Lessons learned: Treatment with BEZ235 has not been shown to demonstrate increased efficacy compared with everolimus and may be associated with a poorer tolerability profile.The hypothesis of dual targeting of the phosphatidylinositol 3-kinase and mammalian target of rapamycin pathways in patients with advanced pancreatic neuroendocrine tumors may warrant further study using other agents.
Background: This phase II study investigated whether targeting the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway via PI3K, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) inhibition using BEZ235 may be more effective than mTORC1 inhibition with everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET) who are naïve to mTOR inhibitor therapy.
Methods: Patients with advanced pNET were randomized (1:1) to oral BEZ235 400 mg twice daily or oral everolimus 10 mg once daily on a continuous dosing schedule. The primary endpoint was progression-free survival (PFS). Secondary endpoints included safety, overall response rate (ORR), overall survival (OS), and time to treatment failure.
Results: Enrollment in this study was terminated early (62 enrolled of the 140 planned). The median PFS was 8.2 months (95% confidence interval [CI]: 5.3 to not evaluable [NE]) with BEZ235 versus 10.8 months (95% CI: 8.1-NE) with everolimus (hazard ratio 1.53; 95% CI: 0.72-3.25). The most commonly reported all-grade adverse events (>50% of patients regardless of study treatment relationship) with BEZ235 were diarrhea (90.3%), stomatitis (74.2%), and nausea (54.8%).
Conclusion: BEZ235 treatment in mTOR inhibitor-naïve patients with advanced pNET did not demonstrate increased efficacy compared with everolimus and may be associated with a poorer tolerability profile.
经验总结
• 与依维莫司相比,BEZ235 治疗未显示出疗效增加,可能与耐受性较差相关。
• 晚期胰腺神经内分泌肿瘤患者中磷脂酰肌醇3‐激酶和哺乳动物雷帕霉素靶蛋白通路的双靶向假设可能需要使用其他药物进行进一步研究。
摘要
背景.该II期研究考察的内容是,在未接受过哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂治疗的晚期胰腺神经内分泌肿瘤(pNET)患者中,使用BEZ235靶向通过磷脂酰肌醇3‐激酶(PI3K)、mTOR复合物1(mTORC1)和mTOR复合物2(mTORC2)抑制的PI3K/mTOR通路是否比使用依维莫司的mTORC1抑制效果更好。
方法.晚期pNET患者随机以连续给药方案(1:1)口服BEZ235 400 mg每天两次或口服依维莫司10 mg每天一次。主要终点为无进展生存期(PFS)。次要终点包括安全性、总缓解率(ORR)、总生存期(OS)和至治疗失败的时间。
结果.本研究的入组提前终止(计划入组140名,实际入组62名)。BEZ235组的中位PFS为8.2个月[95%置信区间(CI):5.3至无法评估(NE)],而依维莫司组为10.8个月(95% CI:8.1‐NE)(风险比 1.53;95% CI:0.72‐3.25)。BEZ235最常报告的所有等级不良事件(>50%的患者,不考虑研究治疗关系)为腹泻(90.3%)、口腔炎(74.2%)和恶心(54.8%)。
结论.未接受过mTOR抑制剂治疗的晚期pNET患者的BEZ235治疗未显示出与依维莫司相比增强的疗效,这可能与耐受性较差相关。
Trial registration: ClinicalTrials.gov NCT01628913.
©AlphaMed Press; the data published online to support this summary is the property of the authors.