Efficacy and biomarker analysis of nivolumab plus gemcitabine and cisplatin in patients with unresectable or metastatic biliary tract cancers: results from a phase II study
Efficacy and biomarker analysis of nivolumab plus gemcitabine and cisplatin in patients with unresectable or metastatic biliary tract cancers: results from a phase II study
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纳武单抗联合吉西他滨和顺铂治疗不可切除或转移性胆道癌患者的疗效和生物标志物分析：II 期研究结果。
DOI：
10.1136/jitc-2019-000367
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发表时间：
2020-01-01
影响因子：
10.9
通讯作者：
Han, Weidong
中科院分区：
文献类型：
--
作者：
Feng, Kaichao;Liu, Yang;Han, Weidong
背景不可切除或转移性胆道癌（BTC）患者的预后低得令人无法接受。本研究旨在确定免疫检查点抑制剂nivolumab联合化疗治疗晚期btc的疗效、安全性和预测性生物标志物。方法：在这项开放标签、单臂、II期试验中，化疗和免疫治疗组合由吉西他滨1000mg /m(2)、顺铂75mg /m(2)和纳武单抗3mg /kg组成，每3周给药一次，最多6个周期。对在联合治疗后达到疾病控制的患者给予吉西他滨加尼伏鲁那的维持治疗。主要终点为客观有效率。次要结局包括安全性、疾病控制率（DCR）、无进展生存期（PFS）和总生存期（OS）。探索性目的是评估预测临床反应和预后的生物标志物。结果32例患者入组，中位年龄为60岁（27-69岁）。截至2019年9月31日，中位随访时间为12.8个月（95% CI 10.8至14.8）。27例可评价反应的患者接受了中位4 （IQR, 3-6）个周期的联合治疗，其中15例（55.6%）患者达到客观缓解，其中5例（18.6%）患者达到完全缓解（CR）， DCR为92.6%。在A队列中对吉西他滨或顺铂化疗耐药的6例患者中，1例达到CR， 1例达到部分缓解。在B队列中，21名化疗患者中有13名（61.9%）实现了客观缓解。A+B组所有患者的中位PFS为6.1个月。中位OS为8.5个月，12个月OS率为33.3%。最常见的3级或以上不良事件是血小板减少症（56%）和中性粒细胞减少症（22%）。适应度可能是预测临床反应的生物标志物。治疗期间血清可溶性FasL、MCP-1和干扰素γ的变化与预后相关。结论：Nivolumab联合吉西他滨和顺铂治疗晚期btc患者具有良好的疗效和可管理的安全性。
Background The prognosis of patients with unresectable or metastatic biliary tract cancer (BTC) is unacceptably low. This study aimed to determine the efficacy, safety and predictive biomarkers of the immune checkpoint inhibitor nivolumab in combination with chemotherapy in advanced BTCs.Methods In this open-label, single-arm, phase II trial, a chemotherapy and immunotherapy combination consisting of gemcitabine 1000 mg/m(2), cisplatin 75 mg/m(2) and nivolumab 3 mg/kg was administered every 3 weeks for up to six cycles. Maintenance treatment with gemcitabine plus nivolurnab was administered to patients achieving disease control following the combination therapy. The primary outcome was the objective response rate. Secondary outcomes included safety, disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). The exploratory objective was to assess biomarkers for predicting clinical response and prognosis.Results Thirty-two patients with a median age of 60 (range 27-69) years were enrolled. As of September 31, 2019, the median follow-up was 12.8 (95% CI 10.8 to 14.8) months. Twenty-seven response-evaluable patients received a median of 4 (IQR, 3-6) cycles of combination therapy, of whom 15 (55.6%) patients achieved an objective response, including 5 (18.6%) with a complete response (CR), and the DCR was 92.6%. Of the six patients in cohort A who were resistant to gemcitabine-based or cisplatin-based chemotherapy, one achieved CR and one achieved partial response. Thirteen of 21 chemotherapynaive patients (61.9%) in cohort B achieved an objective response. The median PFS of all patients in cohorts A+B was 6.1 months. The median OS was 8.5 months, with a 33.3% 12-month OS rate. The most frequent grade 3 or higher adverse events were thrombocytopenia (56%) and neutropenia (22%). Fitness might be a biomarker for predicting clinical response. On-therapy changes in serum soluble FasL, MCP-1 and interferon-gamma were correlated with prognosis.Conclusions Nivolumab in combination with gemcitabine and cisplatin offers promising efficacy and a manageable safety profile for patients with advanced BTCs.