Long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosine kinase inhibitor therapy
Long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosine kinase inhibitor therapy
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DOI：
10.1093/annonc/mdw228
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发表时间：
2016-09-01
影响因子：
50.5
通讯作者：
George, S.
中科院分区：
文献类型：
--
作者：
Ben-Ami, E.;Barysauskas, C. M.;George, S.
我们的研究提供了最长的随访晚期GIST患者在这个II期试验中接受瑞格非尼治疗。观察到外显子11 KIT突变和SDH缺陷型GIST的特别益处。自由使用的剂量减少和治疗中断需要优化长期药物exposure.This制药商发起的试验提供了理由的III期GRID研究导致全球监管机构批准瑞格非尼作为三线治疗转移性胃肠道间质瘤（GIST）的患者。我们报告的基因型分析，长期的安全性，并从这个初始试验的活性结果瑞格非尼在GIST.The试验进行了2010年2月至2014年1月之间，在成人转移性GIST患者中，失败后，至少伊马替尼和舒尼替尼。患者口服瑞戈非尼，160 mg，每日一次，28天为一个周期的第1-21天。临床获益率（CBR），定义为完全或部分缓解（PR），或按照RECIST 1.1标准持续16周的疾病稳定，无进展生存期（PFS），总生存期（OS），长期安全性数据，以及功能成像的代谢反应。中位随访时间为41个月。33例患者中有25例记录了CBR [76%; 95%置信区间（CI）58%-89%]，包括6例PR。中位PFS为13.2个月（95% CI 9.2-18.3个月），包括4例在研究结束时保持无进展的患者，每例患者均实现了超过3年的临床获益（范围36.8-43.5个月）。中位OS为25个月（95% CI 13.2-39.1个月）。携带KIT 11号外显子突变的患者中位PFS最长（13.4个月），而携带KIT/PDGFRA野生型、非SDH缺陷型肿瘤的患者中位PFS为1.6个月（P < 0.0001）。长期安全性特征与既往报告一致;手足皮肤反应和高血压是剂量降低的最常见原因。值得注意的是，瑞戈非尼在SDH缺陷型GIST患者中诱导了客观缓解和持久获益。对接受瑞戈非尼治疗的转移性GIST患者的长期随访表明，原发性KIT 11号外显子突变患者和SDH缺陷型GIST患者尤其获益。经常需要调整剂量以管理治疗相关毒性。NCT 01068769。
Our study provides the longest follow-up of advanced GIST patients treated with regorafenib in this phase II trial. Particular benefit among exon 11 KIT mutations and SDH-deficient GIST were observed. Liberal use of dose reductions and treatment breaks were required to optimize long-term drug exposure.This investigator-initiated trial provided the justification for the phase III GRID study resulting in worldwide regulatory approval of regorafenib as a third-line therapy for patients with metastatic gastrointestinal stromal tumors (GIST). We report the genotype analyses, long-term safety, and activity results from this initial trial of regorafenib in GIST.The trial was conducted between February 2010 and January 2014, among adult patients with metastatic GIST, after failure of at least imatinib and sunitinib. Patients received regorafenib orally, 160 mg once daily, days 1-21 of a 28-day cycle. Clinical benefit rate (CBR), defined as complete or partial response (PR), or stable disease lasting a parts per thousand yen16 weeks per RECIST 1.1, progression-free survival (PFS), overall survival (OS), long-term safety data, and metabolic response by functional imaging were assessed.Thirty-three patients received at least one dose of regorafenib. The median follow-up was 41 months. CBR was documented in 25 of 33 patients [76%; 95% confidence interval (CI) 58% to 89%], including six PRs. The median PFS was 13.2 months (95% CI 9.2-18.3 months) including four patients who remained progression-free at study closure, each achieving clinical benefit for more than 3 years (range 36.8-43.5 months). The median OS was 25 months (95% CI 13.2-39.1 months). Patients whose tumors harbored a KIT exon 11 mutation demonstrated the longest median PFS (13.4 months), whereas patients with KIT/PDGFRA wild-type, non-SDH-deficient tumors experienced a median 1.6 months PFS (P < 0.0001). Long-term safety profile is consistent with previous reports; hand-foot skin reaction and hypertension were the most common reasons for dose reduction. Notably, regorafenib induced objective responses and durable benefit in SDH-deficient GIST.Long-term follow-up of patients with metastatic GIST treated with regorafenib suggests particular benefit among patients with primary KIT exon 11 mutations and those with SDH-deficient GIST. Dose modifications are frequently required to manage treatment-related toxicities.NCT01068769.