Milton Daniel T, Riely Gregory J, Azzoli Christopher G, Gomez Jorge E, Heelan Robert T, Kris Mark G, Krug Lee M, Pao William, Pizzo Barbara, Rizvi Naiyer A, Miller Vincent A
Department of Medicine, Thoracic Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center and the Weill Medical College of Cornell University, New York, New York, USA.
Cancer. 2007 Aug 1;110(3):599-605. doi: 10.1002/cncr.22816.
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).
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.
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.
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.
临床前研究表明，抑制PI3K/Akt/mTOR通路可恢复耐药癌细胞系对吉非替尼的敏感性。开展了一项1期研究，评估mTOR抑制剂依维莫司与吉非替尼联合用药，以确定晚期非小细胞肺癌（NSCLC）患者中依维莫司与吉非替尼的每日剂量。
对病情进展的NSCLC患者每日口服依维莫司和吉非替尼。患者按依维莫司每日剂量水平5毫克和10毫克分为3组入组。所有患者每日接受吉非替尼250毫克。
入组10例患者。依维莫司与每日250毫克吉非替尼联用时，最大耐受剂量为5毫克。2例接受依维莫司10毫克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，两种药物在t(max)、C(max)和AUC(0 - 8h)方面均无一致的显著相互作用。在8例可评估反应的患者中发现2例部分影像学缓解。
建议进一步研究每日5毫克依维莫司与每日250毫克吉非替尼联合用药。已确定的2例影像学缓解令人鼓舞。NSCLC患者的2期试验正在进行。
