A phase I trial of high dose gefitinib for patients with leptomeningeal metastases from non-small cell lung cancer

There are few effective treatment options for leptomeningeal metastasis (LM) in non-small-cell lung cancer (NSCLC). This study assessed the feasibility of high-dose gefitinib in patients with LM from NSCLC harboring EGFR mutations or prior systemic response to EGFR-TKI. This phase I open-label trial...

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Bibliographic Details
Published in:	Oncotarget Vol. 6; no. 6; pp. 4527 - 4536
Main Authors:	Jackman, David M, Cioffredi, Leigh A, Jacobs, Lorraine, Sharmeen, Farhana, Morse, Linda K, Lucca, Joan, Plotkin, Scott R, Marcoux, Paul J, Rabin, Michael S, Lynch, Thomas J, Johnson, Bruce E, Kesari, Santosh
Format:	Journal Article
Language:	English
Published:	United States Impact Journals LLC 28-02-2015
Subjects:	Aged Antineoplastic Agents - administration & dosage Antineoplastic Agents - adverse effects Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - secondary Clinical Research Paper Disease-Free Survival Dose-Response Relationship, Drug Female Humans Lung Neoplasms - drug therapy Lung Neoplasms - pathology Male Maximum Tolerated Dose Meningeal Neoplasms - drug therapy Meningeal Neoplasms - secondary Middle Aged Quinazolines - administration & dosage Quinazolines - adverse effects
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Summary:	There are few effective treatment options for leptomeningeal metastasis (LM) in non-small-cell lung cancer (NSCLC). This study assessed the feasibility of high-dose gefitinib in patients with LM from NSCLC harboring EGFR mutations or prior systemic response to EGFR-TKI. This phase I open-label trial of a novel gefitinib dosing schedule employed a 3+3 design. Eligible NSCLC patients with LM had known EGFR mutations and/or prior response to EGFR-TKI. Patients alternated 2 weeks of high-dose daily gefitinib (dose levels: 750 mg, 1000 mg, 1250 mg) with 2 weeks of maintenance therapy (500 mg daily). Primary endpoints were safety and toxicity. Secondary endpoints included overall survival (OS), neurological progression-free survival, radiological response, and cytological response in cerebrospinal fluid (CSF). Seven patients were treated: 3 at 750 mg dose level, 4 at 1000 mg dose level. There were no DLTs at the 750 mg dose level, and one DLT (toxic epidermal necrolysis) at the 1000 mg dose level. The study was closed due to slow accrual. Median neurological PFS was 2.3 months (range 1.6-4.0 months); median OS was 3.5 months (range 1.6-5.1 months). Though there were no radiologically documented remissions of LM disease, four patients had improvement in neurological symptoms. One patient cleared their CSF of NSCLC cells, while 2 others had decrease in malignant cells in CSF. Although the MTD was not defined due to slow accrual, this study provides important information about the tolerability and CSF penetration of high-dose gefitinib as a therapeutic option for modest palliation for NSCLC patients with LM and a known EGFR mutation.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1949-2553 1949-2553
DOI:	10.18632/oncotarget.2886