IMPORTANCE Isocitrate dehydrogenase 1 (IDH1) variations occur in up to approximately 20% of patients with intrahepatic cholangiocarcinoma. In the ClarIDHy trial, progression-free survival as determined by central review was significantly improved with ivosidenib vs placebo. OBJECTIVE To report the final overall survival (OS) results from the ClarIDHy trial, which aimed to demonstrate the efficacy of ivosidenib (AG-120)-a first-in-class, oral, small-molecule inhibitor of mutant IDH1-vs placebo for patients with unresectable or metastatic cholangiocarcinoma with IDH1 mutation. DESIGN, SETTING, AND PARTICIPANTS This multicenter, randomized, double-blind, placebo-controlled, clinical phase 3 trial was conducted from February 20, 2017, to May 31, 2020, at 49 hospitals across 6 countries among patients aged 18 years or older with cholangiocarcinoma with IDH1 mutation whose disease progressed with prior therapy. INTERVENTIONS Patients were randomized 2:1 to receive ivosidenib, 500 mg, once daily or matched placebo. Crossover from placebo to ivosidenib was permitted if patients had disease progression as determined by radiographic findings. MAIN OUTCOMES AND MEASURES The primary end point was progression-free survival as determined by blinded independent radiology center (reported previously). Overall survival was a key secondary end point. The primary analysis of OS followed the intent-to-treat principle. Other secondary end points included objective response rate, safety and tolerability, and quality of life. RESULTS Overall, 187 patients (median age, 62 years [range, 33-83 years]) were randomly assigned to receive ivosidenib (n = 126; 82 women [65%]; median age, 61 years [range, 33-80 years]) or placebo (n = 61; 37 women [61%]; median age, 63 years [range, 40-83 years]); 43 patients crossed over from placebo to ivosidenib. The primary end point of progression-free survival was reported elsewhere. Median OS was 10.3 months (95% CI, 7.8-12.4 months) with ivosidenib vs 7.5 months (95% CI, 4.8-11.1 months) with placebo (hazard ratio, 0.79 [95% CI, 0.56-1.12]; 1-sided P = .09). When adjusted for crossover, median OS with placebo was 5.1 months (95% CI, 3.8-7.6 months; hazard ratio, 0.49 [95% CI, 0.34-0.70]; 1-sided P < .001). The most common grade 3 or higher treatment-emergent adverse event (≥5%) reported in both groups was ascites (11 patients [9%] receiving ivosidenib and 4 patients [7%] receiving placebo). Serious treatment-emergent adverse events considered ivosidenib related were reported in 3 patients (2%). There were no treatment-related deaths. Patients receiving ivosidenib reported no apparent decline in quality of life compared with placebo. CONCLUSIONS AND RELEVANCE This randomized clinical trial found that ivosidenib was well tolerated and resulted in a favorable OS benefit vs placebo, despite a high rate of crossover. These data, coupled with supportive quality of life data and a tolerable safety profile, demonstrate the clinical benefit of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02989857.

中文翻译：

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Ivosidenib 对伴有 IDH1 突变的晚期胆管癌患者的最终总体生存疗效结果：3 期随机临床 ClarIDHy 试验。

重要性异柠檬酸脱氢酶 1 (IDH1) 变异发生在大约 20% 的肝内胆管癌患者中。在 ClarIDHy 试验中，与安慰剂相比，ivosidenib 显着改善了中央审查确定的无进展生存期。目的 报告 ClarIDHy 试验的最终总生存期 (OS) 结果，该试验旨在证明 ivosidenib (AG-120)（一种一流的、口服的、突变 IDH1 的小分子抑制剂）与安慰剂相比的疗效患有 IDH1 突变的不可切除或转移性胆管癌患者。设计、设置和参与者 这项多中心、随机、双盲、安慰剂对照、临床 3 期试验于 2017 年 2 月 20 日至 2020 年 5 月 31 日进行，在 6 个国家的 49 家医院的 18 岁或以上患有 IDH1 突变的胆管癌患者中，这些患者的疾病在先前的治疗中进展。干预 患者以 2:1 的比例随机接受 ivosidenib，500 mg，每天一次或匹配的安慰剂。如果患者有放射学检查结果确定的疾病进展，则允许从安慰剂交叉到 ivosidenib。主要结果和措施 主要终点是由盲法独立放射中心确定的无进展生存期（先前报告）。总生存期是一个关键的次要终点。OS 的主要分析遵循意向治疗原则。其他次要终点包括客观反应率、安全性和耐受性以及生活质量。结果 总体而言，187 名患者（中位年龄，62 岁 [范围，33-83 岁]）被随机分配接受 ivosidenib（n = 126；82 名女性 [65%]；中位年龄，61 岁 [范围，33-80 岁]）或安慰剂（n = 61；37 名女性 [61% ]；中位年龄，63 岁 [范围，40-83 岁])；43 名患者从安慰剂过渡到 ivosidenib。无进展生存期的主要终点在别处报告。ivosidenib 组的中位 OS 为 10.3 个月（95% CI，7.8-12.4 个月），而安慰剂组为 7.5 个月（95% CI，4.8-11.1 个月）（风险比，0.79 [95% CI，0.56-1.12]；单侧P = .09）。校正交叉后，安慰剂组的中位 OS 为 5.1 个月（95% CI，3.8-7.6 个月；风险比，0.49 [95% CI，0.34-0.70]；单侧 P < .001）。两组报告的最常见的 3 级或更高级别的治疗出现的不良事件（≥5%）是腹水（11 名患者 [9%] 接受 ivosidenib 和 4 名患者 [7%] 接受安慰剂）。3 名患者（2%）报告了认为与 ivosidenib 相关的严重治疗中出现的不良事件。没有与治疗相关的死亡。与安慰剂相比，接受 ivosidenib 的患者报告生活质量没有明显下降。结论和相关性 这项随机临床试验发现 ivosidenib 耐受性良好，与安慰剂相比，尽管交叉率很高，但其 OS 获益更佳。这些数据，加上支持性的生活质量数据和可耐受的安全性概况，证明了 ivosidenib 对伴有 IDH1 突变的晚期胆管癌患者的临床益处。试验注册 ClinicalTrials.gov 标识符：NCT02989857。与安慰剂相比，接受 ivosidenib 的患者报告生活质量没有明显下降。结论和相关性 这项随机临床试验发现 ivosidenib 耐受性良好，与安慰剂相比，尽管交叉率很高，但其 OS 获益更佳。这些数据，加上支持性的生活质量数据和可耐受的安全性概况，证明了 ivosidenib 对伴有 IDH1 突变的晚期胆管癌患者的临床益处。试验注册 ClinicalTrials.gov 标识符：NCT02989857。与安慰剂相比，接受 ivosidenib 的患者报告生活质量没有明显下降。结论和相关性 这项随机临床试验发现 ivosidenib 耐受性良好，与安慰剂相比，尽管交叉率很高，但其 OS 获益更佳。这些数据，加上支持性的生活质量数据和可耐受的安全性概况，证明了 ivosidenib 对伴有 IDH1 突变的晚期胆管癌患者的临床益处。试验注册 ClinicalTrials.gov 标识符：NCT02989857。再加上支持性的生活质量数据和可耐受的安全性，证明了 ivosidenib 对伴有 IDH1 突变的晚期胆管癌患者的临床益处。试验注册 ClinicalTrials.gov 标识符：NCT02989857。再加上支持性的生活质量数据和可耐受的安全性，证明了 ivosidenib 对伴有 IDH1 突变的晚期胆管癌患者的临床益处。试验注册 ClinicalTrials.gov 标识符：NCT02989857。