A phase II trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma: NCCTG N057K
A phase II trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma: NCCTG N057K
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DOI：
10.1093/neuonc/nou328
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发表时间：
2015-09-01
期刊：
影响因子：
15.9
通讯作者：
Sarkaria, Jann N.
中科院分区：
文献类型：
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作者：
Ma, Daniel J.;Galanis, Evanthia;Sarkaria, Jann N.
哺乳动物雷帕霉素靶蛋白（mTOR）在磷脂酰肌醇-3激酶（PI 3 K）/Akt通路中起作用，是细胞存活的关键调节剂。这项临床试验评估了mTOR抑制剂依维莫司与常规替莫唑胺（TMZ）为基础的放化疗的联合治疗。新诊断的多形性胶质母细胞瘤患者符合这项单臂II期研究的条件。依维莫司（70 mg/wk）在放疗和TMZ前1周开始，随后是辅助TMZ，并持续至疾病进展。主要终点是12个月时的总生存率，次要终点是毒性和进展时间。在开始放射/TMZ之前，在初始2剂依维莫司之前和之后，用3 '-脱氧-3'-F-18-氟胸苷（（FLT）-F-18）-PET/CT对11名患者进行成像。对有足够肿瘤标本的影像学患者进行免疫组化和聚焦外显子测序分析。14%的患者出现4级血液学毒性。12%的患者至少有一次4级非血液学毒性，有一次治疗相关死亡。12个月时的总生存率为64%，中位进展时间为6.4个月。在具有（FLT）-F-18-PET数据的患者中，4/9例在2剂依维莫司后出现部分缓解。聚焦外显子测序显示，与无应答者相比，（FLT）-F-18-PET应答者PI 3 K/Akt/mTOR或结节性硬化症复合体/神经纤维瘤病1型通路发生改变的可能性较小。（FLT）-F-18-PET研究表明，在遗传上不同的肿瘤子集中具有初始抗增殖作用，但与传统治疗的历史对照相比，这并没有转化为明显的生存益处。
The mammalian target of rapamycin (mTOR) functions within the phosphatidylinositol-3 kinase (PI3K)/Akt pathway as a critical modulator of cell survival. This clinical trial evaluated the combination of the mTOR inhibitor everolimus with conventional temozolomide (TMZ)-based chemoradiotherapy.Newly diagnosed patients with glioblastoma multiforme were eligible for this single arm, phase II study. Everolimus (70 mg/wk) was started 1 week prior to radiation and TMZ, followed by adjuvant TMZ, and continued until disease progression. The primary endpoint was overall survival at 12 months, and secondary endpoints were toxicity and time to progression. Eleven patients were imaged with 3'-deoxy-3'-F-18-fluorothymidine ((FLT)-F-18)-PET/CT before and after the initial 2 doses of everolimus before initiating radiation/TMZ. Imaged patients with sufficient tumor samples also underwent immunohistochemical and focused exon sequencing analysis.This study accrued 100 evaluable patients. Fourteen percent of patients had grade 4 hematologic toxicities. Twelve percent had at least one grade 4 nonhematologic toxicity, and there was one treatment-related death. Overall survival at 12 months was 64% and median time to progression was 6.4 months. Of the patients who had (FLT)-F-18-PET data, 4/9 had a partial response after 2 doses of everolimus. Focused exon sequencing demonstrated that (FLT)-F-18-PET responders were less likely to have alterations within the PI3K/Akt/mTOR or tuberous sclerosis complex/neurofibromatosis type 1 pathway compared with nonresponders.Combining everolimus with conventional chemoradiation had moderate toxicity. (FLT)-F-18-PET studies suggested an initial antiproliferative effect in a genetically distinct subset of tumors, but this did not translate into an appreciable survival benefit compared with historical controls treated with conventional therapy.