University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
Clin Cancer Res. 2010 Dec 1;16(23):5900-7. doi: 10.1158/1078-0432.CCR-10-0802. Epub 2010 Nov 2.
Mammalian target of rapamycin (mTOR) is a promising target in small cell lung cancer (SCLC). We designed a phase II study of everolimus, an mTOR inhibitor, in previously treated, relapsed SCLC.
Patients were treated with everolimus 10 mg orally daily until disease progression. The primary endpoint was disease control rate (DCR) at 6 weeks. PI3K/Akt signaling pathway biomarkers were evaluated on baseline tumor tissue.
A total of 40 patients were treated: 23 had 1 prior regimen/sensitive relapse, 4 had 1 prior regimen/refractory, and 13 had 2 prior regimens. Twenty-eight patients received 2 or more cycles of everolimus, 7 received 1 cycle, and 5 did not complete the first cycle. Best response in 35 evaluable patients: 1 (3%) partial response (in sensitive relapse), 8 (23%) stable disease, and 26 (74%) progression; DCR at 6 weeks was 26% (95% CI = 11-40). Median survival was 6.7 months and median time to progression was 1.3 months. Grade 3 toxicities included thrombocytopenia (n = 2), neutropenia (n = 2), infection (n = 2), pneumonitis (n = 1), fatigue (n = 1), elevated transaminases (n = 1), diarrhea (n = 2), and acute renal failure (n = 1). High phosphorylated AKT expression was modestly associated with overall survival (HR = 2.07; 95% CI = 0.97-4.43). Baseline S6 kinase protein expression was significantly higher in patients with disease control versus patients with progression (P = 0.0093).
Everolimus was well tolerated but had limited single-agent antitumor activity in unselected previously treated patients with relapsed SCLC. Further evaluation in combination regimens for patients with sensitive relapse may be considered.
哺乳动物雷帕霉素靶蛋白（mTOR）是小细胞肺癌（SCLC）的一个有前途的靶点。我们设计了一项关于依维莫司（一种 mTOR 抑制剂）在既往治疗、复发的 SCLC 中的 II 期研究。
患者每天口服依维莫司 10mg，直至疾病进展。主要终点为 6 周时的疾病控制率（DCR）。在基线肿瘤组织上评估 PI3K/Akt 信号通路生物标志物。
共治疗 40 例患者：23 例有 1 次既往方案/敏感复发，4 例有 1 次既往方案/难治性，13 例有 2 次既往方案。28 例患者接受了 2 个或更多周期的依维莫司治疗，7 例接受了 1 个周期，5 例未完成第一个周期。35 例可评价患者的最佳反应：1 例（3%）部分缓解（在敏感复发中），8 例（23%）稳定疾病，26 例（74%）进展；6 周时的 DCR 为 26%（95%CI=11-40）。中位生存期为 6.7 个月，中位疾病进展时间为 1.3 个月。3 级毒性包括血小板减少症（n=2）、中性粒细胞减少症（n=2）、感染（n=2）、肺炎（n=1）、疲劳（n=1）、转氨酶升高（n=1）、腹泻（n=2）和急性肾衰竭（n=1）。高磷酸化 AKT 表达与总生存期中度相关（HR=2.07；95%CI=0.97-4.43）。与疾病进展患者相比，疾病控制患者的 S6 激酶蛋白表达在基线时显著更高（P=0.0093）。
依维莫司耐受性良好，但在未经选择的既往治疗、复发的 SCLC 患者中，单药治疗的抗肿瘤活性有限。对于敏感复发的患者，可考虑联合治疗方案进一步评估。
