不可切除胆道恶性肿瘤免疫及靶向治疗的现状与思考

doi:10.16139/j.1007-9610.2025.06.14

摘要/Abstract

摘要：

胆道恶性肿瘤（BTC）是一组高度恶性的实体瘤，5年生存率仅10%。对于不可切除的BTC病人，吉西他滨联合顺铂是既往标准的一线治疗方案。随着免疫与靶向疗法在其他实体瘤上取得显著的疗效，其在不可切除BTC中的疗效已有不少研究报道。本文概述不可切除BTC的靶免治疗现状，并重点介绍免疫检查点抑制剂（ICI）与靶向成纤维细胞生长因子受体（FGFR）、异柠檬酸脱氢酶（IDH）和人表皮生长因子受体2（HER2）等靶点的研究成果以及靶免治疗未来的发展趋势，以期对开发更有效的治疗策略有所裨益。

关键词: 胆道恶性肿瘤, 免疫治疗, 靶向治疗, 生物标志物

Abstract:

Biliary tract cancer (BTC) represents a group of highly malignant solid tumors with a five-year survival rate of only 10%. For patients with unresectable BTC, gemcitabine combined with cisplatin has been the conventional first-line treatment regimen. With the remarkable efficacy of immunotherapy and targeted therapy observed in other solid tumors, numerous studies have investigated their potential in unresectable BTC. This article provides an overview of the current status of targeted and immunotherapeutic approaches for unresectable BTC, with a focus on research advancements in immune checkpoint inhibitor (ICI) and targeted agents against fibroblast growth factor receptor(FGFR), isocitrate dehydrogenase(IDH), and human epidermal growth factor receptor 2(HER2), as well as future trends in immunotherapy and targeted therapy, aiming to contribute to the development of more effective treatment strategies.

Key words: Biliary tract cancer, Immunotherapy, Targeted therapy, Biomarker

中图分类号:

R735.8

余立钦, 严潇宇, 王蒲雄志, 王伟, 王坚. 不可切除胆道恶性肿瘤免疫及靶向治疗的现状与思考[J]. 外科理论与实践, 2025, 30(06): 544-550.

YU Liqin, YAN Xiaoyu, WANG Puxiongzhi, WANG Wei, WANG Jian. Current status and reflections on immunotherapy and targeted therapy for unresectable biliary tract cancer[J]. Journal of Surgery Concepts & Practice, 2025, 30(06): 544-550.

参考文献 65

[1]	TARIQ N U, MCNAMARA M G, VALLE J W. Biliary tract cancers: current knowledge, clinical candidates and future challenges[J]. Cancer Manag Res, 2019, 11:2623-2642. doi: 10.2147/CMAR URL
[2]	VALLE J W, LAMARCA A, GOYAL L, et al. New horizons for precision medicine in biliary tract cancers[J]. Cancer Discov, 2017, 7(9):943-962. doi: 10.1158/2159-8290.CD-17-0245 pmid: 28818953
[3]	BRANDI G, RIZZO A, DALL'OLIO F G, et al. Percutaneous radiofrequency ablation in intrahepatic cholangiocarcinoma: a retrospective single-center experience[J]. Int J Hyperthermia, 2020, 37(1):479-485. doi: 10.1080/02656736.2020.1763484 URL
[4]	ZHAO D Y, LIM K H. Current biologics for treatment of biliary tract cancers[J]. J Gastrointest Oncol, 2017, 8(3):430-440. doi: 10.21037/jgo.2017.05.04 pmid: 28736630
[5]	KIM R D, CHUNG V, ALESE O B, et al. A phase 2 multi-institutional study of nivolumab for patients with advanced refractory biliary tract cancer[J]. JAMA Oncol, 2020, 6(6):888-894. doi: 10.1001/jamaoncol.2020.0930 pmid: 32352498
[6]	PIHA-PAUL S A, OH D Y, UENO M, et al. Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: results from the KEYNOTE-158 and KEYNOTE-028 studies[J]. Int J Cancer, 2020, 147(8):2190-2198. doi: 10.1002/ijc.v147.8 URL
[7]	UENO M, IKEDA M, MORIZANE C, et al. Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: a non-randomised, multicentre, open-label, phase 1 study[J]. Lancet Gastroenterol Hepatol, 2019, 4(8):611-621. doi: 10.1016/S2468-1253(19)30086-X URL
[8]	HACK S P, ZHU A X. Atezolizumab: an investigational agent for the treatment of biliary tract cancer[J]. Expert Opin Investig Drugs, 2021, 30(10):1007-1015. doi: 10.1080/13543784.2021.1974838 URL
[9]	LIN J, YANG X, LONG J, et al. Pembrolizumab combined with lenvatinib as non-first-line therapy in patients with refractory biliary tract carcinoma[J]. Hepatobiliary Surg Nutr, 2020, 9(4):414-424. doi: 10.21037/hbsn URL
[10]	LEE S H, LEE H S, LEE S H, et al. Efficacy and safety of pembrolizumab for gemcitabine/cisplatin-refractory biliary tract cancer: a multicenter retrospective study[J]. J Clin Med, 2020, 9(6):1769. doi: 10.3390/jcm9061769 URL
[11]	MARABELLE A, LE D T, ASCIERTO P A, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase Ⅱ KEYNOTE-158 study[J]. J Clin Oncol, 2020, 38(1):1-10.
[12]	SILVA V W, ASKAN G, DANIEL T D, et al. Biliary carcinomas: pathology and the role of DNA mismatch repair deficiency[J]. Chin Clin Oncol, 2016, 5(5):62. doi: 10.21037/cco.2016.10.04 pmid: 27829276
[13]	MCNAMARA M G, JACOBS T, LAMARCA A, et al. Impact of high tumor mutational burden in solid tumors and challenges for biomarker application[J]. Cancer Treat Rev, 2020, 89:102084. doi: 10.1016/j.ctrv.2020.102084 URL
[14]	MARABELLE A, FAKIH M, LOPEZ J, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study[J]. Lancet Oncol, 2020, 21(10):1353-1365. doi: S1470-2045(20)30445-9 pmid: 32919526
[15]	LI W, WANG Y, YU Y, et al. Toripalimab in advanced biliary tract cancer[J]. Innovation (Camb), 2022, 3(4):100255.
[16]	JEONG S Y, HONG J Y, PARK J O, et al. The efficacy of immune checkpoint inhibitors in biliary tract cancer with KRAS mutation[J]. Therap Adv Gastroenterol, 2023, 16:17562848231170484.
[17]	CHEN X, WANG D, LIU J, et al. Genomic alterations in biliary tract cancer predict prognosis and immunotherapy outcomes[J]. J Immunother Cancer, 2021, 9(11):e003214. doi: 10.1136/jitc-2021-003214 URL
[18]	OH D Y, RUTH HE A, QIN S, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer[J]. NEJM Evid, 2022, 1(8):EVIDoa2200015.
[19]	KELLEY R K, UENO M, YOO C, et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial[J]. Lancet, 2023, 401(10391):1853-1865. doi: 10.1016/S0140-6736(23)00727-4 pmid: 37075781
[20]	OH D Y, HE A R, QIN S, et al. Durvalumab plus chemotherapy in advanced biliary tract cancer: 3-year overall survival update from the phase Ⅲ TOPAZ-1 study[J]. J Hepatol,2025:S0168-8278(25)02201-9.
[21]	CHEN X, WU X, WU H, et al. Camrelizumab plus gemcitabine and oxaliplatin (GEMOX) in patients with advanced biliary tract cancer: a single-arm, open-label, phase Ⅱ trial[J]. J Immunother Cancer, 2020, 8(2):e001240. doi: 10.1136/jitc-2020-001240 URL
[22]	CHEN X, QIN S, GU S, et al. Camrelizumab plus oxaliplatin-based chemotherapy as first-line therapy for advanced biliary tract cancer: a multicenter, phase 2 trial[J]. Int J Cancer, 2021, 149(11):1944-1954. doi: 10.1002/ijc.v149.11 URL
[23]	MONGE C, PEHRSSON E C, XIE C, et al. A phase Ⅱ study of pembrolizumab in combination with capecitabine and oxaliplatin with molecular profiling in patients with advanced biliary tract carcinoma[J]. Oncologist, 2022, 27(3):e273-e285. doi: 10.1093/oncolo/oyab073 URL
[24]	KAAKOUR D, HAGOPIAN G, LEE S, et al. Durable responses in patients with advanced cholangiocarcinoma on sequential dual-agent immunotherapy after progressing on single-agent immunotherapy[J]. Am J Clin Oncol, 2022, 45(10):410-414. doi: 10.1097/COC.0000000000000941 URL
[25]	TEICHER B A. TGFβ-directed therapeutics: 2020[J]. Pharmacol Ther, 2021, 217:107666. doi: 10.1016/j.pharmthera.2020.107666 URL
[26]	YOO C, OH D Y, CHOI H J, et al. Phase Ⅰ study of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with pretreated biliary tract cancer[J]. J Immunother Cancer, 2020, 8(1):e000564. doi: 10.1136/jitc-2020-000564 URL
[27]	PILONES K A, VANPOUILLE-BOX C, DEMARIA S. Combination of radiotherapy and immune checkpoint inhibitors[J]. Semin Radiat Oncol, 2015, 25(1):28-33. doi: 10.1016/j.semradonc.2014.07.004 pmid: 25481263
[28]	CHEN Y, WEI M, SHEN S, et al. The combination of radiation therapy and immunotherapy is effective and well-tolerated for unresectable biliary tract cancer[J]. Int J Radiat Oncol Biol Phys, 2022, 113(4):816-824. doi: 10.1016/j.ijrobp.2022.03.019 URL
[29]	VITALE L A, THOMAS L J, HE L Z, et al. Development of CDX-1140, an agonist CD40 antibody for cancer immunotherapy[J]. Cancer Immunol Immunother, 2019, 68(2):233-245. doi: 10.1007/s00262-018-2267-0 pmid: 30382327
[30]	KELLEY R K, MITCHELL E, BEHR S, et al. Phase 2 trial of pembrolizumab (PEM) plus granulocyte macrophage colony stimulating factor (GM-CSF) in advanced biliary cancers (ABC): clinical outcomes and biomarker analyses[J]. J Clin Oncol, 2018, 36(15_suppl):4087.
[31]	KAM A E, MASOOD A, SHROFF R T. Current and emerging therapies for advanced biliary tract cancers[J]. Lancet Gastroenterol Hepatol, 2021, 6(11):956-969. doi: 10.1016/S2468-1253(21)00171-0 URL
[32]	SUTHERLAND M, AHMED O, ZAIDI A, et al. Current progress in systemic therapy for biliary tract cancers[J]. J Hepatobiliary Pancreat Sci, 2022, 29(10):1094-1107. doi: 10.1002/jhbp.v29.10 URL
[33]	ABOU-ALFA G K, SAHAI V, HOLLEBECQUE A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study[J]. Lancet Oncol, 2020, 21(5):671-684. doi: 10.1016/S1470-2045(20)30109-1 URL
[34]	JAVLE M, ROYCHOWDHURY S, KELLEY R K, et al. Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study[J]. Lancet Gastroenterol Hepatol, 2021, 6(10):803-815. doi: 10.1016/S2468-1253(21)00196-5 URL
[35]	GOYAL L, MERIC-BERNSTAM F, HOLLEBECQUE A, et al. Futibatinib for FGFR2-rearranged intrahepatic cholangiocarcinoma[J]. N Engl J Med, 2023, 388(3):228-239. doi: 10.1056/NEJMoa2206834 URL
[36]	BEKAII-SAAB T S, VALLE J W, VAN CUTSEM E, et al. FIGHT-302: first-line pemigatinib vs. gemcitabine plus cisplatin for advanced cholangiocarcinoma with FGFR2 rearrangements[J]. Future Oncol, 2020, 16(30):2385-2399. doi: 10.2217/fon-2020-0429 URL
[37]	QUEIROZ M M, LIMA N F JR, BIACHI DE CASTRIA T. Immunotherapy and targeted therapy for advanced biliary tract cancer: adding new flavors to the pizza[J]. Cancers (Basel), 2023, 15(7):1970. doi: 10.3390/cancers15071970 URL
[38]	SCHÖNHERR H, AYAZ P, TAYLOR A M, et al. Disco-very of lirafugratinib (RLY-4008), a highly selective irreversible small-molecule inhibitor of FGFR2[J]. Proc Natl Acad Sci U S A, 2024, 121(6):e2317756121.
[39]	MOEINI A, SIA D, BARDEESY N, et al. Molecular pathogenesis and targeted therapies for intrahepatic cholangiocarcinoma[J]. Clin Cancer Res, 2016, 22(2):291-300. doi: 10.1158/1078-0432.CCR-14-3296 pmid: 26405193
[40]	ABOU-ALFA G K, MACARULLA T, JAVLE M M, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study[J]. Lancet Oncol, 2020, 21(6):796-807. doi: 10.1016/S1470-2045(20)30157-1 URL
[41]	ZAREI M, HUE J J, HAJIHASSANI O, et al. Clinical development of IDH1 inhibitors for cancer therapy[J]. Cancer Treat Rev, 2022, 103:102334. doi: 10.1016/j.ctrv.2021.102334 URL
[42]	ARTEAGA C L, ENGELMAN J A. ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics[J]. Cancer Cell, 2014, 25(3):282-303. doi: 10.1016/j.ccr.2014.02.025 pmid: 24651011
[43]	TELLA S H, KOMMALAPATI A, BORAD M J, et al. Second-line therapies in advanced biliary tract cancers[J]. Lancet Oncol, 2020, 21(1):e29-e41. doi: 10.1016/S1470-2045(19)30733-8 pmid: 31908303
[44]	VOGEL A, KASPER S, BITZER M, et al. PICCA study: panitumumab in combination with cisplatin/gemcitabine chemotherapy in KRAS wild-type patients with biliary cancer-a randomised biomarker-driven clinical phase Ⅱ AIO study[J]. Eur J Cancer, 2018, 92:11-19. doi: 10.1016/j.ejca.2017.12.028 URL
[45]	MALKA D, CERVERA P, FOULON S, et al. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial[J]. Lancet Oncol, 2014, 15(8):819-828. doi: 10.1016/S1470-2045(14)70212-8 pmid: 24852116
[46]	LEE J, PARK S H, CHANG H M, et al. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study[J]. Lancet Oncol, 2012, 13(2):181-188. doi: 10.1016/S1470-2045(11)70301-1 pmid: 22192731
[47]	BALASUBRAMANIAN B, YACQUB-USMAN K, VENKATRAMAN S, et al. Targeting FGFRs using PD173074 as a novel therapeutic strategy in cholangiocarcinoma[J]. Cancers(Basel), 2023, 15(9):2528.
[48]	MORIZANE C, UENO M, IKEDA M, et al. Update for: new developments in systemic therapy for advanced biliary tract cancer[J]. Jpn J Clin Oncol, 2025, 55(3):210-218. doi: 10.1093/jjco/hyaf016 pmid: 39902800
[49]	OSTWAL V, MANDAVKAR S, BHARGAVA P, et al. Trastuzumab plus gemcitabine-cisplatin for treatment-naïve human epidermal growth factor receptor 2-positive biliary tract adenocarcinoma: a multicenter, open-label, phase Ⅱ study (TAB)[J]. J Clin Oncol, 2024, 42(7):800-807. doi: 10.1200/JCO.23.01193 URL
[50]	LEE C K, CHON H J, CHEON J, et al. Trastuzumab plus FOLFOX for HER2-positive biliary tract cancer refractory to gemcitabine and cisplatin: a multi-institutional phase 2 trial of the Korean cancer study group (KCSG-HB19-14)[J]. Lancet Gastroenterol Hepatol, 2023, 8(1):56-65. doi: 10.1016/S2468-1253(22)00335-1 URL
[51]	NAKAMURA Y, MIZUNO N, SUNAKAWA Y, et al. Tucatinib and trastuzumab for previously treated human epidermal growth factor receptor 2-positive metastatic biliary tract cancer (SGNTUC-019): a phase Ⅱ basket study[J]. J Clin Oncol, 2023, 41(36):5569-5578.
[52]	HARDING J J, FAN J, OH D Y, et al. Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study[J]. Lancet Oncol, 2023, 24(7):772-782. doi: 10.1016/S1470-2045(23)00242-5 pmid: 37276871
[53]	OHBA A, MORIZANE C, KAWAMOTO Y, et al. Trastuzumab deruxtecan in human epidermal growth factor receptor 2-expressing biliary tract cancer (HERB; NCCH1805): a multicenter, single-arm, phase Ⅱ trial[J]. J Clin Oncol, 2024, 42(27):3207-3217. doi: 10.1200/JCO.23.02010 URL
[54]	LI J, GUO Y, XUE J, et al. First-in-human phase Ⅰ study of anti-HER2 ADC MRG002 in patients with relapsed/refractory solid tumors[J]. J Clin Oncol, 2020,38(15_suppl):TPS1101-TPS1101(2020).
[55]	PEI S N, LIAO C K, CHEN Y S, et al. A novel combination of bevacizumab with chemotherapy improves therapeutic effects for advanced biliary tract cancer: a retrospective, observational study[J]. Cancers (Basel), 2021, 13(15):3831. doi: 10.3390/cancers13153831 URL
[56]	MOFFAT G T, HU Z I, MERIC BERNSTAM F, et al. KRAS allelic variants in biliary tract cancers[J]. JAMA Netw Open, 2024, 7(5):e249840. doi: 10.1001/jamanetworkopen.2024.9840 URL
[57]	BEKAII SAAB T S, YAEGER R, SPIRA A I, et al. Adagrasib in advanced solid tumors harboring a KRAS^G12C mutation[J]. J Clin Oncol, 2023, 41(25):4097-4106.
[58]	HO J, FIOCCO C, SPENCER K. Treating biliary tract cancers: new targets and therapies[J]. Drugs, 2022, 82(17):1629-1647. doi: 10.1007/s40265-022-01808-x
[59]	SUBBIAH V, LASSEN U, ÉLEZ E, et al. Dabrafenib plus trametinib in patients with BRAF^V600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial[J]. Lancet Oncol, 2020, 21(9):1234-1243. doi: 10.1016/S1470-2045(20)30321-1 URL
[60]	MIYAMOTO M, OJIMA H, IWASAKI M, et al. Prognostic significance of overexpression of c-Met oncoprotein in cholangiocarcinoma[J]. Br J Cancer, 2011, 105(1):131-138. doi: 10.1038/bjc.2011.199
[61]	WANG Y, JIANG M, ZHU J, et al. The safety and efficacy of lenvatinib combined with immune checkpoint inhibitors therapy for advanced hepatocellular carcinoma[J]. Biomed Pharmacother, 2020, 132:110797. doi: 10.1016/j.biopha.2020.110797 pmid: 33068935
[62]	ZHANG Q, LIU X, WEI S, et al. Lenvatinib plus PD-1 inhibitors as first-line treatment in patients with unresectable biliary tract cancer: a single-arm, open-label, phase Ⅱ study[J]. Front Oncol, 2021, 11:751391. doi: 10.3389/fonc.2021.751391 URL
[63]	WANG D, YANG X, LONG J, et al. The efficacy and safety of apatinib plus camrelizumab in patients with previously treated advanced biliary tract cancer: a prospective clinical study[J]. Front Oncol, 2021, 11:646979. doi: 10.3389/fonc.2021.646979 URL
[64]	FOUASSIER L, MARZIONI M, AFONSO M B, et al. Signalling networks in cholangiocarcinoma: molecular pathogenesis, targeted therapies and drug resistance[J]. Liver Int, 2019, 39(Suppl 1):43-62. doi: 10.1111/liv.2019.39.issue-S1 URL
[65]	YOKOI K, KOBAYASHI A, MOTOYAMA H, et al. Survival pathway of cholangiocarcinoma via AKT/mTOR signaling to escape RAF/MEK/ERK pathway inhibition by sorafenib[J]. Oncol Rep, 2018, 39(2):843-850.