Optimizing Patient Pathways in Advanced Biliary Tract Cancers: Recent Advances and a French Perspective

Abstract

Biliary tract cancers (BTCs) are a heterogeneous group of tumors that are rare in Western countries and have a poor prognosis. Three subgroups are defined by their anatomical location (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma and gallbladder carcinoma) and exhibit distinct clinical, molecular, and epidemiologic characteristics. Most patients are diagnosed at an advanced disease stage and are not eligible for curative-intent resection. In addition to first- and second-line chemotherapies (CisGem and FOLFOX, respectively), biologic therapies are now available that target specific genomic alterations identified in BTC. To date, targets include alterations in the genes for isocitrate dehydrogenase (IDH) 1, fibroblast growth factor receptor (FGFR) 2, v-raf murine sarcoma viral oncogene homolog B1 (BRAF), human epidermal growth factor receptor 2 (HER2 or ERRB2), and neurotrophic tyrosine receptor kinase (NTRK), and for those leading to DNA mismatch repair deficiency. Therapies targeting these genomic alterations have demonstrated clinical benefit for patients with BTC. Despite these therapeutic advancements, genomic diagnostic modalities are not widely used in France, owing to a lack of clinician awareness, local availability of routine genomic testing, and difficulties in obtaining health insurance reimbursement. The addition of durvalumab, a monoclonal antibody targeting the immune checkpoint programmed cell death ligand-1, to CisGem in the first-line treatment of advanced BTC has shown an overall survival benefit in the TOPAZ-1 trial. Given the high mortality rates associated with BTC and the life-prolonging therapeutic options now available, it is hoped that the data presented here will support updates to the clinical management of BTC in France.

Fig. 1

Age-standardized mortality rates per 100,000 patients across selected countries, broken down according to intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma, as well as according to men and women, in 2015 [26]. Reprinted from J Hepatol, 71, Bertuccio P, et al. Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma, 104–14, Copyright (2019), with permission from Elsevier. ASMR age-standardized mortality rates, ECC extrahepatic cholangiocarcinoma, ICC intrahepatic cholangiocarcinoma

Fig. 2

Effects of IDH1/2 mutations and D-2HG accumulation on cellular metabolism, redox states, and DNA damage repair [97]. Material from: Molenaar RJ, et al. Wild-type and mutated IDH1/2 enzymes and therapy responses. Oncogene. Published 2018 by Springer Nature, reproduced with permission of SNCSC. αKG α-ketoglutarate, ALKBH alkylation repair homolog, ATM ataxia-telangiectasia mutated, ATP5 adenosine triphosphate synthase, CoA coenzyme A, COX cytochrome C oxidase, D-2HG D-2-hydroxyglutarate, ETC electron transport chain, FOXO forkhead box proteins, HuR human antigen R, IDH isocitrate dehydrogenase, KDM lysine histone demethylase, mut mutation, NAD(P) nicotinamide dinucleotide (phosphate), NAD(P)H nicotinamide dinucleotide (phosphate), reduced, NAM nicotinamide, NAMPT nicotinamide phosphoribosyltransferase, NAPRT1 nicotinate phosphoribosyltransferase domain containing 1, NMN nicotinamide mononucleotide, NRF2 nuclear factor (erythroid-derived 2)-like, ROS reactive oxygen species, wt wildtype

Fig. 3

Kaplan-Meier plot of the probability of progression-free survival in the intention-to-treat population comparing ivosidenib and placebo groups [85]. Reprinted from Lancet Oncol, 21, Abou-Alfa GK, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study, 796-807, Copyright (2020), with permission from Elsevier. CI confidence interval, HR hazard ratio

Fig. 4

Best percentage change from baseline in target lesion size for individual patients with fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements in the FIGHT-202 study of pemigatinib [86]. Colored bars indicate confirmed responses assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. *Patient had a decrease in target lesion size but was not evaluable for response using RECIST. Reprinted from Lancet Oncol, 21, Abou-Alfa GK, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study, 671-84, Copyright (2020), with permission from Elsevier

Fig. 5

Selected targetable mutations in biliary tract cancers presenting rates, as well as those more common within particular subtypes [, , , –161]. BRAF proto-oncogene B-Raf, BTC biliary tract cancer, CDKN2A/B cyclin-dependent kinase inhibitor 2A/B, dMMR/MSI-H deficient mismatch repair/microsatellite instability-high, eCCA extrahepatic cholangiocarcinoma, ERBB erb-b2 receptor tyrosine kinase, FGFR fibroblast growth factor receptor, GBC gallbladder cancer, iCCA intrahepatic cholangiocarcinoma, IDH isocitrate dehydrogenase, KRAS Kirsten rat sarcoma viral oncogene homolog, MET MET proto-oncogene receptor tyrosine kinase, MGMT methylguanine-DNA methyltransferase, mTOR mammalian target of rapamycin, NTRK neurotrophic tyrosine receptor kinase, PI3K phosphoinositide 3-kinase, PRKACA/B protein kinase A/B catalytic subunit, PTEN phosphatase and tensin homolog, TP53 tumor protein P53