Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.
Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.
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DOI：
10.1016/s1470-2045(20)30109-1
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发表时间：
2020-05
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影响因子：
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通讯作者：
Vogel A
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作者：
Abou-Alfa GK;Sahai V;Hollebecque A;Vaccaro G;Melisi D;Al-Rajabi R;Paulson AS;Borad MJ;Gallinson D;Murphy AG;Oh DY;Dotan E;Catenacci DV;Van Cutsem E;Ji T;Lihou CF;Zhen H;Féliz L;Vogel A
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、强效的FGFR 1、2和3口服抑制剂。本研究评价了pemigatinib在既往接受过治疗的局部晚期或转移性胆管癌伴和不伴FGFR 2融合或重排患者中的安全性和抗肿瘤活性。在这项多中心、开放标签、单组、多队列、II期研究中，（FIGHT-202），从美国、欧洲、中东和亚洲的146个学术或社区研究中心招募的18岁或18岁以上至少接受过一次既往治疗后疾病进展且东部肿瘤协作组（ECOG）体能状态为0-2的患者被分配到三个队列之一：具有FGFR 2融合或重排的患者、具有其他FGF/FGFR改变的患者或无FGF/FGFR改变的患者。所有入组患者均接受起始剂量13.5 mg口服pemigatinib，每日一次（21天为一周期;给药2周，停药1周），直至疾病进展、不可接受的毒性、撤回知情同意或医生决定。主要终点是FGFR 2融合或重排患者中达到客观缓解的患者比例，在接受至少一剂培美替尼的所有患者中进行集中评估。本研究注册于ClinicalTrials.gov，NCT 02924376，并完成入组。在2017年1月17日至2019年3月22日期间，146例患者入组：107例FGFR 2融合或重排，20例其他FGF/FGFR改变，18例无FGF/FGFR改变，1例FGF/FGFR改变未确定。中位随访时间为17.8个月（IQR 11.6 - 21.3）。38例（35.5%[95% CI 26.5 - 45.4]）FGFR 2融合或重排患者实现了客观缓解（3例完全缓解和35例部分缓解）。总体而言，高磷血症是最常见的所有级别不良事件，不考虑原因（88/146例患者[60%]）。93例（64%）患者发生了3级或更严重的不良事件（不考虑原因）;最常见的是低磷酸盐血症（18例[12%]）、关节痛（9例[6%]）、口腔炎（8例[5%]）、低钠血症（8例[5%]）、腹痛（7例[5%]）和疲劳（7例[5%]）。65例（45%）患者发生严重不良事件;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例（49%）患者在研究期间死亡，最常见的原因是疾病进展（61例[42%]）;没有死亡被认为与治疗相关。这些数据支持pemigatinib在既往接受过治疗的FGFR 2融合或重排胆管癌患者中的治疗潜力。Incyte Corporation.
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. 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 sitesin 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. 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. These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements. Incyte Corporation.