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
Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Oncotarget. 2015 Feb 28;6(6):4527-36. doi: 10.18632/oncotarget.2886.
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.
非小细胞肺癌（NSCLC）软脑膜转移（LM）的有效治疗选择很少。本研究评估了高剂量吉非替尼在伴有EGFR突变或既往对EGFR-TKI有全身反应的NSCLC-LM患者中的可行性。
这项关于新型吉非替尼给药方案的I期开放标签试验采用3+3设计。符合条件的NSCLC-LM患者已知有EGFR突变和/或既往对EGFR-TKI有反应。患者在2周的高剂量每日吉非替尼（剂量水平：750毫克、1000毫克、1250毫克）与2周的维持治疗（每日500毫克）之间交替。主要终点是安全性和毒性。次要终点包括总生存期（OS）、无神经进展生存期、放射学反应以及脑脊液（CSF）中的细胞学反应。
7名患者接受了治疗：3名在750毫克剂量水平，4名在1000毫克剂量水平。750毫克剂量水平未出现剂量限制毒性（DLT），1000毫克剂量水平出现1例DLT（中毒性表皮坏死松解症）。由于入组缓慢，研究提前结束。中位无神经进展生存期为2.3个月（范围1.6 - 4.0个月）；中位总生存期为3.5个月（范围1.6 - 5.1个月）。虽然LM疾病没有放射学记录的缓解，但4名患者的神经症状有所改善。1名患者脑脊液中的NSCLC细胞清除，另外2名患者脑脊液中的恶性细胞减少。
尽管由于入组缓慢未确定最大耐受剂量（MTD），但本研究提供了关于高剂量吉非替尼的耐受性和脑脊液穿透性的重要信息，作为伴有已知EGFR突变的NSCLC-LM患者适度姑息治疗的一种选择。
