BACKGROUND Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements. METHODS In this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13·5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov, NCT02924376, and enrolment is completed. FINDINGS Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17·8 months (IQR 11·6-21·3). 38 (35·5% [95% CI 26·5-45·4]) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 [60%] of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 [12%]), arthralgia (nine [6%]), stomatitis (eight [5%]), hyponatraemia (eight [5%]), abdominal pain (seven [5%]), and fatigue (seven [5%]). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven [5%]), pyrexia (seven [5%]), cholangitis (five [3%]), and pleural effusion (five [3%]). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 [42%]); no deaths were deemed to be treatment related. INTERPRETATION These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements. FUNDING Incyte Corporation.

中文翻译：

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Pemigatinib 用于治疗既往治疗过的局部晚期或转移性胆管癌：一项多中心、开放标签、2 期研究。

背景成纤维细胞生长因子受体（FGFR）2基因改变参与胆管癌的发病机制。Pemigatinib 是一种选择性、有效的口服 FGFR1、2 和 3 抑制剂。本研究评估了 Pemigatinib 对于既往接受过治疗、伴有或不伴有 FGFR2 融合或重排的局部晚期或转移性胆管癌患者的安全性和抗肿瘤活性。方法 在这项多中心、开放标签、单臂、多队列 2 期研究 (FIGHT-202) 中，年龄为 18 岁或以上、在至少接受过一次治疗且符合东部肿瘤合作组 (ECOG) 表现状态后出现疾病进展的患者从美国、欧洲、中东和亚洲的 146 个学术或社区中心招募的 0-2 名患者被分配到三个队列之一：FGFR2 融合或重排的患者、有其他 FGF/FGFR 改变的患者或患者没有 FGF/FGFR 改变。所有入组患者均接受每日一次口服 13·5 mg 培米加替尼的起始剂量（21 天周期；用药 2 周，停药 1 周），直至疾病进展、出现不可接受的毒性、撤回同意或医生决定。主要终点是 FGFR2 融合或重排患者中获得客观缓解的患者比例，在接受至少一剂培米加替尼的所有患者中进行集中评估。本研究已在 ClinicalTrials.gov 注册，NCT02924376，并已完成入组。结果 2017年1月17日至2019年3月22日期间，入组了146名患者：107名患者存在FGFR2融合或重排，20名患者存在其他FGF/FGFR改变，18名患者无FGF/FGFR改变，1名患者存在未确定的FGF/FGFR改变。中位随访时间为 17·8 个月 (IQR 11·6-21·3)。38 名（35·5% [95% CI 26·5-45·4]）FGFR2 融合或重排患者获得了客观缓解（3 名完全缓解和 35 名部分缓解）。总体而言，无论何种原因，高磷酸盐血症是最常见的所有级别不良事件（146 名患者中的 88 名 [60%]）。93 名 (64%) 患者出现 3 级或更严重的不良事件（无论原因如何）；最常见的是低磷血症（18 [12%]）、关节痛（9 [6%]）、口腔炎（8 [5%]）、低钠血症（8 [5%]）、腹痛（7 [5%]）、和疲劳（七[5%]）。65 名（45%）患者出现严重不良事件；最常见的是腹痛（7 例 [5%]）、发热（7 例 [5%]）、胆管炎（5 例 [3%]）和胸腔积液（5 例 [3%]）。总体而言，71 名患者 (49%) 在研究期间死亡，最常见的原因是疾病进展 (61 名患者 [42%])；没有死亡被认为与治疗有关。解释 这些数据支持pemigatinib对于既往接受过治疗的FGFR2融合或重排的胆管癌患者的治疗潜力。资助因塞特公司。