- © 2011 by American Society of Clinical Oncology
CSF Concentration of the Anaplastic Lymphoma Kinase Inhibitor Crizotinib
Case Report
We describe the case of a 29-year-old white man with a never-smoking history and EML4-ALK-E20A20 stage IV non–small-cell lung cancer (NSCLC) whose disease had progressed after first-line cisplatin plus pemetrexed and second-line erlotinib. He started crizotinib at 200 mg twice daily and attained significant symptomatic improvement and minor tumor regression of his intrathoracic disease best classified as stable disease.1 Before start of therapy, brain imaging studies showed no abnormalities. His systemic disease retained radiographic control with crizotinib when he presented with new-onset headaches 7.5 months into his treatment course. Magnetic resonance imaging of the brain disclosed small enhancing masses throughout the supratentorial and infratentorial brain, as well as the leptomeninges. The sagittal view of the T1-weighted sequence shows these masses, with black arrows highlighting some of the lesions (Fig 1). CSF cytology was positive for malignant cells. The patient received 30 Gy of whole-brain radiotherapy. Crizotinib was restarted at 250 mg twice daily during month 8 after the initiation of drug. Two weeks later, CSF and plasma were sampled 5 hours after a dose of crizotinib 250 mg. Concentrations of crizotinib were measured using a validated high-performance liquid chromatography with tandem mass spectrometry method (Pfizer, La Jolla, CA).2 The plasma concentration of crizotinib was measured at 237 ng/mL (0.53 μmol/L), whereas the CSF concentration was 0.616 ng/mL (0.0014 μmol/L), with a CSF-to-plasma ratio of 0.0026. The low drug level in the CSF implies poor blood-brain barrier penetration of the drug. This low CSF-to-plasma ratio may explain the persistent systemic disease control of crizotinib with the concurrent appearance of brain metastases. The patient's CNS symptoms eventually progressed, his intrathoracic disease increased, and crizotinib was discontinued on month 9 from the start of drug. Despite consecutive therapies with docetaxel, pemetrexed, and carboplatin plus gemcitabine, the disease continued to progress, and the patient died less than 3 months later.
Discussion
Crizotinib (molecular weight, 450.34) is an anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI)3 that leads to responses in most patients with NSCLC harboring ALK translocations.1 In preclinical models, the antiproliferative effects of crizotinib are more prominent in NSCLCs with ALK translocations. Using a panel of NSCLC lines and a standard growth inhibition assay in which cells are assessed by the CellTiter 96 AQueous One solution proliferation kit (Promega, Madison, WI) after 72 hours of exposure of 5,000 cells per well to increasing concentrations of crizotinib, a cell line with the EML4-ALK-E13A20 translocation (NCI-H3122) has a 50% inhibitory concentration (IC50) of 0.24 μmol/L (Fig 2). Other cell lines with epidermal growth factor receptor (EGFR) or V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, such as NCI-H3255 (EGFR-L858R), HCC827 (EGFR-delE746_A750), and A549 (KRAS-G12S), have IC50 values that exceed 2 μmol/L of crizotinib (Fig 2).
The reported median trough plasma total concentration of crizotinib at 250 mg twice daily (its recommended dosing scheme for phase II and III trials in NSCLC) is 256 ng/mL (0.57 μmol/L), exceeding the target efficacious levels for EML4-ALK and other ALK fusion proteins in kinase and cell line assays.2 This favorable pharmacokinetic profile may explain the radiographic response rate (close to 60%) and prolonged progression-free survival observed with crizotinib in patients with ALK-translocated NSCLC.1 However, the penetration of crizotinib into the CSF and how this affects CNS metastasis have not been previously reported.
Our findings in the patient presented here are important because they point toward the low penetration of crizotinib within the CSF. Preclinical and clinical work exists regarding brain and CNS penetration of various anticancer agents.4 Usually, surrogate end points (such as CSF-to-plasma ratios) are used to determine whether a drug can be transported into the CNS and penetrate the blood-brain barrier. Some cytotoxic chemotherapies, such as the topoisomerase I inhibitor topotecan and the alkylating agent prodrug temozolomide, have high CSF-to-plasma ratios.4,5 Therefore, these agents have been used successfully as therapies for metastatic and primary brain tumors. In contrast, oral TKIs, in general, have a low CSF-to-plasma ratio.4 The poor penetration of other small-molecule adenosine triphosphate–mimetic TKIs into the CSF has been previously reported for imatinib,4 gefitinib,6 and erlotinib.7
The importance of the CSF-to-plasma concentration ratio for a TKI has become evident for NSCLCs with EGFR activating (exon 19 deletions or L858R) mutations. Cells harboring the L858R or delE746_A750 EGFR mutations have IC50 values less than 0.1 μmol/L for the EGFR TKIs gefitinib and erlotinib.8 Gefitinib (at 250 mg/d; serum trough concentration of approximately 0.5 μmol/L) and erlotinib (at 150 mg/d; serum trough concentration of > 2 μmol/L) are able to achieve remarkable rates of antitumor response in patients harboring these oncogene mutations.8–10 However, resistance to continued EGFR inhibition is common. Acquired systemic resistance through the selection of resistant mutations (such as EGFR-T790M) or amplification of other oncogenes (such as the hepatocyte growth factor receptor MET) is usually detected after 6 to 12 months of therapy.11,12 One additional recognized mechanism of pharmacokinetic resistance, a poor CSF-to-plasma ratio, occurs in patients who continue to have systemic disease control with gefitinib or erlotinib but display progression or new-onset CNS disease. In the few reported patients, most CNS-progressing tumor cells lacked classical mechanisms of acquired resistance (ie, lacked EGFR-T790M), and the CSF-to-plasma ratio of either gefitinib or erlotinib was less than 0.01.6,7 The use of enhanced pulsatile dosing schedules (such as erlotinib at 1,500 mg once weekly) or concentrations (such as gefitinib at 1,000 mg/d) of these EGFR inhibitors was able to overcome the poor CSF penetration of these drugs and improved CNS symptoms in patients.6,7
Because ALK-translocated NSCLCs respond to the ALK TKI crizotinib in a similar fashion as EGFR-mutated NSCLCs do to EGFR TKIs,9,10,13 it is possible to speculate that some patients, such as the one described here, may develop a CNS-specific pharmacokinetic resistance as a result of poor CSF/plasma penetration of crizotinib in the absence of genetic mechanisms of resistance to ALK TKIs.14 However, some patients on the initial trial of crizotinib with untreated or previously treated brain metastases from NSCLC had long periods of systemic disease control with this ALK TKI without CNS progression.1 Further confirmatory studies are needed to determine patient and tumor characteristics that alter the pattern of CNS response to crizotinib.
In summary, crizotinib seems to penetrate poorly the blood-brain barrier, and this pharmacokinetic property may hinder the anticancer effect of this drug in metastatic brain tumors. The brain may be a susceptible site for progression of NSCLCs with ALK translocations that are being targeted by crizotinib.1 Alternative dosing schemes or increased doses may be warranted in patients with systemic disease control and CNS progression while on crizotinib.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: Zhongzhou Shen, Pfizer (C); Weiwei Tan, Pfizer (C); Keith D. Wilner, Pfizer (C) Consultant or Advisory Role: Daniel B. Costa, Pfizer (C) Stock Ownership: Zhongzhou Shen, Pfizer; Weiwei Tan, Pfizer; Keith D. Wilner, Pfizer Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None
Acknowledgment
We thank the investigators and participants of the phase I clinical trial of crizotinib, A8081001 (NCT00585195). This work was funded and sponsored by Pfizer and funded in part through Career Development Award No. CDA-15431 from the American Society of Clinical Oncology Cancer Foundation (D.B.C.) and a Joan's Legacy/Michael R. Pascucci Lung Cancer Association Grant from United Against Lung Cancer (S.K.).
