Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study
Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study
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DOI：
10.1016/s1470-2045(15)70081-1
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发表时间：
2015-04-01
期刊：
影响因子：
51.1
通讯作者：
Hammer, Gary D.
中科院分区：
文献类型：
--
作者：
Fassnacht, Martin;Berruti, Alfredo;Hammer, Gary D.
背景
肾上腺皮质癌是一种罕见的侵袭性癌症，可选择的治疗方法很少。林西替尼（OSI - 906）是一种有效的口服小分子胰岛素样生长因子1受体（IGF - 1R）和胰岛素受体抑制剂，已显示出可接受的耐受性以及抗肿瘤活性的初步证据。我们将林西替尼与安慰剂进行对比，以研究其在晚期肾上腺皮质癌患者中的疗效。
方法
在这项国际性、双盲、安慰剂对照的3期研究中，从9个国家的临床研究点招募了经组织学证实为局部晚期或转移性肾上腺皮质癌的成年患者。患者通过基于网络的集中随机化系统按2∶1的比例随机分配，每日两次口服150mg林西替尼或安慰剂，并根据既往肾上腺皮质癌全身细胞毒性化疗情况、东部肿瘤协作组（ECOG）体能状态以及随机分组时是否使用一种或多种口服降糖治疗进行分层。通过盲法区组大小和随机区组排列隐藏分配情况。主要终点是总生存期，从随机分组日期计算至任何原因导致的死亡。主要分析在意向性治疗人群中进行。本研究在ClinicalTrials.gov注册，注册号为NCT00924989。
结果
在2009年12月2日至2011年7月11日期间，共纳入139例患者，其中90例被分配至林西替尼组，49例被分配至安慰剂组。由于林西替尼未能提高无进展生存期或总生存期，根据数据监测委员会的建议，该试验于2012年3月19日揭盲。在数据库锁定时，基于92例死亡病例，林西替尼组和安慰剂组在总生存期方面未观察到差异（中位生存期分别为323天[95%置信区间256 - 507]和356天[249 - 556]；风险比为0.94[95%置信区间0.61 - 1.44]；P = 0.77）。林西替尼组中最常见的3级或更严重的治疗相关不良事件为疲劳（3例[3%]患者，安慰剂组无）、恶心（2例[2%]，安慰剂组无）和高血糖（2例[2%]，安慰剂组无）。林西替尼组中无不良事件被认为与治疗相关；安慰剂组中有1例死亡（因败血症和巨结肠）被认为与治疗相关。
解释
林西替尼未能提高总生存期，因此不建议将其作为这类一般患者人群的治疗方法。对胰岛素样生长因子1受体和胰岛素受体抑制剂的进一步研究，以及对反应者进行基因分析，可能为肾上腺皮质癌的个体化和改进治疗选择铺平道路。
Background Adrenocortical carcinoma is a rare, aggressive cancer for which few treatment options are available. Linsitinib (OSI-906) is a potent, oral small molecule inhibitor of both IGF-1R and the insulin receptor, which has shown acceptable tolerability and preliminary evidence of anti-tumour activity. We assessed linsitinib against placebo to investigate efficacy in patients with advanced adrenocortical carcinoma.Methods In this international, double-blind, placebo-controlled phase 3 study, adult patients with histologically confirmed locally advanced or metastatic adrenocortical carcinoma were recruited at clinical sites in nine countries. Patients were randomly assigned (2:1) twice-daily 150 mg oral linsitinib or placebo via a web-based, centralised randomisation system and stratified according to previous systemic cytotoxic chemotherapy for adrenocortical carcinoma, Eastern Cooperative Oncology Group performance status, and use of one or more oral antihyperglycaemic therapy at randomisation. Allocation was concealed by blinded block size and permuted block randomisation. The primary endpoint was overall survival, calculated from date of randomisation until death from any cause. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00924989.Findings Between Dec 2, 2009, and July 11, 2011, 139 patients were enrolled, of whom 90 were assigned to linsitinib and 49 to placebo. The trial was unblinded on March 19, 2012, based on data monitoring committee recommendation due to the failure of linsitinib to increase either progression-free survival or overall survival. At database lock and based on 92 deaths, no difference in overall survival was noted between linsitinib and placebo (median 323 days [95% CI 256-507] vs 356 days [249-556]; hazard ratio 0.94 [95% CI 0.61-1.44]; p= 0.77). The most common treatment-related adverse events of grade 3 or worse in the linsitinib group were fatigue (three [3%] patients vs no patients in the placebo group), nausea (two [2%] vs none), and hyperglycaemia (two [2%] vs none). No adverse events in the linsitinib group were deemed to be treatment related; one death (due to sepsis and megacolon) in the placebo group was deemed to be treatment related.Interpretation Linsitinib did not increase overall survival and so cannot be recommended as treatment for this general patient population. Further studies of IGF-1R and insulin receptor inhibitors, together with genetic profiling of responders, might pave the way toward individualised and improved therapeutic options in adrenocortical carcinoma.