Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial
Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial
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DOI：
10.1016/s1470-2045(15)70156-7
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发表时间：
2015-06-01
期刊：
影响因子：
51.1
通讯作者：
Kim, Tae Won
中科院分区：
文献类型：
--
作者：
Li, Jin;Qin, Shukui;Kim, Tae Won
在国际随机3期CORRECT试验（NCT 01103323）中，瑞戈非尼显著改善了治疗难治性转移性结直肠癌患者的总生存期。在CORRECT的760例患者中，111例为亚洲人（主要是日本人）。这项3期试验是为了评估瑞戈非尼在更广泛的亚洲难治性转移性结直肠癌患者中的应用，而不是在CORRECT.Methods中进行的研究。这项随机、双盲、安慰剂对照、平行组、3期试验在中国大陆、香港、韩国、台湾和越南的25家医院进行，我们招募了18岁或以上患有进展性转移性结直肠癌的亚洲患者，这些患者之前接受过至少两种治疗线或无法耐受标准治疗。患者的东部肿瘤协作组体能状态为0或1，预期寿命至少为3个月，骨髓、肝脏和肾功能良好，无其他不受控制的医学疾病。我们随机分配病人（2：1;使用计算机生成的单中心随机化列表[由研究资助者准备]和交互式语音应答系统;区组大小为6;按转移部位[单个器官vs多个器官]和自诊断转移性疾病的时间[= 18个月]分层），在每个28天周期的第1-21天接受口服瑞戈非尼160 mg每日一次或安慰剂;两组患者均接受最佳支持治疗。参与者、研究者和研究资助者对治疗分配不知情。主要终点是总生存期，我们在意向治疗的基础上分析数据。本试验已在ClinicalTrials注册。在2012年4月29日至2013年2月6日期间，我们筛选了243名患者，并将204名患者随机分配接受瑞格非尼（136名[67%]）或安慰剂（68名[33%]）。在中位随访7.4个月后，（IQR 4.3-12.2），瑞戈非尼组的总生存期显著优于安慰剂组（风险比0.55，95%CI 0.40-0.77，单侧p=0.00016;瑞戈非尼组的中位总生存期为8.8个月[95% CI 7.3-9.8]，安慰剂组为6.3个月[4.8-7.6]。在136名瑞格非尼接受者中有132名（97%）和68名安慰剂接受者中有31名（46%）发生了药物相关不良事件。最常见的3级或3级以上瑞戈非尼相关不良事件为手足皮肤反应（瑞格非尼组136例患者中有22例[16%] vs安慰剂组0例），高血压（15例[11%] vs安慰剂组68例患者中的2例[3%]），高胆红素血症（9例[7%] vs 1例[1%]），低磷血症（9例[7%] vs无），丙氨酸氨基转移酶浓度升高（9例[7%] vs无），天冬氨酸转氨酶浓度升高（8例[6%] vs无）、脂肪酶浓度升高（6例[4%] vs 1例[1%]）和斑丘疹（6例[4%] vs无）。与药物相关的严重不良事件发生在瑞格非尼组的12名（9%）患者和安慰剂组的3名（4%）患者中。解释这项3期试验是第二个显示瑞格非尼与安慰剂相比在治疗难治性转移性结直肠癌患者中的总生存益处的试验，证实了瑞戈非尼作为标准治疗后疾病进展的患者的重要治疗选择的作用。在本试验中，之前的标准治疗不一定包括靶向治疗。在这种情况下，不良事件通常与瑞戈非尼已知的安全性特征一致。
Background In the international randomised phase 3 CORRECT trial (NCT01103323), regorafenib significantly improved overall survival versus placebo in patients with treatment-refractory metastatic colorectal cancer. Of the 760 patients in CORRECT, 111 were Asian (mostly Japanese). This phase 3 trial was done to assess regorafenib in a broader population of Asian patients with refractory metastatic colorectal cancer than was studied in CORRECT.Methods In this randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done in 25 hospitals in mainland China, Hong Kong, South Korea, Taiwan, and Vietnam, we recruited Asian patients aged 18 years or older with progressive metastatic colorectal cancer who had received at least two previous treatment lines or were unable to tolerate standard treatments. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and adequate bone marrow, liver, and renal function, without other uncontrolled medical disorders. We randomly allocated patients (2:1; with a computer-generated unicentric randomisation list [prepared by the study funder] and interactive voice response system; block size of six; stratified by metastatic site [single vs multiple organs] and time from diagnosis of metastatic disease [= 18 months]) to receive oral regorafenib 160 mg once daily or placebo on days 1-21 of each 28 day cycle; patients in both groups were also to receive best supportive care. Participants, investigators, and the study funder were masked to treatment assignment. The primary endpoint was overall survival, and we analysed data on an intention-to-treat basis. This trial is registered with ClinicalTrials. gov, number NCT01584830.Findings Between April 29, 2012, and Feb 6, 2013, we screened 243 patients and randomly assigned 204 patients to receive either regorafenib (136 [67%]) or placebo (68 [33%]). After a median follow-up of 7.4 months (IQR 4.3-12.2), overall survival was significantly better with regorafenib than it was with placebo (hazard ratio 0.55, 95% CI 0.40-0.77, one-sided p=0.00016; median overall survival 8.8 months [95% CI 7.3-9.8] in the regorafenib group vs 6.3 months [4.8-7.6] in the placebo group). Drug-related adverse events occurred in 132 (97%) of 136 regorafenib recipients and 31 (46%) of 68 placebo recipients. The most frequent grade 3 or higher regorafenib-related adverse events were hand-foot skin reaction (22 [16%] of 136 patients in the regorafenib group vs none in the placebo group), hypertension (15 [11%] vs two [3%] of 68 patients in the placebo group), hyperbilirubinaemia (nine [7%] vs one [1%]), hypophosphataemia (nine [7%] vs none), alanine aminotransferase concentration increases (nine [7%] vs none), aspartate aminotransferase concentration increases (eight [6%] vs none), lipase concentration increases (six [4%] vs one [1%]), and maculopapular rash (six [4%] vs none). Drug-related serious adverse events occurred in 12 (9%) patients in the regorafenib group and three (4%) in the placebo group.Interpretation This phase 3 trial is the second to show an overall survival benefit with regorafenib compared with placebo in patients with treatment-refractory metastatic colorectal cancer, substantiating the role of regorafenib as an important treatment option for patients whose disease has progressed after standard treatments. In this trial, preceding standard treatments did not necessarily include targeted treatments. Adverse events were generally consistent with the known safety profile of regorafenib in this setting.