Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
James Cancer Hospital, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; Department of Internal Medicine, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
Lancet Gastroenterol Hepatol. 2021 Oct;6(10):803-815. doi: 10.1016/S2468-1253(21)00196-5. Epub 2021 Aug 3.
Treatment options are sparse for patients with advanced cholangiocarcinoma after progression on first-line gemcitabine-based therapy. FGFR2 fusions or rearrangements occur in 10-16% of patients with intrahepatic cholangiocarcinoma. Infigratinib is a selective, ATP-competitive inhibitor of fibroblast growth factor receptors. We aimed to evaluate the antitumour activity of infigratinib in patients with locally advanced or metastatic cholangiocarcinoma, FGFR2 alterations, and previous gemcitabine-based treatment.
This multicentre, open-label, single-arm, phase 2 study recruited patients from 18 academic centres and hospitals in the USA, Belgium, Spain, Germany, Singapore, Taiwan, and Thailand. Eligible participants were aged 18 years or older, had histologically or cytologically confirmed, locally advanced or metastatic cholangiocarcinoma and FGFR2 fusions or rearrangements, and were previously treated with at least one gemcitabine-containing regimen. Patients received 125 mg of oral infigratinib once daily for 21 days of 28-day cycles until disease progression, intolerance, withdrawal of consent, or death. Radiological tumour evaluation was done at baseline and every 8 weeks until disease progression via CT or MRI of the chest, abdomen, and pelvis. The primary endpoint was objective response rate, defined as the proportion of patients with a best overall response of a confirmed complete or partial response, as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors, version 1.1. The primary outcome and safety were analysed in the full analysis set, which comprised all patients who received at least one dose of infigratinib. This trial is registered with ClinicalTrials.gov, NCT02150967, and is ongoing.
Between June 23, 2014, and March 31, 2020, 122 patients were enrolled into our study, of whom 108 with FGFR2 fusions or rearrangements received at least one dose of infigratinib and comprised the full analysis set. After a median follow-up of 10·6 months (IQR 6·2-15·6), the BICR-assessed objective response rate was 23·1% (95% CI 15·6-32·2; 25 of 108 patients), with one confirmed complete response in a patient who only had non-target lesions identified at baseline and 24 partial responses. The most common treatment-emergent adverse events of any grade were hyperphosphataemia (n=83), stomatitis (n=59), fatigue (n=43), and alopecia (n=41). The most common ocular toxicity was dry eyes (n=37). Central serous retinopathy-like and retinal pigment epithelial detachment-like events occurred in 18 (17%) patients, of which ten (9%) were grade 1, seven (6%) were grade 2, and one (1%) was grade 3. There were no treatment-related deaths.
Infigratinib has promising clinical activity and a manageable adverse event profile in previously treated patients with locally advanced or metastatic cholangiocarcinoma harbouring FGFR2 gene fusions or rearrangements, and so represents a potential new therapeutic option in this setting.
QED Therapeutics and Novartis.
吉西他滨为基础的一线治疗进展后，晚期胆管癌患者的治疗选择有限。10-16%的肝内胆管癌患者存在 FGFR2 融合或重排。英菲格拉替尼是一种选择性、ATP 竞争性成纤维细胞生长因子受体抑制剂。我们旨在评估英菲格拉替尼在局部晚期或转移性胆管癌、FGFR2 改变和先前接受基于吉西他滨治疗的患者中的抗肿瘤活性。
这项多中心、开放标签、单臂、2 期研究从美国、比利时、西班牙、德国、新加坡、中国台湾和泰国的 18 个学术中心和医院招募了患者。符合条件的患者年龄在 18 岁或以上，组织学或细胞学证实为局部晚期或转移性胆管癌，且存在 FGFR2 融合或重排，并且之前接受过至少一种含吉西他滨的治疗方案。患者接受每日一次口服 125mg 英菲格拉替尼，28 天为一个周期，21 天为一个治疗周期，直至疾病进展、不耐受、患者撤回同意或死亡。在基线和每 8 周通过胸部、腹部和骨盆的 CT 或 MRI 进行肿瘤影像学评估，直至疾病进展。主要终点是客观缓解率，定义为根据实体瘤反应评价标准 1.1，由盲法独立中心审查（BICR）评估的最佳总体缓解（完全缓解或部分缓解）患者比例。主要结局和安全性在全分析集中进行分析，该分析集包括至少接受过一次英菲格拉替尼治疗的所有患者。这项试验在 ClinicalTrials.gov 上注册，注册号为 NCT02150967，正在进行中。
在 2014 年 6 月 23 日至 2020 年 3 月 31 日期间，共有 122 名患者入组了我们的研究，其中 108 名 FGFR2 融合或重排患者接受了至少一剂英菲格拉替尼，纳入全分析集。中位随访 10.6 个月（IQR 6.2-15.6）后，BICR 评估的客观缓解率为 23.1%（95%CI 15.6-32.2；108 例患者中有 25 例），1 例患者仅基线时存在非靶病灶，1 例患者确认完全缓解，24 例患者部分缓解。任何级别的最常见治疗相关不良事件是高磷血症（n=83）、口腔炎（n=59）、疲劳（n=43）和脱发（n=41）。最常见的眼部毒性是干眼症（n=37）。中央浆液性视网膜病变样和视网膜色素上皮脱离样事件发生在 18 例（17%）患者中，其中 10 例（9%）为 1 级，7 例（6%）为 2 级，1 例（1%）为 3 级。无治疗相关死亡。
英菲格拉替尼在先前接受过治疗的局部晚期或转移性胆管癌患者中具有良好的临床疗效和可管理的不良事件谱，这些患者存在 FGFR2 基因融合或重排，因此代表了该患者群体的潜在新治疗选择。
QED Therapeutics 和诺华。
