Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial.
Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial.
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DOI：
10.1016/s0140-6736(12)61857-1
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发表时间：
2013-01-26
期刊：
影响因子：
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通讯作者：
GRID study investigators
中科院分区：
文献类型：
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作者：
Demetri GD;Reichardt P;Kang YK;Blay JY;Rutkowski P;Gelderblom H;Hohenberger P;Leahy M;von Mehren M;Joensuu H;Badalamenti G;Blackstein M;Le Cesne A;Schöffski P;Maki RG;Bauer S;Nguyen BB;Xu J;Nishida T;Chung J;Kappeler C;Kuss I;Laurent D;Casali PG;GRID study investigators
到目前为止，只有两种药物，伊马替尼和舒尼替尼，显示出对胃肠道间质瘤(GIST)患者的临床益处，但几乎所有转移性GIST最终都对这些药物产生抗药性，导致致命的疾病进展。这项3期试验评估了瑞格拉非尼在至少伊马替尼和舒尼替尼无效后进展的转移性和/或无法切除的胃肠道间质瘤患者中的有效性和安全性。患者被随机分成2：1，在每个4周周期的前3周，每天接受瑞格拉非尼160毫克口服或服用安慰剂，并在双臂给予最佳支持性治疗。主要终点是无进展生存期(PFS)。随着病情的发展，服用安慰剂的患者可以改用瑞格拉非尼。次要终点包括总存活率(OS)、客观应答率、疾病控制率(DCR：持续12周的≥持续稳定疾病加上完全或部分应答的比率)和安全性。这项试验在ClinicalTrials.gov(NCT01271712)上注册。从2011年1月至8月，在17个国家的57个中心对240名患者进行了筛查，199名患者随机接受瑞格拉非尼(n=133)或匹配的安慰剂(n=66)治疗。每一次独立盲中心回顾的中位PFS分别为4.8个月和0.9个月(危险比[HR]0.27，95%可信区间[CI]0.19-0.39；p<；0.0001)。进展后，服用安慰剂的66名患者中有56名(84.8%)转而服用瑞格拉非尼，导致两组患者的OS无显著差异(HR为0.77，95%CI为0.42-1.41；p=0.199)。部分缓解或病情稳定者，瑞格非尼组101例(75.9%)，安慰剂组23例(34.8%)。DCR分别为52.6%(70/133例)和9.1%(6/66例)。132名瑞格拉非尼患者中130名(98.5%)和66名安慰剂患者中45名(68.2%)报告了与药物相关的不良事件。与≥3级相关的不良反应最常见的是高血压(31/132，23.5%)、手足皮肤反应(26/132，19.7%)和腹泻(7/132，5.3%)。与安慰剂相比，在至少伊马替尼和舒尼替尼无效后进展的晚期GIST患者中，瑞格拉非尼显著改善了PFS和DCR。
To date, only two agents, imatinib and sunitinib, have shown clinical benefit in patients with gastrointestinal stromal tumours (GISTs), but almost all metastatic GISTs eventually develop resistance to these agents, resulting in fatal disease progression. This phase 3 trial assessed efficacy and safety of regorafenib in patients with metastatic and/or unresectable GIST progressing after failure of at least imatinib and sunitinib. Patients were randomised 2:1 to receive either regorafenib 160 mg orally daily or placebo, plus best supportive care in both arms, for the first 3 weeks of each 4-week cycle. The primary endpoint was progression-free survival (PFS). Upon disease progression, patients on placebo could cross over to regorafenib. Secondary endpoints included overall survival (OS), objective response rate, disease control rate (DCR: rate of durable stable disease lasting for ≥12 weeks plus complete or partial responses), and safety. This trial is registered at ClinicalTrials.gov (NCT01271712). From January to August 2011, 240 patients were screened at 57 centres in 17 countries, and 199 patients were randomised to receive regorafenib (n=133) or matching placebo (n=66). Median PFS per independent blinded central review was 4·8 months and 0·9 months, respectively (hazard ratio [HR] 0·27, 95% confidence interval [CI] 0·19–0·39; p<0·0001). Following progression, 56/66 patients (84·8%) on placebo crossed over to regorafenib, resulting in no significant difference in OS between study arms (HR 0·77, 95% CI 0·42–1·41; p=0·199). A best response of partial response or stable disease was observed in 101/133 patients (75·9%) on regorafenib and 23/66 patients (34·8%) on placebo. DCR was 52·6% (70/133 patients) and 9·1% (6/66 patients), respectively. Drug-related adverse events were reported in 130 (98·5%) of 132 regorafenib patients and 45 (68·2%) of 66 placebo patients. The most common grade ≥3 regorafenib-related adverse events were hypertension (31/132, 23·5%), hand–foot skin reaction (26/132, 19·7%), and diarrhoea (7/132, 5·3%). Regorafenib significantly improved PFS and DCR, compared with placebo, in patients with advanced GIST progressing after failure of at least imatinib and sunitinib.