Advances in Immunooncology and Precision Medicine in Cholangiocarcinoma

Timothy J. Brown; Thomas B. Karasic

doi:10.1055/s-0044-1787013

Digestive Disease Interventions, Table of Contents

Digestive Disease Interventions 2024; 08(04): 228-238
DOI: 10.1055/s-0044-1787013

Review Article

Advances in Immunooncology and Precision Medicine in Cholangiocarcinoma

Authors

Timothy J. Brown

¹Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas

²Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
Thomas B. Karasic

²Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania

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

Full Text

References

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
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
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
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
5 Brindley PJ, Bachini M, Ilyas SI. et al. Cholangiocarcinoma. Nat Rev Dis Primers 2021; 7 (01) 65
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
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
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
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
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
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
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
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
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
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
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
17 NCCN Clinical Practice Guidelines in Oncology Biliary Tract Cancers Version 3. 2023 . Published online November 8, 2023
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
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
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
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
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
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
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
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
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
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
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
29 Dang L, White DW, Gross S. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009; 462 (7274) 739-744
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
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
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
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
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
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
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
37 Carapeto F, Bozorgui B, Shroff RT. et al. The immunogenomic landscape of resected intrahepatic cholangiocarcinoma. Hepatology 2022; 75 (02) 297-308
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
39 Babina IS, Turner NC. Advances and challenges in targeting FGFR signalling in cancer. Nat Rev Cancer 2017; 17 (05) 318-332
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
71 Salama AKS, Li S, Macrae ER. et al. Dabrafenib and trametinib in patients with tumors with BRAF^V600E mutations: results of the NCI-MATCH trial subprotocol H. J Clin Oncol 2020; 38 (33) 3895-3904
72 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. Lancet Oncol 2020; 21 (09) 1234-1243
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
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
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
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
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
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
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
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
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
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
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
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
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
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