Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study.
Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study.
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DOI：
10.1016/s1470-2045(20)30157-1
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发表时间：
2020-06
期刊：
影响因子：
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通讯作者：
Zhu AX
中科院分区：
文献类型：
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作者：
Abou-Alfa GK;Macarulla T;Javle MM;Kelley RK;Lubner SJ;Adeva J;Cleary JM;Catenacci DV;Borad MJ;Bridgewater J;Harris WP;Murphy AG;Oh DY;Whisenant J;Lowery MA;Goyal L;Shroff RT;El-Khoueiry AB;Fan B;Wu B;Chamberlain CX;Jiang L;Gliser C;Pandya SS;Valle JW;Zhu AX
异柠檬酸脱氢酶1（IDH 1）突变发生在约13%的肝内胆管癌患者中，这是一种相对罕见的癌症，临床结局较差。这项国际III期研究的目的是评估ivosidenib（AG-120）-突变IDH 1的小分子靶向抑制剂-在既往接受过治疗的IDH 1突变型胆管癌患者中的疗效和安全性。这项多中心、随机、双盲、安慰剂对照、III期研究纳入了来自6个国家49家医院的患者，这些患者年龄至少为18岁，患有组织学证实的晚期IDH 1突变型胆管癌，在既往治疗中发生进展，既往接受过最多2种晚期疾病治疗方案，东部肿瘤协作组体能状态评分为0或1，和根据实体瘤疗效评价标准第1.1版定义的可测量病灶。患者被随机分配（2：1），区组大小为6，并通过交互式基于网络的应答系统按既往晚期疾病全身治疗方案的数量分层，接受口服ivosidenib 500 mg或匹配的安慰剂，每日一次，连续28天为一个周期。根据研究者评估，允许安慰剂与伊沃昔单抗交叉治疗放射学进展。主要终点是独立中心审查的无进展生存期。意向治疗人群用于主要疗效分析。在所有接受过至少一剂ivosidenib或安慰剂的患者中评估安全性。Enhanced已完成;本研究已在ClinicalTrials.gov注册，NCT 02989857。在2017年2月20日至2019年1月31日期间，对230例患者进行了资格评估，截至2019年1月31日数据截止日期，185例患者被随机分配至ivosidenib（n=124）或安慰剂（n=61）。无进展生存期的中位随访时间为6.9个月（IQR 2.8 - 10.9）。与安慰剂相比，ivosidenib组的无进展生存期显著改善（中位2.7个月[95% CI 1.6 - 4.2] vs 1.4个月[1.4 - 1.6];风险比0.37; 95% CI 0.25 - 0.54;单侧p<0.0001）。两个治疗组中最常见的3级或更严重的不良事件是腹水（59名接受安慰剂的患者中有4名[7%]，121名接受ivosidenib的患者中有9名[7%]）。在接受ivosidenib的121名患者中有36名（30%）报告了严重不良事件，在接受安慰剂的59名患者中有13名（22%）报告了严重不良事件。无治疗相关死亡。与安慰剂组相比，ivosidenib组的无进展生存期显著改善，并且ivosidenib的耐受性良好。这项研究显示了在晚期IDH 1突变型胆管癌中靶向IDH 1突变的临床益处。
Isocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. The aim of this international phase 3 study was to assess the efficacy and safety of ivosidenib (AG-120)—a small-molecule targeted inhibitor of mutated IDH1—in patients with previously treated IDH1-mutant cholangiocarcinoma. This multicentre, randomised, double-blind, placebo-controlled, phase 3 study included patients from 49 hospitals in six countries aged at least 18 years with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on previous therapy, and had up to two previous treatment regimens for advanced disease, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (2:1) with a block size of 6 and stratified by number of previous systemic treatment regimens for advanced disease to oral ivosidenib 500 mg or matched placebo once daily in continuous 28-day cycles, by means of an interactive web-based response system. Placebo to ivosidenib crossover was permitted on radiological progression per investigator assessment. The primary endpoint was progression-free survival by independent central review. The intention-to-treat population was used for the primary efficacy analyses. Safety was assessed in all patients who had received at least one dose of ivosidenib or placebo. Enrolment is complete; this study is registered with ClinicalTrials.gov, NCT02989857. Between Feb 20, 2017, and Jan 31, 2019, 230 patients were assessed for eligibility, and as of the Jan 31, 2019 data cutoff date, 185 patients were randomly assigned to ivosidenib (n=124) or placebo (n=61). Median follow-up for progression-free survival was 6·9 months (IQR 2·8–10·9). Progression-free survival was significantly improved with ivosidenib compared with placebo (median 2·7 months [95% CI 1·6–4·2] vs 1·4 months [1·4–1·6]; hazard ratio 0·37; 95% CI 0·25–0·54; one-sided p<0·0001). The most common grade 3 or worse adverse event in both treatment groups was ascites (four [7%] of 59 patients receiving placebo and nine [7%] of 121 patients receiving ivosidenib). Serious adverse events were reported in 36 (30%) of 121 patients receiving ivosidenib and 13 (22%) of 59 patients receiving placebo. There were no treatment-related deaths. Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivosidenib was well tolerated. This study shows the clinical benefit of targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma.