http://www.roche.com) alone. bral spinal fluid (CSF) cytology was positive for malignant That treatment has been ongoing for.15 months. adenocarcinoma (Fig. 1). However, tumor material was insuf- Case Presentation ficient to perform immunohistochemistry for ALK, fluorescence The patient is a 29-year-old Persian never-smoker woman who in situ hybridization for ALK break-apart analysis, or reverse was diagnosed with stage IIIA NSCLC at age 22. She received transcription polymerase chain reaction to detect potential curative surgical resection and adjuvant cisplatin and Navelbine acquired resistant ALK mutations. Pretreatment MRI also (GlaxoSmithKline, Research Triangle Park, NC, http://www.gsk. revealed diffuse enhancement of the meninges (Fig. 2A, 2C). com) chemotherapy. She remained free of disease for the next 3 By the time of alectinib initiation, the patient had years but then developed malignant pleural effusion and spinal experienced significant side effects from the high dose of metastasis. She received thoracic spine radiation and completed steroids, including oral thrush and vaginal candidiasis, despite six cycles of carboplatin, paclitaxel, and bevacizumab chemo- oral fluconazole treatment; weight gain; truncal obesity; fluid therapy with partial response.Three months later she was found retention; and insomnia. She was able to taper off Decadron to have at least 10 small brain lesions and received whole-brain after 10 days on alectinib. A lumbar puncture 14 days after radiation. Her tumor tested positive for rearrangement of the startingalectinib revealed significantlydecreased but persistent anaplastic lymphoma kinase (ALK) gene, and she was enrolled malignant cells. Her dysarthria symptoms returned briefly while into the randomized phase III trial comparing docetaxel and off steroids; the dose of alectinib was increased to 750 mg twice pemetrexed with crizotinib (PROFILE1007, NCT00932893). She daily, and steroids at 2 mg twice daily were reinitiated. Her was randomized to the chemotherapy arm (docetaxel) and leptomeningeal carcinomatosis symptoms resolved and never achieved stable disease after four cycles of docetaxel, which was recurred. A repeated lumbar puncture 4 weeks after initiation stopped because of patient intolerance. Six months later she of alectinib revealed clearance of malignant cells. A 6-week relapsed with osseous metastasis including the pelvis and follow-up MRI of the brain and entire spine showed resolu- received radiation to the pelvis. She then crossed over to tion of the meningeal enhancement (Fig. 2B, 2D). The patient crizotinib 250 mg twice daily in November 2011, and crizotinib was eventually weaned off all steroids within 2 months of was reduced to 200 mg twice daily after 2 months because of alectinib and has remained asymptomatic ongoing for .15 neutropenia. She achieved a complete response systematically. months. A repeated CTscan of the chest, abdomen, and pelvis Eighteen months into her crizotinib treatment she developed in November 2014 revealed continual systemic control with transient double vision, but magnetic resonance imaging no evidence of visceral disease and stable bone metastasis. (MRI) performed at that time did not reveal any abnormality. Approximately 1 month later she developed right hand Discussion paresthesia, right facial numbness, and dysarthria and, with Alectinib is a second-generation ALK inhibitor that has demon- repeated MRI, was found to have leptomeningeal carcinoma- strated clinical activity against brainmetastasis inpatientswith tosis diffusely involving the cerebellum and cervical spinal cord. ALK-rearranged NSCLC who were ALK inhibitor na¨ ıve [4] or She was started on Decadron (Merck & Co., Inc., Whitehouse resistant to crizotinib [5]. From the report of the dose-finding The Oncologist 2015;20:224–226 www.TheOncologist.com ©AlphaMed Press 2015 Downloaded from https://academic.oup.com/oncolo/article/20/2/224/6399029 by DeepDyve user on 01 February 2022 Ou, Sommers, Azada et al. 225 alectinib in the CSF and in the serum, with a ratio of ∼0.75 indicating a very high degree of penetration of alectinib into the CNS [5]. Consequently, when the rapid steroid taper within 2 weeks of initiating alectinib treatment did not completely eliminate the leptomeningeal carcinomatosis symptoms of our patient, we increased the dose of alectinib to 750 mg twice daily and restarted steroid treatment, followed by a prolonged but successfulsteroidtaper(2months).Indeed,750mgtwicedailywas welltoleratedbythepatientwithoutanylaboratoryabnormalities, in concordance with the phase I results of the U.S. alectinib trial. However, given the potentially higher level of alectinib that is achievable in the CSF with a 750-mg twice-dailydose,the excellent leptomeningeal carcinomatosis control with alectinib in our patient may not be translatable at the 600-mg twice-daily dose, although a recent publication after submission of this case report Figure 1. Malignant cells in the cerebral spinal fluid before showed that alectinib at 600 mg twice daily also had significant alectinib treatment. activity against leptomeningeal carcinomatosis in ALK-positive NSCLC patients who failed crizotinib and ceritinib [6]. Given that the patient is not on protocol treatment, no paired alectinib plasma/CSF ratio was determined. Crizotinib has been shown to achieve a very low CSF/plasma level based on one case report of a patient with ALK rearrange- ment whoalsoprogressed oncrizotinibwithisolatedleptomen- ingeal carinomatosis [7]. Progression in the central nervous system (CNS) is a leading cause of crizotinib failure [8]. Several approaches have been tried to treat leptomeningeal carcinoma- tosisinpatientswith ALK-rearranged NSCLC. Ahn and colleagues havecombined crizotinib and intrathecal(IT)methotrexate(MTX) in treating two crizotinib-na¨ ıve patients with ALK-rearranged NSCLC [9]. Both patients were able to receive IT MTX for 5 months before one had symptomatic deterioration and the other developed necrotizing leukoencephalopathy from IT MTX [9]. Ceritinib, a second-generation ALK inhibitor, had been shown to be effective under compassionate use for.5 months at the time ofthe reportinacrizotinib-resistant patientswithALK-rearranged NSCLC who developed carcinomatosis meningitis [10]. Another second-generation ALK inhibitor, AP26113, has also shown consistent CNS activity in crizotinib-resistant ALK-rearranged patients [11], but to date there is no report of single-agent AP26113 activity against leptomeningeal carcinomatosis arising in crizotinib-resistant patients with ALK-rearranged NSCLC. Other strategies that have been used to treat brain metastasis in pa- tients with ALK-rearrangedNSCLC,suchascrizotinibwithhigh- dose systemic chemotherapy [12], once-daily dosing instead of twice daily [13], or high-dose cirizotinib [14], have not been reported in patients with leptomeningeal carcinomatosis. Leptomeningeal carcinomatosis seemed to be a late pre- Figure 2. Images of the cerebellum before and after 6 weeks of sentation of advanced stage IV NSCLC [3, 15]. Overall survival of alectinib treatment, showing resolution of the meningeal enhance- ment. (A, B): Axial magnetic resonance imaging (MRI). (C, D): Coronal NSCLC patients with leptomeningeal carcinomatosis remains MRI images of the cerebellum before and after 6 weeks of alectinib poor. Consequently, leptomeningeal carcinomatosis is usually treatment showing resolution of the meningeal enhancement. an exclusion criterion in the vast majority of NSCLC clinical trials. Even when leptomeningeal carcinomatosis is allowed, as in the portion of the alectinib phase I/II trial conducted in the U.S. (AF- AF-002JGtrial,patientswithleptomeningealcarcinomatosishave 002JG, NCT01588028), an initial objective response rate of 52% in to be asymptomatic off all steroids for at least 2 weeks, and that brain metastasis was observed with alectinib [4]. The recom- is quite difficulty to achieve without any concurrent treatment mended phase II dose for alectinib was determined to be 600 mg because leptomeningeal carcinomatosis is usually diagnosed when patients become symptomatic. Furthermore, leptomenin- orally twice daily, although there was no significant difference in the serum pharmacokinectics of alectinib at 600 mg or 750 mg geal carcinomatosis is considered nonmeasurable by Response twice daily [5]. However, a linear correlation seems to exist Evaluation Criteria in Solid Tumors, making assessment of re- between the concentrations of free (non-albumin-bound) sponse to treatment in a clinical trial difficult.With the advent of www.TheOncologist.com ©AlphaMed Press 2015 Downloaded from https://academic.oup.com/oncolo/article/20/2/224/6399029 by DeepDyve user on 01 February 2022 226 Alectinib for Leptomeningeal Carcinomatosis 2. Shaw AT, Kim DW, Nakagawa K et al. Crizotinib versus chemotherapy in second-generation ALK inhibitors that have demonstrated CNS advanced ALK-positive lung cancer. N Engl J Med 2013;368:2385–2394. activity, the activity of these ALK inhibitors in brain metastasis 3. Gainor JF, Ou SH, Logan J et al.The central nervous system as a sanctuary including leptomeningeal carcinomatosis are being investigated site in ALK-positive non-small-cell lung cancer. J Thorac Oncol 2013;8: systemically [16]. Meanwhile, case reports such as our current 1570–1573. patient case and the patient case by Arrondeau et al. [10] are 4. Seto T, Kiura K, Nishio M et al. CH5424802 (RO5424802) for patients how we can communicate the efficacy of second-generation with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP ALK inhibitors in leptomeningeal carcinomatosis in patients study): A single-arm, open-label, phase 1-2 study. Lancet Oncol 2013;14: with ALK-rearranged NSCLC. 590–598. 5. Gadgeel SM, Gandhi L, Riely GJ et al. Safety and activity of alectinib Acknowledgments against systemic disease and brain metastases in patients with crizotinib- We thank Jared D. Grace at Hoffmann-La Roche Inc. and Gina resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): Results from M. Davis and Dr. Patricia Keegan, Division of Oncology the dose-finding portion of a phase 1/2 study. Lancet Oncol 2014;15: 1119–1128. Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, for rapid permission and approval of 6. Gainor JF, Sherman AS, Willoughby K et al. Alectinib salvages CNS metastases in ALK-positive lung cancer patients previously treated with the emergency single-patient investigational new drug crizotinib and ceritinib. J Thorac Oncol 2014 [Epub ahead of print]. application allowing the use of alectinib for our patient. 7. Costa DB, Kobayashi S, Pandya SS et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol 2011;29: Author Contributions e443–e445. Conception/Design: Sai-Hong Ignatius Ou Provision of study material or patients: Sai-Hong Ignatius Ou, Michele C. 8. Ou SHI, Janne ¨ PA, Bartlett CH et al. Clinical benefit of continuing ALK Azada, Edward B. Garon inhibition with crizotinib beyond initial disease progression in patients with Collection and/or assembly of data: Sai-Hong Ignatius Ou, Karen R. Sommers, advanced ALK-positive NSCLC. Ann Oncol 2014;25:415–422. Michele C. Azada, Edward B. Garon Data analysis and interpretation: Sai-Hong Ignatius Ou, Karen R. Sommers, 9. Ahn HK, Han B, Lee SJ et al. ALK inhibitor crizotinib combined with Michele C. Azada, Edward B. Garon intrathecal methotrexate treatment for non-small cell lung cancer with Manuscript writing: Sai-Hong Ignatius Ou, Michele C. Azada, Edward B. Garon leptomeningeal carcinomatosis. Lung Cancer 2012;76:253–254. Final approval of manuscript: Sai-Hong Ignatius Ou, Karen R. Sommers, 10. Arrondeau J, Ammari S, Besse B et al. LDK378 compassionate use for Michele C. Azada, Edward B. Garon treating carcinomatous meningitis in an ALK translocated non-small-cell lung SAI-HONG IGNATIUS OU cancer. J Thorac Oncol 2014;9:e62–e63. KAREN R. SOMMERS 11. Gettinger SN, Bazhenova L, Salgia R et al. Updated efficacy and safety of MICHELE C. AZADA the ALK inhibitor AP26113 in patients (pts) with advanced malignancies, Chao Family Comprehensive Cancer Center, Department of including ALK1 non-small cell lung cancer (NSCLC). J Clin Oncol 2014;32(suppl): 8047a. Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange, California, USA 12. Gandhi L, Drappatz J, Ramaiya NH et al. High-dose pemetrexed in combination with high-dose crizotinib for the treatment of refractory CNS EDWARD B. GARON metastases in ALK-rearranged non-small-cell lung cancer. J Thorac Oncol 2013; Jonsson Comprehensive Cancer Center, Department of Medicine, 8:e3–e5. Division of Hematology-Oncology, University of California Los 13. Peled N, Zach L, Liran O et al. Effective crizotinib schedule for brain Angeles School of Medicine, Los Angeles, California, USA metastases in ALK rearrangement metastatic non-small-cell lung cancer. J Thorac Oncol 2013;8:e112–e113. Disclosures 14. Kim YH, Ozasa H, Nagai H et al. High-dose crizotinib for brain metastases Sai-Hong Ignatius Ou: Roche/Genentech (RF, H); Edward B. Garon: Merck, refractory to standard-dose crizotinib. J Thorac Oncol 2013;8:e85–e86. Bristol-Myers Squib (C/A); Merck, Genentech, AstraZeneca, Pfizer, 15. Lee SJ, Lee JI, Nam DH et al. Leptomeningeal carcinomatosis in non- Novartis, Puma (RF).The other authors indicated no financial relationship. (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert small-cell lung cancer patients: Impact on survival and correlated prognostic testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/ factors. J Thorac Oncol 2013;8:185–191. inventor/patent holder; (SAB) Scientific advisory board 16. Awad MM, Shaw AT. ALK inhibitors in non-small cell lung cancer: Crizotinib and beyond. Clin Adv Hematol Oncol 2014;12:429–439. REFERENCES 1. Solomon BJ, Mok T, Kim DW et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Eng J Med 2014;371:2167–2177. http://dx.doi.org/10.1634/theoncologist.2014-0309 The ©AlphaMed Press 2015 Oncologist

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The OncologistOxford University Press

Published: Feb 1, 2015

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