Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall-cell lung cancer
Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall-cell lung cancer
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DOI：
10.1002/cncr.22816
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发表时间：
2007-08-01
期刊：
影响因子：
6.2
通讯作者：
Miller, Vincent A.
中科院分区：
文献类型：
--
作者：
Milton, Daniel T.;Riely, Gregory J.;Miller, Vincent A.
背景临床前研究已经证明，PI 3 K/Akt/mTOR通路的抑制恢复了耐药癌细胞系中吉非替尼的敏感性。进行了一项mTOR抑制剂依维莫司和吉非替尼联合治疗晚期非小细胞肺癌（NSCLC）患者的I期研究，以确定依维莫司和吉非替尼的日剂量。对患有进行性NSCLC的患者每日给予口服依维莫司和吉非替尼。患者入组3例患者队列，依维莫司剂量水平为每日5和10 mg。所有患者均接受吉非替尼250 mg/d治疗。入组了10例患者。当每日给予吉非替尼250 mg时，依维莫司的最大耐受剂量为5 mg。两名接受依维莫司10 mg剂量水平治疗的患者出现剂量限制性毒性，包括5级低血压和3级口腔炎。药代动力学研究表明，两种药物的t（max）、C-max和AUC（0-8h）均无一致的显著相互作用。在8例缓解可评价患者中，确定了2例部分放射学缓解。对于进一步的研究，推荐每日5 mg依维莫司联合每日250 mg吉非替尼。识别出的2例放射学缓解令人鼓舞。正在NSCLC患者中进行II期试验。
Background. Preclinical studies have demonstrated that the inhibition of the PI3K/Akt/mTOR pathway restores gefitinib sensitivity in resistant cancer cell lines. A phase 1 study was conducted of the combination of everolimus, an mTOR inhibitor, and gefitinib to determine a daily dose of everolimus with gefitinib in patients with advanced nonsmall-cell lung cancer (NSCLC).Methods. oral everolimus and gefitinib were both administered daily to patients with progressive NSCLC. Patients were enrolled in 3-patient cohorts at everolimus dose levels of 5 and 10 mg daily. All patients received gefitinib 250 mg daily.Results. Ten patients were enrolled. The maximum tolerated dose of everolimus was 5 mg when administered daily with gefitinib 250 mg. Two patients who were treated at the 10 mg dose level of everolimus experienced dose-limiting toxicity, including grade 5 hypotension and grade 3 stomatitis. Pharmacokinetic studies demonstrated no consistent, significant interaction on the t(max), C-max, and AUC(0-8h) of either agent. Two partial radiographic responses were identified among the 8 response-evaluable patients.Conclusions. For further study, everolimus at a dose of 5 mg daily in combination with daily gefitinib 250 mg is recommended. The 2 radiographic responses identified are encouraging. A phase 2 trial in patients with NSCLC is under way.