Dong Xiang, Zhang Zewu, Zhang Qin, Chen Lu, Cao Guangtai, Liu Chen, Song Tianqiang, Lu Wei, Zhang Wei
Department of Hepatobiliary Cancer, Research Center for Prevention and Treatment of Liver Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital. National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Huan Hu Xi Road, Tianjin, 300060, China.
Department of Hepatobiliary Surgery, Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine, Cangzhou, Hebei, China.
J Cancer Res Clin Oncol. 2023 May;149(5):1917-1927. doi: 10.1007/s00432-022-04166-z. Epub 2022 Jul 8.
The combination of gemcitabine-based chemotherapy and immune checkpoint inhibitors has a good efficacy in advanced biliary tract cancer (BTC). The multi-target TKI lenvatinib and NGS-guided targeted therapy are also promising in BTC treatment. This study aimed to explore the performance of GemOX plus sintilimab and TKI (either lenvatinib or by NGS-guided targeted therapy) for local advanced or metastatic BTCs.
This prospective single-arm study included patients with local advanced or metastatic BTCs and applied intravenous infusion of standard GemOX plus sintilimab and lenvatinib (no targetable gene alterations) or targeted therapy based on NGS (olaparib for BRCA1/2 mutation, dasatinib for IDH1/2 mutation, afatinib for EGFR amplification, lenvatinib for PDGFR and KIT mutation, and lenvatinib for FGFR/KIT mutation).
From November 2020 to December 2021, 22 patients BTCs (6 GBC, 14 iCCA, 1 pCCA and 1 dCCA cases) were enrolled, with an average age of 58.4 years. Partial response (PR) was achieved in 10 cases, stable disease (SD) in 9 cases and progression disease (PD) in 3 cases (13.6%). The objective response rate (ORR) was 45.5%, and the disease control rate (DCR) was 86.4%. During the treatment, the incidence of adverse reactions was 81.8%, and the incidence of grade 3/4 adverse events was 9.09%. For 14 patients with NGS, 5 patients were treated by targeted therapy and there were 1 SD and 4 PR cases. For four patients with positive PD-L1 expression, the ORR was 100%. While among the three patients with super-progression markers such as RET, MDM2 and FGF14/STK24, there were two SD and one PD cases.
In patients with advanced BTCs, the combination of GemOX plus sintilimab and lenvatinib or NGS-guided targeted therapy showed promising ORR and DCR, especially for the patients with positive PD-L1 expression and targetable gene alterations.
基于吉西他滨的化疗与免疫检查点抑制剂联合应用在晚期胆管癌（BTC）中具有良好疗效。多靶点酪氨酸激酶抑制剂（TKI）乐伐替尼和基于二代测序（NGS）引导的靶向治疗在BTC治疗中也颇具前景。本研究旨在探索吉西他滨奥沙利铂（GemOX）联合信迪利单抗及TKI（乐伐替尼或基于NGS引导的靶向治疗）用于局部晚期或转移性BTC的疗效。
这项前瞻性单臂研究纳入了局部晚期或转移性BTC患者，采用静脉输注标准的GemOX联合信迪利单抗及乐伐替尼（无可靶向的基因改变）或基于NGS的靶向治疗（奥拉帕利用于BRCA1/2突变，达沙替尼用于IDH1/2突变，阿法替尼用于表皮生长因子受体（EGFR）扩增，乐伐替尼用于血小板衍生生长因子受体（PDGFR）和原癌基因c-KIT（KIT）突变，以及乐伐替尼用于成纤维细胞生长因子受体（FGFR）/KIT突变）。
2020年11月至2021年12月，共纳入22例BTC患者（6例胆囊癌（GBC）、14例肝内胆管癌（iCCA）、1例肝门部胆管癌（pCCA）和1例远端胆管癌（dCCA）），平均年龄58.4岁。10例患者达到部分缓解（PR），9例疾病稳定（SD），3例疾病进展（PD）（13.6%）。客观缓解率（ORR）为45.5%，疾病控制率（DCR）为86.4%。治疗期间，不良反应发生率为81.8%，3/4级不良事件发生率为9.09%。对于14例进行NGS检测的患者，5例接受靶向治疗，其中1例SD，4例PR。对于4例程序性死亡受体配体1（PD-L1）表达阳性的患者，ORR为100%。而在3例具有RET、小鼠双微体2（MDM2）和FGF14/丝氨酸/苏氨酸蛋白激酶24（STK24）等超进展标志物的患者中，2例SD，1例PD。
在晚期BTC患者中，GemOX联合信迪利单抗及乐伐替尼或基于NGS引导的靶向治疗显示出有前景的ORR和DCR，尤其是对于PD-L1表达阳性和有可靶向基因改变的患者。
