Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: Results of a phase II study
Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: Results of a phase II study
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DOI：
10.1200/jco.2008.16.7858
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发表时间：
2008-09-10
影响因子：
45.3
通讯作者：
Meric-Bernstam, Funda
中科院分区：
文献类型：
--
作者：
Yao, James C.;Phan, Alexandria T.;Meric-Bernstam, Funda
目的评价依维莫司（RAD001）联合奥曲肽长效可重复用药（LAR）治疗晚期中低级别神经内分泌肿瘤的疗效。方法RAD001 5 mg/d（30例）或10 mg/d（30例），奥曲肽LAR 30 mg/d，每28 d一次。30例类癌和30例胰岛细胞患者入组。结果治疗总有效率为20%。根据每个方案，13例患者部分缓解（22%），42例患者病情稳定（SD; 70%）， 5例患者病情进展（8%）。总中位无进展生存期（PFS）为60周。已知SD患者入组时的中位PFS长于疾病进展的患者（74周vs 50周；P = 0.01）。中位总生存期尚未达到。1年、2年和3年生存率分别为83%、81%和78%。在37例嗜铬粒蛋白A升高的患者中，26例（70%）达到正常化或降低50%以上。最常见的毒性是轻度口腔溃疡。在bb0 = 10%的患者中发生的3/4级毒性包括低磷血症（11%）、疲劳（11%）和腹泻（11%）。治疗与乳酸脱氢酶（LDH）的剂量依赖性升高有关。第4周LDH升高低于109 U/L的患者PFS较短（38 vs 69周；P = 0.01）。在接受选择性配对治疗前和治疗后活检的患者中，治疗还与增殖标志物Ki-67的降低相关（P = 0.04）。结论rad001与奥曲肽LAR联合用药5、10 mg/d耐受性良好，具有良好的抗肿瘤活性。正在进行确证性研究。
PurposeEvaluate the activity of everolimus (RAD001) in combination with octreotide long-acting repeatable (LAR) in patients with advanced low- to intermediate-grade neuroendocrine tumors.MethodsTreatment consisted of RAD001 5 mg/d (30 patients) or 10 mg/d (30 patients) and octreotide LAR 30 mg every 28 days. Thirty carcinoid and 30 islet cell patients were enrolled.ResultsIntent-to-treat response rate was 20%. Per protocol, there were 13 with partial responses (22%), 42 with stable disease (SD; 70%), and five patients with progressive disease (8%). Overall median progression-free survival (PFS) was 60 weeks. Median PFS for patients with known SD at entry was longer than for those who had progressive disease (74 v 50 weeks; P = .01). Median overall survival has not been reached. One-, 2-, and 3-year survival rates were 83%, 81%, and 78%, respectively. Among 37 patients with elevated chromogranin A, 26 (70%) achieved normalization or more than 50% reduction. Most common toxicity was mild aphthous ulceration. Grade 3/4 toxicities occurring in >= 10% of patients included hypophosphatemia (11%), fatigue (11%), and diarrhea (11%). Treatment was associated with a dose-dependent rise in lactate dehydrogenase (LDH). Those with lower than 109 U/L rise in LDH at week 4 had shorter PFS (38 v 69 weeks; P = .01). Treatment was also associated with a decrease in proliferation marker Ki-67 among patients who underwent optional paired pre- and post-treatment biopsy (P = .04).ConclusionRAD001 at 5 or 10 mg/d was well tolerated in combination with octreotide LAR, with promising antitumor activity. Confirmatory studies are ongoing.