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Digestive Disease Interventions
DOI: 10.1055/s-0044-1787013
Review Article

Advances in Immunooncology and Precision Medicine in Cholangiocarcinoma

Timothy J. Brown 
1   Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
2   Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
,
Thomas B. Karasic 
2   Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
› Author Affiliations Funding NIH/NCI L30CA274783 (T.J.B.).
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Abstract

Cholangiocarcinoma (CCA) is an uncommon but morbid cancer arising from the intrahepatic or extrahepatic bile ducts. CCA is frequently asymptomatic at early stages and is often unresectable or metastatic at the time of initial diagnosis. While chemotherapy remains the mainstay of treatment for most patients with advanced disease, the addition of immunotherapy to frontline treatment has improved survival and provided an alternative to perpetual chemotherapy. Furthermore, a variety of targeted therapies have demonstrated benefit in patients with specific biomarkers including FGFR2 fusions, IDH1 mutations, HER2 overexpression, and tumor agnostic markers such as NTRK and RET fusions, among others. This review will summarize the established roles of immunotherapy, targeted therapies, and their combinations in CCA as well as treatment strategies that are under development with potential to impact clinical practice in the coming years.

Keywords

cholangiocarcinoma - biliary tract cancer - immunooncology - precision medicine


Publication History

Received: 17 January 2024

Accepted: 20 April 2024

Article published online:
15 May 2024

© 2024. Thieme. All rights reserved.

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  • References

  • 1 Bertuccio P, Malvezzi M, Carioli G. et al. Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma. J Hepatol 2019; 71 (01) 104-114
    CrossrefPubMedGoogle Scholar
  • 2 Banales JM, Cardinale V, Carpino G. et al. Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol 2016; 13 (05) 261-280
    CrossrefPubMedGoogle Scholar
  • 3 Yao KJ, Jabbour S, Parekh N, Lin Y, Moss RA. Increasing mortality in the United States from cholangiocarcinoma: an analysis of the National Center for Health Statistics Database. BMC Gastroenterol 2016; 16 (01) 117
    CrossrefPubMedGoogle Scholar
  • 4 Clements O, Eliahoo J, Kim JU, Taylor-Robinson SD, Khan SA. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a systematic review and meta-analysis. J Hepatol 2020; 72 (01) 95-103
    CrossrefPubMedGoogle Scholar
  • 5 Brindley PJ, Bachini M, Ilyas SI. et al. Cholangiocarcinoma. Nat Rev Dis Primers 2021; 7 (01) 65
    CrossrefPubMedGoogle Scholar
  • 6 Lee YT, Wang JJ, Luu M. et al. Comparison of clinical features and outcomes between intrahepatic cholangiocarcinoma and hepatocellular carcinoma in the United States. Hepatology 2021; 74 (05) 2622-2632
    CrossrefPubMedGoogle Scholar
  • 7 Gad MM, Saad AM, Faisaluddin M. et al. Epidemiology of cholangiocarcinoma; United States incidence and mortality trends. Clin Res Hepatol Gastroenterol 2020; 44 (06) 885-893
    CrossrefPubMedGoogle Scholar
  • 8 Izquierdo-Sanchez L, Lamarca A, La Casta A. et al. Cholangiocarcinoma landscape in Europe: diagnostic, prognostic and therapeutic insights from the ENSCCA Registry. J Hepatol 2022; 76 (05) 1109-1121
    CrossrefPubMedGoogle Scholar
  • 9 Valle J, Wasan H, Palmer DH. et al; ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010; 362 (14) 1273-1281
    CrossrefPubMedGoogle Scholar
  • 10 Lamarca A, Palmer DH, Wasan HS. et al; Advanced Biliary Cancer Working Group. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol 2021; 22 (05) 690-701
    CrossrefPubMedGoogle Scholar
  • 11 Lee H, Ross JS. The potential role of comprehensive genomic profiling to guide targeted therapy for patients with biliary cancer. Therap Adv Gastroenterol 2017; 10 (06) 507-520
    CrossrefPubMedGoogle Scholar
  • 12 Weinberg BA, Xiu J, Lindberg MR. et al. Molecular profiling of biliary cancers reveals distinct molecular alterations and potential therapeutic targets. J Gastrointest Oncol 2019; 10 (04) 652-662
    CrossrefPubMedGoogle Scholar
  • 13 Lowery MA, Ptashkin R, Jordan E. et al. Comprehensive molecular profiling of intrahepatic and extrahepatic cholangiocarcinomas: potential targets for intervention. Clin Cancer Res 2018; 24 (17) 4154-4161
    CrossrefPubMedGoogle Scholar
  • 14 Zimmer CL, Filipovic I, Cornillet M. et al. Mucosal-associated invariant T-cell tumor infiltration predicts long-term survival in cholangiocarcinoma. Hepatology 2022; 75 (05) 1154-1168
    CrossrefPubMedGoogle Scholar
  • 15 Kitano Y, Okabe H, Yamashita YI. et al. Tumour-infiltrating inflammatory and immune cells in patients with extrahepatic cholangiocarcinoma. Br J Cancer 2018; 118 (02) 171-180
    CrossrefPubMedGoogle Scholar
  • 16 Ma C, Zhang Q, Greten TF. MDSCs in liver cancer: a critical tumor-promoting player and a potential therapeutic target. Cell Immunol 2021; 361: 104295
    CrossrefPubMedGoogle Scholar
  • 17 NCCN Clinical Practice Guidelines in Oncology Biliary Tract Cancers Version 3. 2023 . Published online November 8, 2023
    PubMedGoogle Scholar
  • 18 Job S, Rapoud D, Dos Santos A. et al. Identification of four immune subtypes characterized by distinct composition and functions of tumor microenvironment in intrahepatic cholangiocarcinoma. Hepatology 2020; 72 (03) 965-981
    CrossrefPubMedGoogle Scholar
  • 19 Oh DY, Ruth He A, Qin S. et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid 2022; 1 (08) a2200015
    PubMedGoogle Scholar
  • 20 Kelley RK, Ueno M, Yoo C. et al; KEYNOTE-966 Investigators. 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. Lancet 2023; 401 (10391): 1853-1865
    CrossrefPubMedGoogle Scholar
  • 21 Piha-Paul SA, Oh DY, 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. Int J Cancer 2020; 147 (08) 2190-2198
    CrossrefPubMedGoogle Scholar
  • 22 Klein O, Kee D, Nagrial A. et al. Evaluation of combination nivolumab and ipilimumab immunotherapy in patients with advanced biliary tract cancers: subgroup analysis of a phase 2 nonrandomized clinical trial. JAMA Oncol 2020; 6 (09) 1405-1409
    CrossrefPubMedGoogle Scholar
  • 23 Sahai V, Griffith KA, Beg MS. et al. A randomized phase 2 trial of nivolumab, gemcitabine, and cisplatin or nivolumab and ipilimumab in previously untreated advanced biliary cancer: BilT-01. Cancer 2022; 128 (19) 3523-3530
    CrossrefPubMedGoogle Scholar
  • 24 Doki Y, Ueno M, Hsu CH. et al. Tolerability and efficacy of durvalumab, either as monotherapy or in combination with tremelimumab, in patients from Asia with advanced biliary tract, esophageal, or head-and-neck cancer. Cancer Med 2022; 11 (13) 2550-2560
    CrossrefPubMedGoogle Scholar
  • 25 Marabelle A, Le DT, Ascierto PA. 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 Clin Oncol 2020; 38 (01) 1-10
    CrossrefPubMedGoogle Scholar
  • 26 Maio M, Ascierto PA, Manzyuk L. et al. Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase II KEYNOTE-158 study. Ann Oncol 2022; 33 (09) 929-938
    CrossrefPubMedGoogle Scholar
  • 27 Andre T, Berton D, Curigliano G. et al. Safety and efficacy of anti–PD-1 antibody dostarlimab in patients (pts) with mismatch repair-deficient (dMMR) solid cancers: Results from GARNET study. J Clin Oncol 2021; 39 (03) 9
    CrossrefPubMedGoogle Scholar
  • 28 Andre T, Berton D, Curigliano G. et al. Efficacy and safety of dostarlimab in patients (pts) with mismatch repair deficient (dMMR) solid tumors: analysis of 2 cohorts in the GARNET study. J Clin Oncol 2022; 40 (16) 2587-2587
    CrossrefPubMedGoogle Scholar
  • 29 Dang L, White DW, Gross S. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009; 462 (7274) 739-744
    CrossrefPubMedGoogle Scholar
  • 30 Boscoe AN, Rolland C, Kelley RK. Frequency and prognostic significance of isocitrate dehydrogenase 1 mutations in cholangiocarcinoma: a systematic literature review. J Gastrointest Oncol 2019; 10 (04) 751-765
    CrossrefPubMedGoogle Scholar
  • 31 Abou-Alfa GK, Macarulla T, Javle MM. et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 2020; 21 (06) 796-807
    CrossrefPubMedGoogle Scholar
  • 32 Casak SJ, Pradhan S, Fashoyin-Aje LA. et al. FDA approval summary: ivosidenib for the treatment of patients with advanced unresectable or metastatic, chemotherapy refractory cholangiocarcinoma with an IDH1 mutation. Clin Cancer Res 2022; 28 (13) 2733-2737
    CrossrefPubMedGoogle Scholar
  • 33 Zhu AX, Macarulla T, Javle MM. et al. Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: the Phase 3 randomized clinical ClarIDHy trial. JAMA Oncol 2021; 7 (11) 1669-1677
    CrossrefPubMedGoogle Scholar
  • 34 Wu MJ, Shi L, Dubrot J. et al. Mutant IDH inhibits IFNγ-TET2 signaling to promote immunoevasion and tumor maintenance in cholangiocarcinoma. Cancer Discov 2022; 12 (03) 812-835
    CrossrefPubMedGoogle Scholar
  • 35 Sia D, Hoshida Y, Villanueva A. et al. Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. Gastroenterology 2013; 144 (04) 829-840
    CrossrefPubMedGoogle Scholar
  • 36 Xiang X, Liu Z, Zhang C. et al. IDH mutation subgroup status associates with intratumor heterogeneity and the tumor microenvironment in intrahepatic cholangiocarcinoma. Adv Sci (Weinh) 2021; 8 (17) e2101230
    CrossrefPubMedGoogle Scholar
  • 37 Carapeto F, Bozorgui B, Shroff RT. et al. The immunogenomic landscape of resected intrahepatic cholangiocarcinoma. Hepatology 2022; 75 (02) 297-308
    CrossrefPubMedGoogle Scholar
  • 38 Celgene. Study of Orally Administered Enasidenib (AG-221) in Adults with Advanced Solid Tumors, Including Glioma, or Angioimmunoblastic T-cell Lymphoma, With an IDH2 Mutation. Accessed November 21, 2023 at: https://clinicaltrials.gov/study/NCT02273739?tab=results
    PubMedGoogle Scholar
  • 39 Babina IS, Turner NC. Advances and challenges in targeting FGFR signalling in cancer. Nat Rev Cancer 2017; 17 (05) 318-332
    CrossrefPubMedGoogle Scholar
  • 40 Wu YM, Su F, Kalyana-Sundaram S. et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov 2013; 3 (06) 636-647
    CrossrefPubMedGoogle Scholar
  • 41 Arai Y, Totoki Y, Hosoda F. et al. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology 2014; 59 (04) 1427-1434
    CrossrefPubMedGoogle Scholar
  • 42 Abou-Alfa GK, Sahai V, Hollebecque A. et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol 2020; 21 (05) 671-684
    CrossrefPubMedGoogle Scholar
  • 43 Patel TH, Marcus L, Horiba MN. et al. FDA approval summary: pemigatinib for previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with FGFR2 fusion or other rearrangement. Clin Cancer Res 2023; 29 (05) 838-842
    CrossrefPubMedGoogle Scholar
  • 44 Bekaii-Saab TS, Valle JW, Van Cutsem E. et al. FIGHT-302: first-line pemigatinib vs gemcitabine plus cisplatin for advanced cholangiocarcinoma with FGFR2 rearrangements. Future Oncol 2020; 16 (30) 2385-2399
    CrossrefPubMedGoogle Scholar
  • 45 Incyte. A Study to Evaluate the Efficacy and Safety of Pemigatinib Versus Chemotherapy in Unresectable or Metastatic Cholangiocarcinoma (FIGHT-302). Accessed November 21, 2023 at: https://www.clinicaltrials.gov/study/NCT03656536
    PubMedGoogle Scholar
  • 46 Goyal L, Meric-Bernstam F, Hollebecque A. et al; FOENIX-CCA2 Study Investigators. Futibatinib for FGFR2-rearranged intrahepatic cholangiocarcinoma. N Engl J Med 2023; 388 (03) 228-239
    CrossrefPubMedGoogle Scholar
  • 47 Gandhy SU, Casak SJ, Mushti SL. et al. FDA approval summary: futibatinib for unresectable advanced or metastatic, chemotherapy refractory intrahepatic cholangiocarcinoma with FGFR2 fusions or other rearrangements. Clin Cancer Res 2023; 29 (20) 4027-4031
    CrossrefPubMedGoogle Scholar
  • 48 Javle M, Roychowdhury S, Kelley RK. 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. Lancet Gastroenterol Hepatol 2021; 6 (10) 803-815
    CrossrefPubMedGoogle Scholar
  • 49 Subbiah V, Sahai V, Maglic D. et al. RLY-4008, the first highly selective FGFR2 inhibitor with activity across FGFR2 alterations and resistance mutations. Cancer Discov 2023; 13 (09) 2012-2031
    CrossrefPubMedGoogle Scholar
  • 50 Hollebecque A, Borad M, Goyal L. et al. LBA12 efficacy of RLY-4008, a highly selective FGFR2 inhibitor in patients (pts) with an FGFR2-fusion or rearrangement (f/r), FGFR inhibitor (FGFRi)-naïve cholangiocarcinoma (CCA): ReFocus trial. Ann Oncol 2022; 33: S1381
    CrossrefPubMedGoogle Scholar
  • 51 Ni S, Li L, Sun X. et al. In vitro and in vivo pharmacokinetics, disposition, and drug-drug interaction potential of tinengotinib (TT-00420), a promising investigational drug for treatment of cholangiocarcinoma and other solid tumors. Eur J Pharm Sci 2024; 192: 106658
    CrossrefPubMedGoogle Scholar
  • 52 Piha-Paul SA, Goel S, Liao CY. et al. Preliminary safety and efficacy of tinengotinib tablets as monotherapy and combination therapy in advanced solid tumors: a phase Ib/II clinical trial. J Clin Oncol 2023; 41 (16) 3019-3019
    CrossrefPubMedGoogle Scholar
  • 53 Javle MM, Fountzilas C, Li D. et al. Phase II study of FGFR1–3 inhibitor tinengotinib as monotherapy in patients with advanced or metastatic cholangiocarcinoma: Interim analysis. J Clin Oncol 2023; 41 (04) 539
    CrossrefPubMedGoogle Scholar
  • 54 Galdy S, Lamarca A, McNamara MG. et al. HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target?. Cancer Metastasis Rev 2017; 36 (01) 141-157
    CrossrefPubMedGoogle Scholar
  • 55 Javle M, Borad MJ, Azad NS. et al. Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol 2021; 22 (09) 1290-1300
    CrossrefPubMedGoogle Scholar
  • 56 Ogitani Y, Aida T, Hagihara K. et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. Clin Cancer Res 2016; 22 (20) 5097-5108
    CrossrefPubMedGoogle Scholar
  • 57 Ohba A, Morizane C, Ueno M. et al. Multicenter phase II trial of trastuzumab deruxtecan for HER2-positive unresectable or recurrent biliary tract cancer: HERB trial. Future Oncol 2022; 18 (19) 2351-2360
    CrossrefPubMedGoogle Scholar
  • 58 Ohba A, Morizane C, Kawamoto Y. et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing unresectable or recurrent biliary tract cancer (BTC): an investigator-initiated multicenter phase 2 study (HERB trial). J Clin Oncol 2022; 40 (16) 4006
    CrossrefPubMedGoogle Scholar
  • 59 Meric-Bernstam F, Makker V, Oaknin A. et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 Phase II trial. J Clin Oncol 2024; 42 (01) 47-58
    CrossrefPubMedGoogle Scholar
  • 60 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 Clin Oncol 2023; 41 (36) 5569-5578
    CrossrefPubMedGoogle Scholar
  • 61 Meric-Bernstam F, Hanna DL, El-Khoueiry AB. et al. Zanidatamab (ZW25) in HER2-positive biliary tract cancers (BTCs): results from a phase I study. J Clin Oncol 2021; 39 (03) 299
    CrossrefPubMedGoogle Scholar
  • 62 Harding JJ, Fan J, Oh DY. et al; HERIZON-BTC-01 Study Group. Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study. Lancet Oncol 2023; 24 (07) 772-782
    CrossrefPubMedGoogle Scholar
  • 63 Modi S, Jacot W, Yamashita T. et al; DESTINY-Breast04 Trial Investigators. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med 2022; 387 (01) 9-20
    CrossrefPubMedGoogle Scholar
  • 64 Westphalen CB, Krebs MG, Le Tourneau C. et al. Genomic context of NTRK1/2/3 fusion-positive tumours from a large real-world population. NPJ Precis Oncol 2021; 5 (01) 69
    CrossrefPubMedGoogle Scholar
  • 65 Drilon A, Laetsch TW, Kummar S. et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med 2018; 378 (08) 731-739
    CrossrefPubMedGoogle Scholar
  • 66 Doebele RC, Drilon A, Paz-Ares L. et al; Trial Investigators. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol 2020; 21 (02) 271-282
    CrossrefPubMedGoogle Scholar
  • 67 Kato S, Subbiah V, Marchlik E, Elkin SK, Carter JL, Kurzrock R. RET aberrations in diverse cancers: next-generation sequencing of 4,871 patients. Clin Cancer Res 2017; 23 (08) 1988-1997
    CrossrefPubMedGoogle Scholar
  • 68 Subbiah V, Wolf J, Konda B. et al. Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Lancet Oncol 2022; 23 (10) 1261-1273
    CrossrefPubMedGoogle Scholar
  • 69 Subbiah V, Cassier PA, Siena S. et al. Pan-cancer efficacy of pralsetinib in patients with RET fusion-positive solid tumors from the phase 1/2 ARROW trial. Nat Med 2022; 28 (08) 1640-1645
    CrossrefPubMedGoogle Scholar
  • 70 Goeppert B, Frauenschuh L, Renner M. et al. BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma. Mod Pathol 2014; 27 (07) 1028-1034
    CrossrefPubMedGoogle Scholar
  • 71 Salama AKS, Li S, Macrae ER. et al. Dabrafenib and trametinib in patients with tumors with BRAFV600E mutations: results of the NCI-MATCH trial subprotocol H. J Clin Oncol 2020; 38 (33) 3895-3904
    CrossrefPubMedGoogle Scholar
  • 72 Subbiah V, Lassen U, Élez E. et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol 2020; 21 (09) 1234-1243
    CrossrefPubMedGoogle Scholar
  • 73 Gouda MA, Subbiah V. Expanding the benefit: dabrafenib/trametinib as tissue-agnostic therapy for BRAF V600E-positive adult and pediatric solid tumors. Am Soc Clin Oncol Educ Book 2023; 43 (43) e404770
    CrossrefPubMedGoogle Scholar
  • 74 Zhou SL, Xin HY, Sun RQ. et al. Association of KRAS variant subtypes with survival and recurrence in patients with surgically treated intrahepatic cholangiocarcinoma. JAMA Surg 2022; 157 (01) 59-65
    CrossrefPubMedGoogle Scholar
  • 75 Bekaii-Saab TS, Spira AI, Yaeger R. et al. KRYSTAL-1: Updated activity and safety of adagrasib (MRTX849) in patients (Pts) with unresectable or metastatic pancreatic cancer (PDAC) and other gastrointestinal (GI) tumors harboring a KRAS G12C mutation. J Clin Oncol 2022; 40 (04) 519
    CrossrefPubMedGoogle Scholar
  • 76 Kim SJ, Akita M, Sung YN. et al. MDM2 amplification in intrahepatic cholangiocarcinomas: its relationship with large-duct type morphology and uncommon KRAS mutations. Am J Surg Pathol 2018; 42 (04) 512-521
    CrossrefPubMedGoogle Scholar
  • 77 LoRusso P, Yamamoto N, Patel MR. et al. The MDM2-p53 antagonist Brigimadlin (BI 907828) in patients with advanced or metastatic solid tumors: results of a phase Ia, first-in-human, dose-escalation study. Cancer Discov 2023; 13 (08) 1802-1813
    CrossrefPubMedGoogle Scholar
  • 78 Yarchoan M, Cope L, Ruggieri AN. et al. Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers. J Clin Invest 2021; 131 (24) e152670
    CrossrefPubMedGoogle Scholar
  • 79 Dennison L, Ruggieri A, Mohan A. et al. Context-dependent immunomodulatory effects of MEK inhibition are enhanced with T-cell agonist therapy. Cancer Immunol Res 2021; 9 (10) 1187-1201
    CrossrefPubMedGoogle Scholar
  • 80 Villanueva L, Lwin Z, Chung HC. et al. Lenvatinib plus pembrolizumab for patients with previously treated biliary tract cancers in the multicohort phase II LEAP-005 study. J Clin Oncol 2021; 39 (03) 321
    CrossrefPubMedGoogle Scholar
  • 81 Yin C, Armstrong SA, Agarwal S. et al. Phase II study of combination pembrolizumab and olaparib in patients with advanced cholangiocarcinoma: Interim results. J Clin Oncol 2022; 40 (04) 452
    CrossrefPubMedGoogle Scholar
  • 82 Lang F, Schrörs B, Löwer M, Türeci Ö, Sahin U. Identification of neoantigens for individualized therapeutic cancer vaccines. Nat Rev Drug Discov 2022; 21 (04) 261-282
    CrossrefPubMedGoogle Scholar
  • 83 Aruga A, Takeshita N, Kotera Y. et al. Long-term vaccination with multiple peptides derived from cancer-testis antigens can maintain a specific T-cell response and achieve disease stability in advanced biliary tract cancer. Clin Cancer Res 2013; 19 (08) 2224-2231
    CrossrefPubMedGoogle Scholar
  • 84 Shirahama T, Muroya D, Matsueda S. et al. A randomized phase II trial of personalized peptide vaccine with low dose cyclophosphamide in biliary tract cancer. Cancer Sci 2017; 108 (05) 838-845
    CrossrefPubMedGoogle Scholar
  • 85 Löffler MW, Chandran PA, Laske K. et al. Personalized peptide vaccine-induced immune response associated with long-term survival of a metastatic cholangiocarcinoma patient. J Hepatol 2016; 65 (04) 849-855
    CrossrefPubMedGoogle Scholar
  • 86 Tran E, Turcotte S, Gros A. et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 2014; 344 (6184) 641-645
    CrossrefPubMedGoogle Scholar