Division of Hematology and Medical Oncology, Portland Veterans Affairs Health Care System, Knight Cancer Institute, Oregon Health and Science University, Portland.
SWOG Statistical Center, Seattle, Washington.
JAMA Oncol. 2017 Jul 1;3(7):944-952. doi: 10.1001/jamaoncol.2016.6728.
After identification of activating mutations of the KIT gene in gastrointestinal stromal tumor (GIST)-the most common sarcomaof the gastrointestinal tract-a phase 2 study demonstrated efficacy of imatinib mesylate in patients with metastatic GIST harboring a KIT exon 11 mutation. Initial results of long-term follow-up have found a survival benefit in this subgroup of patients.
To assess the long-term survival of patients with GIST who were treated in SWOG study S0033 and to present new molecular data regarding treatment outcomes.
DESIGN, SETTING, AND PARTICIPANTS: In this follow-up of randomized clinical trial participants (from December 15, 2000, to September 1, 2001), patients were required to have advanced GIST that was not surgically curable. Postprotocol data collection occurred from August 29, 2011, to July 15, 2015. Using modern sequencing technologies, 20 cases originally classified as having wild-type tumors underwent reanalysis. This intergroup study was coordinated by SWOG, a cooperative group member within the National Clinical Trials Network, with participation by member/affiliate institutions. This follow-up was not planned as part of the initial study.
Patients were randomized to 1 of 2 dose levels of imatinib mesylate, including 400 mg once daily (400 mg/d) vs 400 mg twice daily (800 mg/d), and were treated until disease progression or unacceptable toxic effects of the drug occurred.
The primary end point was overall survival. Updated survival data were correlated with clinical and molecular factors, and patterns of postprotocol therapies were enumerated and described in long-term survivors.
Of 695 eligible patients (376 men [54.1%]; 319 women [45.9%]; mean [SD] age, 60.1 [14.0] years), 189 survived 8 years or longer, including 95 in the 400-mg/d dose arm and 94 in the 800-mg/d arm. The 10-year estimate of overall survival was 23% (95% CI, 20%-26%). Among 142 long-term survivors, imatinib was the sole therapy administered in 69 (48.6%), with additional systemic agents administered to 54 patients (38.0%). Resequencing studies of 20 cases originally classified as KIT/PDGFRA wild-type GIST revealed that 17 (85.0%) harbored a pathogenic mutation, most commonly a mutation of a subunit of the succinate dehydrogenase complex.
A subset of patients with metastatic GIST experiences durable, long-term overall survival with imatinib treatment. Although this study provides guidance for management of GIST harboring the most common KIT and PDGFRA mutations, optimal management of other genotypic subtypes remains unclear.
clinicaltrials.gov Identifier: NCT00009906.
在胃肠道间质瘤（GIST）中鉴定出 KIT 基因的激活突变后 - 这是胃肠道最常见的肉瘤 - 一项 2 期研究表明，伊马替尼甲磺酸盐在转移性 GIST 中具有 KIT 外显子 11 突变的患者中具有疗效。长期随访的初步结果发现，该亚组患者具有生存获益。
评估接受 SWOG 研究 S0033 治疗的 GIST 患者的长期生存情况，并提出有关治疗结果的新分子数据。
设计、地点和参与者：在这项随机临床试验参与者的随访中（从 2000 年 12 月 15 日至 2001 年 9 月 1 日），要求患者患有无法通过手术治愈的晚期 GIST。协议后数据收集于 2011 年 8 月 29 日至 2015 年 7 月 15 日进行。使用现代测序技术，对 20 例最初分类为野生型肿瘤的病例进行了重新分析。这项分组间研究由 SWOG 协调，SWOG 是国家临床试验网络中的合作组成员，其成员/附属机构参与。这次随访不是初始研究的一部分。
患者被随机分配至伊马替尼甲磺酸盐的 2 个剂量水平之一，包括每天 400mg 一次（400mg/d）与每天 400mg 两次（800mg/d），并在疾病进展或不可接受的药物毒性发生之前接受治疗。
主要终点是总生存。更新的生存数据与临床和分子因素相关联，并且在长期幸存者中列举和描述了协议后治疗的模式。
在 695 名合格患者（376 名男性[54.1%]；319 名女性[45.9%]；平均[SD]年龄，60.1[14.0]岁）中，189 名患者存活 8 年或更长时间，其中 95 名在 400mg/d 剂量组，94 名在 800mg/d 剂量组。总生存的 10 年估计值为 23%（95%CI，20%-26%）。在 142 名长期幸存者中，伊马替尼是 69 名（48.6%）唯一接受的治疗，另外 54 名患者（38.0%）接受了额外的系统药物治疗。对最初分类为 KIT/PDGFRA 野生型 GIST 的 20 例病例的重新测序研究显示，其中 17 例（85.0%）存在致病性突变，最常见的是琥珀酸脱氢酶复合物亚基的突变。
转移性 GIST 的亚组患者接受伊马替尼治疗可获得持久的长期总生存。尽管这项研究为具有最常见 KIT 和 PDGFRA 突变的 GIST 提供了管理指导，但其他基因型亚型的最佳管理仍不清楚。
clinicaltrials.gov 标识符：NCT00009906。
