厄洛替尼和替西罗莫司治疗复发性恶性脑胶质瘤患者的 I/II 期研究：北美脑肿瘤联盟试验 04-02。
Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas: North American Brain Tumor Consortium trial 04-02.
机构信息
Center for Neuro-Oncology, Dana Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (P.Y.W., A.D.N., J.D.); Department of Neurosurgery, University of California, San Francisco, San Francisco, California (S.M.C., K.R.L., M.D.P.); University of Texas Health Science Center, San Antonio, Texas (J.G.K.); Division of Neuro-Oncology, Department of Neurology, University of California, Los Angeles, Los Angeles, California (T.F.C.); University of Wisconsin, Madison Wisconsin (H.I.R., M.P.M.); Neurooncology Program, Division of Hematology/Oncology, University of Pittsburgh Medical Center Cancer Pavilion, Pittsburgh, Pennsylvania (F.S.L.); Division of Neuro-Oncology, MD Anderson Cancer Center, Houston, Texas (M.R.G., M.D.G., W.K.A.Y., K.D.A.); Center for Molecular Oncologic Pathology, Dana Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (S.S., A.H.L.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.S., A.H.L., K.L.L.); Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland (J.D.*, J.J.W.).
出版信息
Neuro Oncol. 2014 Apr;16(4):567-78. doi: 10.1093/neuonc/not247. Epub 2014 Jan 26.
BACKGROUND
Inhibition of epidermal growth factor receptor (EGFR) and the mechanistic target of rapamycin (mTOR) may have synergistic antitumor effects in high-grade glioma patients.
METHODS
We conducted a phase I/II study of the EGFR inhibitor erlotinib (150 mg/day) and the mTOR inhibitor temsirolimus. Patients initially received temsirolimus 50 mg weekly, and the dose adjusted based on toxicities. In the phase II component, the primary endpoint was 6-month progression-free survival (PFS6) among glioblastoma patients.
RESULTS
Twenty-two patients enrolled in phase I, 47 in phase II. Twelve phase I patients treated at the maximum tolerated dosage were included in the phase II cohort for analysis. The maximum tolerated dosage was 15 mg temsirolimus weekly with erlotinib 150 mg daily. Dose-limiting toxicities were rash and mucositis. Among 42 evaluable glioblastoma patients, 12 (29%) achieved stable disease, but there were no responses, and PFS6 was 13%. Among 16 anaplastic glioma patients, 1 (6%) achieved complete response, 1 (6%) partial response, and 2 (12.5%) stable disease, with PFS6 of 8%. Tumor levels of both drugs were low, and posttreatment tissue in 3 patients showed no reduction in the mTOR target phosphorylated (phospho-)S6(S235/236) but possible compensatory increase in phospho-Akt(S473). Presence of EGFR variant III, phospho-EGFR, and EGFR amplification did not correlate with survival, but patients with elevated phospho-extracellular signal-regulated kinase or reduced phosphatase and tensin homolog protein expression had decreased progression-free survival at 4 months.
CONCLUSION
Because of increased toxicity, the maximum tolerated dosage of temsirolimus in combination with erlotinib proved lower than expected. Insufficient tumor drug levels and redundant signaling pathways may partly explain the minimal antitumor activity noted.
背景
在高级别脑胶质瘤患者中，表皮生长因子受体（EGFR）抑制剂和雷帕霉素靶蛋白（mTOR）抑制剂可能具有协同抗肿瘤作用。
方法
我们进行了一项 I/II 期研究，评估 EGFR 抑制剂厄洛替尼（150 mg/天）和 mTOR 抑制剂替西罗莫司的作用。患者最初每周接受 50 mg 替西罗莫司，根据毒性调整剂量。在 II 期部分，主要终点是胶质母细胞瘤患者的 6 个月无进展生存期（PFS6）。
结果
22 例患者入组 I 期，47 例入组 II 期。12 例在最大耐受剂量下治疗的 I 期患者被纳入 II 期队列进行分析。最大耐受剂量为替西罗莫司每周 15 mg 联合厄洛替尼 150 mg 每日。剂量限制毒性为皮疹和黏膜炎。在 42 例可评估的胶质母细胞瘤患者中，12 例（29%）疾病稳定，但无缓解，PFS6 为 13%。在 16 例间变性星形细胞瘤患者中，1 例（6%）完全缓解，1 例（6%）部分缓解，2 例（12.5%）疾病稳定，PFS6 为 8%。两种药物的肿瘤水平均较低，3 例患者的治疗后组织中 mTOR 靶标磷酸化（磷酸化）S6（S235/236）未见减少，但磷酸化-Akt（S473）可能代偿性增加。EGFR 变体 III、磷酸化 EGFR 和 EGFR 扩增与生存无关，但磷酸化细胞外信号调节激酶升高或磷酸酶和张力蛋白同源物蛋白表达降低的患者在 4 个月时无进展生存期缩短。
结论
由于毒性增加，替西罗莫司联合厄洛替尼的最大耐受剂量低于预期。肿瘤药物水平不足和冗余信号通路可能部分解释了观察到的最小抗肿瘤活性。
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