Lessons learned: Everolimus does not have sufficient activity to justify its use as single agent in metastatic melanoma.Patients treated with 10 mg per day dose were most likely to require dose reductions.Everolimus appeared to reduce the numbers of regulatory T cells in approximately half of the treated patients; unfortunately, these effects were not correlated with clinical outcomes.
Background: Everolimus (RAD-001) is an orally active rapamycin analogue shown in preclinical data to produce cytostatic cell inhibition, which may be potentially beneficial in treating melanoma. We conducted a phase II study to evaluate the efficacy and safety of everolimus in patients with unresectable metastatic melanoma (MM).
Methods: This study included two cohorts; cohort 1 received 30 mg of everolimus by mouth (PO) weekly, and cohort 2 was dosed with 10 mg of everolimus PO daily. The endpoints of the study were safety, 16-week progression-free survival (PFS), overall survival (OS), and measures of immunomodulatory/antiangiogenic properties with therapy. Tumor samples before therapy and at week 8 of treatment were analyzed. Peripheral blood plasma or mononuclear cell isolates collected prior to therapy and at weeks 8 and 16 and at time of tumor progression were analyzed for vascular endothelial growth factor and regulatory T-cell (Treg) measurements.
Results: A total of 53 patients were enrolled in cohort 1 (n = 24) and cohort 2 (n = 29). Only 2 patients of the first 20 patients enrolled in cohort 2 had treatment responses (25%; 95% confidence interval, 8.6%-49.1%); this result did not allow full accrual to cohort 2, as the study was terminated for futility. Median OS was 12.2 months for cohort 1 versus 8.1 months in cohort 2; no PFS advantage was seen in either group (2.1 months vs. 1.8 months). Dose-limiting toxicities included grade 4 myocardial ischemia (3.4%); grade 3 fatigue, mucositis, and hyperglycemia (10.3%); and anorexia and anemia (6.9%). Everolimus significantly reduced the number of Tregs in approximately half of the treated patients; however, these effects were not correlated with clinical outcomes.
Conclusion: Everolimus does not have sufficient single-agent activity in MM; however, we have identified evidence of biological activity to provide a potential rationale for future combination studies.
经验获取
• 依维莫司的活性不足以证明可用作治疗转移性黑色素瘤的单一药物。
• 每天服用10mg的患者可能最需要减少剂量。
• 在接受依维莫司治疗的患者中,大约一半出现调节性T细胞数量减少;遗憾的是,这些效应与临床结果没有相关性。
摘要
背景. 临床前期数据显示,依维莫司(RAD‐001)是一种口服雷帕霉素活性类似物,具有抑制细胞生长的作用,可能对黑色素瘤的治疗具有潜在的益处。我们进行了一项II期研究,以评估依维莫司治疗不可切除转移性黑色素瘤(MM)患者的疗效和安全性。
方法. 本研究分为两组,第1组每周口服(PO)依维莫司30 mg,第2组每日口服依维莫司10 mg。研究终点包括:安全性、16周无进展生存期(PFS)、总生存期(OS)以及用治疗方法测量免疫调节/抗血管生成特性。分析治疗前及治疗第8周时的肿瘤标本。于治疗前、第8周、第16周及肿瘤进展期间,分别采集外周血浆或单核细胞分离物,对血管内皮生长因子(VEGF)及调节性T细胞(Treg)指标进行分析。
结果. 第1组(n=24)和第2组(n=29)共入组53名患者。第2组前20名入组患者中,仅有2名患者出现治疗反应(25%;95%置信区间:8.6%‐49.1%);这一结果不允许对第2组进行完全招募,因为本研究因无效而终止。第1组的中位OS为12.2个月,第2组为8.1个月;两组均无PFS优势(2.1个月vs 1.8个月)。剂量限制性毒性包括4级心肌缺血(3.4%)、3度疲乏、粘膜炎和高血糖(10.3%)、厌食及贫血(6.9%)。在依维莫司治疗的患者中,约一半患者的Treg数量显著减少,但是这些效应与临床结果无相关性。
结论 在MM治疗中,依维莫司没有足够的单药活性;然而,我们已经确定了生物活性的证据,为今后的联合研究提供了一个潜在的理论基础。
Trial registration: ClinicalTrials.gov NCT00098553.
© AlphaMed Press; the data published online to support this summary are the property of the authors.