Purpose No standard treatment exists for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. Fibroblast growth factor receptor 2 ( FGFR2) fusions/translocations are present in 13% to 17% of intrahepatic cholangiocarcinomas. BGJ398, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown preliminary clinical activity against tumors with FGFR alterations. Methods A multicenter, open-label, phase II study ( ClinicalTrials.gov identifier: NCT02150967) evaluated BGJ398 antitumor activity in patients age ≥ 18 years with advanced or metastatic cholangiocarcinoma containing FGFR2 fusions or other FGFR alterations whose disease had progressed while receiving prior therapy. Patients received BGJ398 125 mg once daily for 21 days, then 7 days off (28-day cycles). The primary end point was investigator-assessed overall response rate. Results Sixty-one patients (35 women; median age, 57 years) with FGFR2 fusion (n = 48), mutation (n = 8), or amplification (n = 3) participated. At the prespecified data cutoff (June 30, 2016), 50 patients had discontinued treatment. All responsive tumors contained FGFR2 fusions. The overall response rate was 14.8% (18.8% FGFR2 fusions only), disease control rate was 75.4% (83.3% FGFR2 fusions only), and estimated median progression-free survival was 5.8 months (95% CI, 4.3 to 7.6 months). Adverse events included hyperphosphatemia (72.1% all grade), fatigue (36.1%), stomatitis (29.5%), and alopecia (26.2%). Grade 3 or 4 treatment-related adverse events occurred in 25 patients (41%) and included hyperphosphatemia (16.4%), stomatitis (6.6%), and palmar-plantar erythrodysesthesia (4.9%). Conclusion BGJ398 is a first-in-class FGFR kinase inhibitor with manageable toxicities that shows meaningful clinical activity against chemotherapy-refractory cholangiocarcinoma containing FGFR2 fusions. This promising antitumor activity supports continued development of BGJ398 in this highly selected patient population.

中文翻译：

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BGJ398 在 FGFR 改变的晚期胆管癌患者中的 II 期研究

目的 对于一线吉西他滨治疗失败的胆管癌患者，尚无标准治疗方法。成纤维细胞生长因子受体 2 (FGFR2) 融合/易位存在于 13% 至 17% 的肝内胆管癌中。BGJ398 是一种口服生物可利用的选择性泛 FGFR 激酶抑制剂，已显示出针对具有 FGFR 改变的肿瘤的初步临床活性。方法 一项多中心、开放标签、II 期研究（ClinicalTrials.gov 注册号：NCT02150967）评估了 BGJ398 对年龄≥18 岁的晚期或转移性胆管癌患者的抗肿瘤活性，这些患者患有含有 FGFR2 融合或其他 FGFR 改变的晚期或转移性胆管癌，这些患者在接受既往治疗时疾病进展。患者接受 BGJ398 125 mg 每天一次，持续 21 天，然后停药 7 天（28 天周期）。主要终点是研究者评估的总体缓解率。结果 61 名具有 FGFR2 融合（n = 48）、突变（n = 8）或扩增（n = 3）的患者（35 名女性；中位年龄 57 岁）参与。在预先指定的数据截止日期（2016 年 6 月 30 日），50 名患者停止了治疗。所有反应性肿瘤均包含 FGFR2 融合。总反应率为 14.8%（仅 FGFR2 融合 18.8%），疾病控制率为 75.4%（仅 FGFR2 融合 83.3%），预计中位无进展生存期为 5.8 个月（95% CI，4.3 至 7.6 个月）。不良事件包括高磷血症（72.1% 所有级别）、疲劳 (36.1%)、口腔炎 (29.5%) 和脱发 (26.2%)。25 名患者 (41%) 发生了 3 级或 4 级治疗相关不良事件，包括高磷血症 (16.4%)、口腔炎 (6.6%)、和掌跖红肿 (4.9%)。结论 BGJ398 是一种一流的 FGFR 激酶抑制剂，具有可控的毒性，对含有 FGFR2 融合的化疗难治性胆管癌显示出有意义的临床活性。这种有前途的抗肿瘤活性支持 BGJ398 在这一高度选择的患者群体中的持续发展。