Department of Internal Medicine I, Endocrine and Diabetes Unit, University Hospital, University of Würzburg, Würzburg, Germany; Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany; Central Laboratory, Research Unit, University Hospital Würzburg, Würzburg, Germany.
Department of Medic Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy.
Lancet Oncol. 2015 Apr;16(4):426-35. doi: 10.1016/S1470-2045(15)70081-1. Epub 2015 Mar 18.
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.
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.
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.
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.
Astellas.
肾上腺皮质癌是一种罕见且侵袭性很强的癌症，目前可用的治疗方法有限。Linsitinib（OSI-906）是一种强效的口服小分子 IGF-1R 和胰岛素受体抑制剂，具有可接受的耐受性和初步的抗肿瘤活性证据。我们评估了 linsitinib 与安慰剂在晚期肾上腺皮质癌患者中的疗效。
在这项国际性、双盲、安慰剂对照的 3 期研究中，在 9 个国家的临床地点招募了组织学证实的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中央随机化系统以 2:1 的比例随机分配每天两次口服 150mg linsitinib 或安慰剂，并根据既往用于治疗肾上腺皮质癌的全身细胞毒性化疗、东部合作肿瘤学组表现状态以及随机时是否使用一种或多种口服降糖药物进行分层。分配通过盲法块大小和随机块分层进行隐藏。主要终点是总生存期，从随机化日期到任何原因导致的死亡。主要分析是在意向治疗人群中进行的。该研究在 ClinicalTrials.gov 注册，编号为 NCT00924989。
2009 年 12 月 2 日至 2011 年 7 月 11 日，共纳入 139 名患者，其中 90 名分配至 linsitinib 组，49 名分配至安慰剂组。由于数据监测委员会建议，基于数据，linsitinib 未能增加无进展生存期或总生存期，试验于 2012 年 3 月 19 日揭盲。在数据库锁定时，根据 92 例死亡数据，未观察到 linsitinib 与安慰剂之间的总生存期差异（中位数 323 天[95%CI 256-507]与 356 天[249-556]；风险比 0.94[95%CI 0.61-1.44]；p=0.77）。linsitinib 组最常见的 3 级或更高级别的治疗相关不良事件为疲劳（3 例[3%]患者 vs 安慰剂组无患者）、恶心（2 例[2%] vs 无）和高血糖（2 例[2%] vs 无）。linsitinib 组无任何不良事件被认为与治疗有关；安慰剂组 1 例死亡（归因于脓毒症和巨结肠）被认为与治疗有关。
Linsitinib 并未增加总生存期，因此不能作为该一般患者人群的治疗推荐。进一步研究 IGF-1R 和胰岛素受体抑制剂，并结合对应答者的基因谱分析，可能为肾上腺皮质癌的个体化和改善治疗选择铺平道路。
Astellas。
