Chest：依维莫司开启肺神经内分泌肿瘤治疗新时代

肺神经内分泌肿瘤（NETs）大约占肺癌的四分之一，其中中低分化患者预后差。对于早期、局限期的肺神经内分泌肿瘤可选择外科手术切除，但对于晚期或无法手术切除患者到目前为止还没有统一的治疗方案。针对这种情况，来自意大利米兰上消化道和神经内分泌肿瘤内科的Nicola Fazio博士等人对RADIANT-2这项随机对照试验结果进行了亚组分析，研究结果发表于2013年4月4日的《胸部》（Chest）杂志上。作者发现依维莫司联合长效奥曲肽可显著延长肺神经内分泌肿瘤患者的无病生存时间（PFS）。

该研究为依维莫司联合长效奥曲肽在治疗晚期NETs（RADIANT-2）临床试验的前瞻性再分析，RADIANT-2试验为一项随机对照试验，共有429例NETs患者纳入研究。研究者从中挑选出44例低中分化的肺神经内分泌肿瘤，其中33例患者接受依维莫司联合长效奥曲肽治疗，11例患者接受安慰剂联合长效奥曲肽治疗，以无疾病进展为主要的研究终点。

研究结果表明，接受依维莫司联合长效奥曲肽在治疗的33例患者中67%的患者肿瘤缩小，而对照组中只有27%的患者肿瘤缩小。中位无病生存时间（PFS）接受依维莫司联合长效奥曲肽组和安慰剂联合长效奥曲肽组分别为：13.63月和5.59月（P=0.228），依维莫司联合长效奥曲肽治疗组的中位PFS是对照组2.4倍。此外发现，依维莫司的主要毒性反应是口腔炎、皮疹、疲劳、腹泻等。

该研究发现，对于晚期肺NET在长效奥曲肽的基础上加用依维莫司可以显著延长患者的PFS。这一研究为进一步临床评估依维莫司治疗肺NET提供了宝贵的证据，开启了治疗晚期肺NET的新时代。
与依维莫司相关的拓展阅读：

• The Lancet：依维莫司可明显抑制结节性硬化症的发展
• 依维莫司可降低乳腺癌的骨骼效应
• FDA批准依维莫司口服混悬剂治疗儿童罕见脑瘤
• EMA推荐依维莫司治疗乳腺癌
• FDA批准依维莫司治疗结节性硬化症相关性肾肿瘤
• NEJM：依维莫司用于绝经后的激素受体阳性的晚期乳腺癌
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Everolimus Plus Octreotide LAR in Patients With Advanced Lung Neuroendocrine Tumors: Analysis of the Phase III, Randomized, Placebo-Controlled RADIANT-2 Study.
ABSTRACT BACKGROUND
The incidence of neuroendocrine tumors (NET) has increased approximately 5-fold since the 1980s. A similar increase in the incidence of lung NET has been reported, but therapy has not been optimized.
METHODS
This exploratory subanalysis evaluated the efficacy and safety of everolimus plus octreotide LAR in a cohort of patients with low-/intermediate-grade advanced lung NET from the phase III, randomized, placebo-controlled RADIANT-2 study. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate, overall survival, change from baseline in biomarker levels, and safety outcomes.
RESULTS
Patients were randomly assigned to everolimus plus octreotide LAR (n = 33) or placebo plus octreotide LAR (n = 11). Median PFS was 13.63 months in the everolimus plus octreotide LAR arm compared with 5.59 months in the placebo plus octreotide LAR arm (relative risk for progression: HR, 0.72; 95% CI, 0.31-1.68; P = 0.228). More patients receiving everolimus plus octreotide LAR (67%) experienced minor tumor shrinkage (not partial response as per RECIST) than those receiving placebo plus octreotide LAR (27%). Most frequently reported adverse events (AEs) included stomatitis, rash, diarrhea, and asthenia. This was consistent with the overall RADIANT-2 trial and the safety profile of everolimus.
CONCLUSION
This exploratory subgroup analysis of the RADIANT-2 trial indicates that in patients with advanced lung NET, the addition of everolimus to octreotide LAR improves median PFS by 2.4-fold compared with placebo plus octreotide LAR. These clinically significant observations support the continued evaluation of everolimus treatment regimens in this patient population.Trial RegistrationEverolimus and Octreotide in Patients With Advanced Carcinoid Tumor,ClinicalTrials.gov, NCT004120611European Institute of Oncology, Milan, Italy; Departments of 2Medical Sciences and 3Endocrine Oncology, Uppsala University, Uppsala, Sweden; 4Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital University of Oxford, Oxford, United Kingdom; 5Novartis Pharmaceuticals Corporation, Florham Park, New Jersey, USA; 6Cedars-Sinai Medical Center, Los Angeles, CaliforniaCorresponding author: Nicola Fazio, MD Director of Upper Gastrointestinal and Neuroendocrine Tumors Unit Department of Medicine Via Ripamonti, 435-20141 Milan, Italy Email: nicola.fazio@ieo.itFinancial Support Funded by Novartis Pharmaceuticals Corporation.