Division of Neuro-Oncology, Neuro-Oncology Center, University of Virginia Health System, Charlottesville, Virginia.
Atlantic Health System, Summit, New Jersey.
Cancer. 2018 Apr 1;124(7):1455-1463. doi: 10.1002/cncr.31219. Epub 2018 Jan 3.
Mitogen-activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)-dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR-2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma.
Patients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ≤2 prior chemotherapy regimens were eligible. The phase 1 endpoint was the maximum tolerated dose (MTD), using a cohorts-of-3 design. The 2-stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)-naive patients and patients who progressed after prior VEGFi.
The MTD was sorafenib at a dose of 200 mg twice daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (progression-free survival at 6 months [PFS6]) in the VEGFi-naive group (17.1%); this finding met the prestudy threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8%), and this did not meet the prestudy threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event of grade ≥3 was observed in 75.5% of the VEGFi-naive patients and in 73.9% of the prior VEGFi patients.
The limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade ≥3. Significant dose reductions that were required in this treatment combination compared with tolerated single-agent doses may have contributed to the lack of efficacy. Cancer 2018;124:1455-63. © 2018 American Cancer Society.
丝裂原活化蛋白激酶（MAPK）的激活和哺乳动物雷帕霉素靶蛋白（mTOR）依赖性信号是胶质母细胞瘤的特征。在目前的研究中，作者对索拉非尼（一种 Raf 激酶和血管内皮生长因子受体 2 [VEGFR-2]的抑制剂）和 mTOR 抑制剂替西罗莫司在复发性胶质母细胞瘤患者中的应用进行了 1/2 期的研究。
符合以下条件的复发性胶质母细胞瘤患者可以入组：患者在手术或放疗加替莫唑胺后疾病进展，且最多接受过 2 种化疗方案。1 期的终点是最大耐受剂量（MTD），采用 3 个队列设计。2 期的 2 阶段研究包括分别针对 VEGF 抑制剂（VEGFi）初治患者和之前接受过 VEGFi 治疗后进展的患者的治疗组。
索拉非尼的 MTD 为每日 2 次，每次 200mg，替西罗莫司的 MTD 为每周 20mg。在接受 2 期剂量治疗的前 41 例可评估患者中，有 7 例 VEGFi 初治组患者（17.1%）在 6 个月时无疾病进展（6 个月无进展生存率 [PFS6]）；这一结果符合研究前的成功标准。在前一组中，仅在接受 2 期剂量治疗的前 41 例可评估患者中，有 4 例（9.8%）达到 PFS6，这不符合研究前的成功标准。两组的中位 PFS 分别为 2.6 个月和 1.9 个月。两组的中位总生存期分别为 6.3 个月和 3.9 个月。至少有 1 例 3 级以上的不良事件发生在 75.5%的 VEGFi 初治患者和 73.9%的既往接受过 VEGFi 治疗的患者中。
目前研究中使用的索拉非尼和替西罗莫司剂量和方案观察到的活性有限，且毒性较大，达到 3 级以上。与可耐受的单药剂量相比，该治疗组合需要显著减少剂量，这可能是疗效缺失的原因。癌症 2018；124:1455-63。© 2018 美国癌症协会。
