替莫唑胺联合 depatuxizumab mafodotin 治疗 EGFR 扩增复发性胶质母细胞瘤患者的安全性和有效性：一项国际多中心 I 期试验的结果。

Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR-amplified, recurrent glioblastoma: results from an international phase I multicenter trial.

机构信息

Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.

Erasmus MC Cancer Institute, Rotterdam, Netherlands.

出版信息

Neuro Oncol. 2019 Jan 1;21(1):106-114. doi: 10.1093/neuonc/noy091.

DOI:10.1093/neuonc/noy091

PMID:29982805

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6303422/

Abstract

BACKGROUND

Patients with glioblastoma (GBM) have a dismal prognosis. Nearly all will relapse with no clear standard of care for recurrent disease (rGBM). Approximately 50% of patients have tumors harboring epidermal growth factor receptor (EGFR) amplification. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) binds cells with EGFR amplification, is internalized, and releases a microtubule toxin, killing the cell. Here we report efficacy, safety and pharmacokinetics (PK) of depatux-m + temozolomide (TMZ) in patients with EGFR-amplified rGBM.

METHODS

M12-356 (NCT01800695) was an open-label study encompassing patients with newly diagnosed or rGBM across 3 treatment arms. Results are reported for adults with EGFR-amplified, measurable rGBM who received depatux-m (0.5-1.5 mg/kg) on days 1 and 15, and TMZ (150-200 mg/m2) on days 1-5 in a 28-day cycle. Patients were bevacizumab and nitrosourea naïve.

RESULTS

There were 60 patients, median age 56 years (range, 20-79). Fifty-nine patients previously received TMZ. Common adverse events (AEs) were blurred vision (63%), fatigue (38%), and photophobia (35%). Grades 3/4 AEs were split between ocular and non-ocular AEs, occurring in 22% of patients each. Systemic PK exposure of depatux-m was dose proportional. The objective response rate was 14.3%, the 6-month progression-free survival rate was 25.2%, and the 6-month overall survival rate was 69.1%.

CONCLUSIONS

Depatux-m + TMZ displayed an AE profile similar to what was described previously. Antitumor activity in this TMZ-refractory population was encouraging. Continued study of depatux-m in patients with EGFR-amplified, newly diagnosed, or recurrent GBM is ongoing in 2 global, randomized trials (NCT02573324, NCT02343406).

摘要

背景

胶质母细胞瘤（GBM）患者预后较差。几乎所有患者都会复发，而复发性疾病（rGBM）目前尚无明确的治疗标准。约 50%的患者存在表皮生长因子受体（EGFR）扩增的肿瘤。抗体药物偶联物 depatuxizumab mafodotin（depatux-m）与具有 EGFR 扩增的细胞结合，被内化，并释放微管毒素，杀死细胞。本研究报告了 depatux-m+替莫唑胺（TMZ）在 EGFR 扩增的 rGBM 患者中的疗效、安全性和药代动力学（PK）。

方法

M12-356（NCT01800695）是一项开放标签研究，纳入了新诊断或 rGBM 的患者，共 3 个治疗组。本研究报告了 EGFR 扩增、可测量 rGBM 的成人患者的结果，这些患者在 28 天的周期中接受 depatux-m（0.5-1.5mg/kg），第 1 天和第 15 天，TMZ（150-200mg/m2），第 1-5 天。患者均未接受贝伐珠单抗和亚硝脲治疗。

结果

共 60 例患者，中位年龄 56 岁（范围 20-79 岁）。59 例患者之前接受过 TMZ 治疗。常见不良事件（AE）为视力模糊（63%）、疲劳（38%）和畏光（35%）。3/4 级 AE 分别为眼部和非眼部 AE，各占患者的 22%。depatux-m 的全身 PK 暴露与剂量呈比例关系。客观缓解率为 14.3%，6 个月无进展生存率为 25.2%，6 个月总生存率为 69.1%。