Modern therapeutic approaches in cholangiocarcinoma: A narrative review of key biomarkers and clinical trials.

Abbreviations

Biliary duct

V-Raf Murine Sarcoma Viral Oncogene Homolog B1

Biliary Tract Cancer

Cholangiocarcinoma

cell-free DNA

Confidence interval

Colorectal cancer

Cytotoxic T-lymphocyte antigen 4

Distal Cholangiocarcinoma

Disease control rate

Mismatch repair deficiency

Duration of response

Epidermal growth factor receptor

Food and Drug Administration

Fibroblast growth factors

Fibroblast Growth Factor Receptor 2

gastroesophageal junction

Human epidermal growth fator receptor 2

Hazard Ratio

Intrahepatic Cholangiocarcinoma

Immune Checkpoint Inhibitor

Isocitrate dehydrogenase

Immunohistochemistry

Interquartile Range

Mitogen-Activated Protein Kinase

Microsatellite instability-high

National Comprehensive Cancer Network

Non-Small-Cell Lung Cancer

Neurotrophic tyrosine receptor kinase

Objective Response Rate

Overall Survival

Perihilar Cholangiocarcinoma

Programmed Death-1

Programmed Death Ligand 1

Progression-Free Survival

Rearranged During Transfection

Tumor mutational burden – high

Tropomyosin Receptor Kinase

Vascular Endothelial Growth Factor Receptor

Introduction

Cholangiocarcinoma (CCA) is the second most common hepatic malignancy after hepatocellular carcinoma [ 1 ]. CCA is an aggressive, epithelial cell malignancy involving the intrahepatic, perihilar, and distal biliary tree [ 1 , 2 ]. These cancers are best classified according to the anatomic subtype: intrahepatic CCA (iCCA), perihilar CCA (pCCA), or distal (dCCA). iCCA arises above the second-order bile ducts, where the cystic duct is the reference point of distinction between pCCA and dCCAs [ 3 ]. Each anatomic subtype is characterized by unique genetic aberrations, clinical presentations, and treatment options [ 4 ].

Detecting cholangiocarcinoma in its early stages is a complex task since many patients are asymptomatic, the anatomical location of the tumors can be hard to access, and the tumors have a dense and multi-cellular structure, which makes cytological diagnosis challenging [ 5 ]. The limited accuracy and availability of diagnostic tools contribute to delays in diagnosis, raising the difficulty of surgical resection with curative intent [ 6 ].

The available systemic therapies are still evolving for patients in advanced-stage or unresectable cholangiocarcinoma [ 7 ]. Untreated patients can evolve with local tumor progression, bile duct obstruction, liver failure, or sepsis from cholangitis and abscesses [ 8 ]. Apart from intrahepatic biliary duct (BD) cancer, the 5-year relative survival rate was best in gallbladder (28.5%), followed by extrahepatic (19.9%) and intrahepatic (10.8%) BD malignancies [ 9 ].

Understanding the molecular mechanisms in CCA progression could aid in developing precision therapy for advanced CCA [ 4 ]. The carcinogenic pathways of CCAs have different etiology, making each pathway a different possibility for targeted therapy for CCA [ 10 ]. Liquid biopsy, a non-invasive method used to assess a patient's health by looking at circulating tumor cells and cell-free DNA in peripheral blood samples, is highly used in these cases [ 11 ]. Cancer patients have higher concentrations of cell-free DNA (cfDNA), which can indicate changes in DNA both before and after therapy [ 12 ]. Cancer may be detected non-invasively by checking the release of tumors' cell-free DNA, which has the same variations as tumor cells [ 13 ]. Circulating cfDNA helps in the identification of those possibilities [ 14 ].

The 2023 National Comprehensive Cancer Network (NCCN) guidelines recommend the investigation of eight possible genetic aberrations: Neurotrophic Tyrosine Receptor Kinase (NTRK) fusion, Microsatellite instability – high (MSI-H)\mismatch repair deficiency (dMMR), tumor mutational burden – high (TMB-H), V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF) V600E mutation, fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement, isocitrate dehydrogenase 1 (IDH1) mutation, human epidermal growth factor receptor 2 (HER2), and RET fusion (Figure I) [ 15 ]. Of these eight markers, six represent oncogenic driver alterations (FGFR2, IDH1, BRAF, HER2, NTRK, RET), while TMB-H and MSI-H/dMMR are genomic signatures that predict response to immune checkpoint inhibitors rather than single-gene targets. This review aims to provide thorough insights into the state of knowledge and prospective improvements in the diagnosis and treatment of CCA.

Review methodology

This was a narrative review performed for relevant studies published between 2019 and 2026. Studies were identified through PubMed, EmBase, and ClinicalTrials.gov. These three databases were identified for their comprehensive coverage of literature, including published peer-reviewed literature, conference proceedings, and clinical trials in development. Search terms included the individual aforementioned oncogenic driver alterations as well as genomic signatures, and the diferente types of CCAs. Articles were excluded if not in English. To ensure a thorough review, no exclusions were done on the basis of the strength of findings. Table 1 Table 1 Summary of relevant recent clinical trials. Table 1 dummy alt text Target Agent Key trial Characteristics N Design Comparison PFS OS RR HER2 Pertuzumab + Trastuzumab MyPathway ( NCT02091141 ) Second-line for metastatic biliary tract cancer 39 Phase IIa, multi-center, non-randomized, open label, multiple basket study Pertuzumab + Trastuzumab 4.0 10.9 23% Trastuzumab-pkrb + GemCis NCT03613168 First line for gallblader, intrahepatic and extrahepatic cancer 4 Open-label, single-arm, single-center, investigator-initiated trial Trastuzumab-pkrb + GemCis 6.1 Not Reached 50% Zanidatamab HERIZON-BTC-01 ( NCT04466891 ) Previously treated, unresectable or metastatic HER2-positive (IHC 2+ or 3+) biliary tract cancer 80 Phase IIb, multicentre, single-arm, open-label Zanidatamab monotherapy 5.5 Not reported 41.3% (full cohort); 51.6% (IHC 3+) IDH1 Ivosidenib NCT02989857 Second or third line for mIDH-1 CCA patients without previous IDH-variant inhibitor therapy. 187 Multicenter, randomized, double-blind, placebo-controlled, clinical phase III Ivosidenib vs Placebo 2.7 vs 1.4 10.3 vs 5.1 2% Olutasidenib (FT-2102) NCT03684811 First or second line for Intrahepatic CCA patients without previous IDH1 inhibitor treatment 19 Open-label, multicenter, nonrandomized, phase Ib/II Olutasidenib 8.29 36.43 0% FGFR2 Futibatinib (TAS-120) FOENIX-CCA2 ( NCT04093362 ) Previously treated, unresectable, locally advanced or metastatic iCCA with FGFR2 fusions or rearrangements 103 Phase II, open-label, single-arm Futibatinib 9.0 21.7 42% Pemigatinib FIGHT-202 NCT02924376 Second or third line for locally advanced or mCCA with disease progression who have not received FGFR inhibitors 146 Multicenter, open-label, single-arm, multicohort, phase 2 study Pemigatinib 7 17.5 37% BRAF Dabrafenib + Trametinib ROAR NCT02034110 Second-line for BRAFV600E-mutated unresectable, metastatic, locally advanced, or recurrent adenocarcinoma of the biliary tract or gallbladder 43 phase 2, open-label, single-arm, multicentre,basket trial Dabrafenib + Trametinib 6.7 14.5 56% Dabrafenib + Trametinib Subprotocol H NCT02465060 Second or third-line for BRAFV600E/K/R/D mutated solid tumors, lymphoma, or multiple myeloma 29 medicine platform trial with flexibility to open and close subprotocols Dabrafenib + Trametinib 11.4 28.6 38% TMB-H pembrolizumab KEYNOTE-158 ( NCT02628067 ) Second or third-line for advanced incurable solid tumour with progression 102 open-label, multicohort, phase II study pembrolizumab 2.1 11.7 29% MSI-H/dMMR pembrolizumab KEYNOTE-158 ( NCT02628067 ) Second or third-line for MSI-H/dMMR advanced noncolorectal cancer 233 nonrandomized, open-label, multisite phase II study pembrolizumab 3.5 20.1 30.8% Pembrolizumab KEYNOTE-164 NCT02460198 Second or third-line for mMSI-H/dMMR CRC 124 phase II open-label, multisite study pembrolizumab 2.3 to 4.1 31.4 33% NTRK Larotrectinib LOXO-101 Trial NCT02637687 Second-line for locally advanced or metastatic solid tumor 55 phase l study Larotrectinib Year 1: 55% of the patients remained PFS ( not been reached) Not been reached 75% Entrectinib ALKA-372–001, STARTRK-1, and STARTRK-2 First or Second-line for metastatic or locally advanced NTRK fusion-positive solid tumours 526 dataset of three clincal trials Entrectinib 11 21 57% RET Fusion Selpercatinib LIBRETTO-001 NCT03157128 Second or third-line for RET fusion-positive tumour 45 ongoing phase 1/2, single-group, open-label, basket trial Selpercatinib 13.2 18 44% Pralsetinib ARROW NCT03037385 First-line for RET fusion–positive solid tumors 23 phase l/ll study Pralsetinib 7 14 57% Abbreviations: MOA – mechanism of action PFS – Progression-free survival OS – Overall survival RR – Response rate mCRC – metastatic Colorectal Cancer FX – FOLFOX CIH – Cetuximab, Irinotecan Hydrochloride. BSC – Best Supportive Care * - 48 months rate OS – Overall survival RR – response rate MSI-H – Microsatellite instability-high PFS – Progression free survival PD-1 – Programmed death-1 dMMR – deficient mismatch repair CTLA-4 – Cytotoxic T lymphocyte-associated antigen 4.

Current landscape of systemic therapy

Before considering molecularly targeted approaches, it is important to contextualize the current standard-of-care backbone against which these strategies are positioned. For most patients with advanced or unresectable biliary tract cancer, first-line treatment remains systemic chemoimmunotherapy [ 16 ]. In 2022, the FDA approved durvalumab in combination with gemcitabine and cisplatin for locally advanced or metastatic biliary tract cancer, based on the phase III TOPAZ-1 trial, which demonstrated an improvement in overall survival with the addition of the PD-L1 inhibitor to standard chemotherapy [ 17 ]. Pembrolizumab plus gemcitabine and cisplatin was subsequently approved in 2023 following the phase III KEYNOTE-966 trial, which showed a similar survival benefit with the addition of this PD-1 inhibitor to first-line chemotherapy [ 18 ]. These regimens have effectively established chemoimmunotherapy as the new first-line standard of care for the majority of patients with advanced biliary tract cancer (BTC), regardless of molecular profile. However, the survival gains achieved with these approaches remain modest, and only a subset of patients are candidates for the targeted therapies that are the focus of this review. Understanding this systemic therapy backdrop is essential for appropriately sequencing targeted agents, which are most often used in the second-line setting after progression on chemoimmunotherapy.

Molecular profiling

There are several relevant molecular biomarkers that will be discussed in detail. Fig. 1 illustrates their distribution. Fig. 1 Relevant biomarkers for molecular profiling of cholangiocarcinomas. Fig 1 dummy alt text

HER2

HER2 is a member of the ErbB/epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases, and its heterodimerization results in the autophosphorylation of tyrosine residues in the heterodimer, initiating a variety of pathways that promote cell proliferation and tumorigenesis [ 19 ]. HER2 overexpression is described in multiple different solid neoplasms, such as breast cancer, gastroesophageal junction (GEJ) cancer, uterine cancer, bladder cancer, colorectal cancer (CRC), non-small-cell lung cancer (NSCLC), and BTC, with incidences ranging from 2% in NSCLCs to over 50% in uterine cancers [ [20] , [21] , [22] , [23] , [24] ].

Approximately 54% of BTC patients are HER2-positive, with an amplification rate of 5–15% in these patients [ [25] , [26] , [27] , [28] ]. In the specific case of cholangiocarcinoma, there is also a different prevalence depending on the anatomical location, but there is an activation of the pathway or overexpression in 5–20% of cholangiocarcinomas [ [29] , [30] , [31] , [32] , [33] ]. The NCCN recommends molecular testing of HER2 overexpression and/or amplification in patients with unresectable or metastatic biliary tract cancer [ 15 ].

Targeted therapies for HER2 began in 1990 with Trastuzumab, an anti-HER2 monoclonal antibody, which interferes with HER2 signaling by destroying receptors, inhibiting dimerization, and inhibiting the PI3K-AKT signaling pathway for breast cancer [ 34 ]. Since then, other HER2-targeted therapies have been developed and tested for various solid neoplasms [ [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] ]. However, until recently, no Food and Drug Administration (FDA)-approved HER2-targeted therapy existed for biliary tract cancer, with multiple phase II clinical trials studying the use of HER2 inhibitors in various combinations [ 15 ]. In November 2024, the FDA approved Zanidatamab-hrii for previously-treated unresectable or metastatic HER2-positive biliary tract cancer [ 44 ].

The ongoing MyPathway non-randomized, multicenter, open-label, and phase IIa study ( NCT02091141 ) evaluated the use of pertuzumab plus trastuzumab for patients with previously treated metastatic biliary tract cancer with HER2 amplification, overexpression, or both. In this study, with a median follow-up of 8.1 months (interquartile range [IQR] 2.7–15.7), the progression-free survival (PFS) was 4.0 months, overall survival (OS) was 10.9 months, with an objective response rate (ORR) of 23% (95% confidence interval [CI] 11–39%) was found [ 45 ]. Another study by Jeong et al. tested the use of a trastuzumab-biosimilar (trastuzumab-pkrb) in combination with gemcitabine plus cisplatin in 4 patients with biliary tract carcinoma and found a partial response in 2 of these patients, the PFS was 6.1 months, the OS could not be reached, and RR was 50% [ 46 ].

One major recent advancement in HER2-targeted therapy for BTC is zanidatamab, a humanized IgG1-like bispecific antibody that binds simultaneously to two non-overlapping extracellular domains of HER2, which thus enhances receptor internalization, antibody-dependent cellular cytotoxicity, and complement-dependent cytotoxicity [ 44 ]. In the phase IIb HERIZON-BTC-01 ( NCT04466891 ), 80 patients with previously treated, unresectable, or metastatic HER2-postive (immunohistochemistry [IHC] 2+ or 3+) BTC were enrolled into Cohort 1 and received zanidatamab monotherapy [ 47 ]. At a median follow-up of 12.4 months, the confirmed ORR by independent central review for the cohort was 41.3% (95% CI 30.4–52.8%). In a pre-planned subgroup analysis of patients with high HER2 expression (IHC 3+, n = 62), the ORR was 51.6% (95% CI 38.6–64.5%), compared to 5.6% (95% CI 0.1–27.3%) in the IHC 2+ subgroup (n = 18). For the responding patients in Cohort 1, the median duration of response was 12.9 months, and the median progression free survival was 5.5 months. Zanidatamab demonstrated a manageable safety profile with no grade 4 or 5 treatment-related adverse events, supporting its role as a meaningful targeted treatment option for patients with treatment-refractory, HER2-positive BTC. The higher ORR of zanidatamab compared with earlier pertuzumab+trastuzumab therapy (23% in MyPathway) is consistent with the mechanistic advantage of simultaneous HER2 blockade. It is important to note, however, that its approval is based on ORR as a surrogate endpoint; confirmatory overall survival data from the ongoing phase III HERIZON-BTC-302 trial ( NCT06282575 ) are awaited. Additionally, the drug received approval from the European Medicines Agency in June 2025 [ 48 ].

IDH1 mutation

IDH is an enzyme capable of catalyzing the reversible oxidative decarboxylation of isocitrate to alpha-ketoglutarate while reducing NADP+ to NADPH, which, although not yet precisely clear, leads to an epigenetic dysregulation of histones and DNA methylation, blocking of cellular differentiation, activation of the Vascular Endothelial Growth Factor Receptor (VEGFR) and chromatin restructuring, which ultimately promotes tumor proliferation and metastasis development [ [49] , [50] , [51] , [52] , [53] , [54] ]. Most mutations in IDH result in the substitution of only one amino acid, mainly affecting arginine 132 residue (R132) in IDH1, arginine 172 (R172) in IDH2, or arginine 140 (R140) in IDH2 [ 52 ].

The IDH1 mutation was first identified in glioblastomas; however, later, an important prevalence was found in several types of cancers, such as chondrosarcoma (40–80%) [ [55] , [56] , [57] ], sinonasal undifferentiated carcinoma (49–82.4%) [ [58] , [59] , [60] , [61] ], angioimmunoblastic T-cell lymphoma (20–32%) [ [62] , [63] , [64] ], acute myeloid leukemia (14–20%) [ [65] , [66] , [67] , [68] ], and in CCA, in which it has a prevalence of approximately 15–20% [ [63] , [64] , [65] ].

In cholangiocarcinoma, IDH mutations also vary according to location, being 13 times more present in intrahepatic than in extrahepatic CCA [ 69 ]. There is also a higher prevalence of mutations in non-Asian centers compared to Asian centers (weighted mean; 16.5% vs. 8.8%; p < 0.001), and in the US specifically, prevalence was found to be 18% (95% CI, 16.4–19.8%) for mutations in IDH1 (mIDH1) [ 69 ]. The most prevalent IDH mutation among mutated patients is the R132 mutation; in 61.5% of these, the mutation is the replacement of arginine to cysteine (R132C) due to a change in the codon of “CGT” to “TGT” [ [69] , [70] , [71] ].

Despite the identification of these mutations being relevant in the pathogenesis of CCA, no association with prognosis was found in most studies [ 32 , [72] , [73] , [74] , [75] , [76] ]. On the other hand, using IDH1 inhibitors in patients with advanced cholangiocarcinoma mIDH1 correlates with a better prognosis [ [77] , [78] , [79] ].

The multicenter, randomized, double-blind, placebo-controlled, clinical phase III ClarlDHy trial evaluated Ivosidenib (AG-120), an oral IDH1 inhibitor, for patients with advanced mIDH1 CCA [ 77 ]. In this study, a median OS of 10.3 months (95% CI, 7.8 – 12.4 months) was found with the use of Ivosidenib and 7.5 months (95% CI, 4.8 – 11.1 months) with the use of a placebo [ 77 ]. When adjusted for crossover, the median OS with placebo was 5.1 months (95% CI, 3.8–7.6 months; hazard ratio [HR] 0.49, 95% CI, 0.34 – 0.70, p < 0.001); the objective response rate was 2% (3 partial responses) [ 77 ]. PFS was also superior with the use of Ivosidenib compared with placebo (HR 0.37, 95% CI 0.25–0.54, p < 0.001) [ 78 ]. Ivosidenib is the only FDA-approved IDH-targeted therapy for previously treated, locally advanced, or metastatic CCA with mIDH1 [ 80 ]. NCCN guidelines indicate that it is a possible tool for these patients [ 15 ]. Reports of acquired resistance to Ivosidenib in cholangiocarcinoma have already been published by acquired IDH2 mutation and a secondary IDH1 mutation, but the exact mechanisms are still poorly understood [ 81 ].

In the phase I/II study, “A study of FT-2102 in Patients With Advanced Solid Tumors and Gliomas With an IDH1 mutation” ( NCT03684811 ) published in 2023, the investigators presented results of the use of Olutasidenib (FT-2102) in hepatobiliary tumors, including iCCA with mIDH1 [ 82 ]. In this study, the overall survival was 36.4 months. Despite an ORR of 12.5% for hepatobiliary tumors, the ORR for iCCA was 0%, with PFS of 8.29 months [ 82 ]. Olutasidenib is currently FDA-approved only for acute myeloid leukemia mIDH1 [ 80 ].

FGFR2 fusion or rearrangement

FGFR is expressed by multiple cells and it is composed mainly by four subtypes: FGFR1, FGFR2, FGFR3 and FGFR4 [ 83 ]. FGFR aberration has been described in several solid tumors [ 84 ], and FGFR2 fusion is a gene alteration present in 10–15% of iCCAs, but in almost no eCCAs [ 85 ]. The fibroblast growth factors (FGFs) pathway consist of 22 humans FGFs and 4 transmembrane receptors with intracellular tyrosine kinase domains (FGFR 1–4) [ 86 ].

The FGF-FGFR signaling is dependent of the FGF binding to the cell surface, leading to intracellular phosphorylation of receptor kinase domains, a cascade of intracellular signaling and gene transcription that activates a number of intracellular survival and proliferative pathways [ 87 ]. The FGF-FGFR interaction is influenced by the tissue expression of ligands and receptors, proteins that can increase the interaction and alterations in the FGFR splicing [ 88 ]. FGFR fusion can result in ligand-independent signaling, leading to constant activation of proliferative pathway [ 89 ].

The first report of FGFR2 fusion in CCA was in 2013 by Wu and colleagues, making the genotyping of the tumor an important diagnostic tool, as the FGFR2 fusion occurs mainly in iCCA [ 85 ]. There is a high correlation of non-fluke iCCA and FGFR2 association [ 85 ].

Lowery et al. conducted a prospective analysis of 195 patients using the MSK-IMPACT platform and found that the highest mutated genes for iCCAs were IDH1 (30%), ARID1A (23%), BAP1 (20%), TP53 (20%) and FGFR2 gene fusions (14%) [ 90 ]. In a separate study, Javle et al. studied 554 patients with CCAs and discovered that FGFR2 and IDH1 mutations were most prevalent in iCCAs and were mutually exclusive [ 32 ]. They also reported that FGFR2 fusions were associated with a better prognosis.

A few studies conducted with FGFR inhibition used non selective tyrosine kinase inhibitors, lucitanib, lenvatinib, pazopanib, dovitinib, regorafenib [ [91] , [92] , [93] ]. These agents inhibit multiple targets such as RET, FLT3, VEGFR, PDGFR and KIT; these drugs had low antitumor efficacy and did not advance to clinical practice [ 94 ].

Studies with selective FGFR inhibitors have a better result. In a phase II trial, Infigratinib (BJG398) [ 95 ], one of the selective FGFR inhibitors, showed a median PFS of 5.8 months in iCCA patients who had FGFR2 fusions and were previously treated. The ORR was 18.8%, the disease control rate (DCR) was 83.3%, and the OS was 12.2 months. The most common toxicities of all grades were hyperphosphatemia, fatigue, stomatitis, alopecia, and constipation, while grade 3–4 adverse events included hypophosphatemia, hyperphosphatemia, and hyponatremia. Another multi-kinase inhibitor, derazantinib (ARQ087) [ 96 ], which is orally bioavailable, was found to have an ORR of 20.7% and a DCR of 82.8% in a recent phase II clinical study.

Pemigatinib, a selective oral FGFR 1–3 inhibitor, has shown therapeutic benefit in patients with cancers expressing specific FGFR mutations and has exhibited anticancer effect in genetically defined tumor models [ [97] , [98] , [99] ]. Pemigatinib is licensed for the treatment of individuals with previously treated, incurable, locally progressed or metastatic cholangiocarcinoma with FGFR2 fusions or other rearrangements in Canada, Europe, Japan, and the USA. The approvals were based on the effectiveness and safety findings from the registrational phase II FIGHT-202 trial [ 97 ], which included patients with previously treated, locally advanced or metastatic CCA that was unresectable and had either or both FGF/FGFR mutations patients (n = 108) with FGFR2 fusions or rearrangements showed an objective response rate (ORR) of 37.0% (95% CI: 27.9% to 46.9%), including four complete responses, stable disease in 45.4% of patients, a median duration of response (DOR) of 8.1 months, a median PFS of 7.0 months, and an estimated median OS of 17.5 months [ 100 ]. Encouraging safety and effectiveness findings from FIGHT-101 ( NCT02393248 ), a phase I/II dose-escalation/dose-expansion trial of Pemigatinib in patients with refractory advanced malignancies, served as the base for the start of FIGHT-202.

A third approved selective FGFR inhibitor, Futibatinib (TAS-120) is notable for its covalent binding to FGFR1–4, which distinguishes it from Pemigatinib and Infigratinib (both reversible inhibitors) [ 101 ]. Futibatinib received FDA-accelerated approval in September 2023 for patients with previously treated, unresectable, locally advanced, or metastatic iCCA harboring FGFR2 fusions or rearrangements, based on the phase 2 FOENIX-CCA2 trial [ 102 ]. In 103 patients with FGFR2-rearranged iCCA, the ORR was 42% (95% CI 32–52%), with a median PFS of 9.0 months and a median OS of 21.7 months. The distinct mechanism of Futibatinib is clinically significant: its covalent binding may overcome acquired resistance mutations in the FGFR2 kinase domain that emerge after treatment with reversible FGFR inhibitors [ 103 ]. However, no head-to-head trials have been conducted.

BRAF

V-raf murine sarcoma viral oncogene homolog B1 (BRAF) belongs to the RAF Family and acts as a protein kinase in the activation of mitogen-activated protein kinase (MAPK), generating the transcription of factors that regulate cell proliferation, differentiation, and survival [ 104 ]. BRAF mutations are the most frequent mutations in the MAPK pathway downstream of RAS, and it is altered in 7–10% of all neoplasms [ 105 , 106 ]. Of these, >90% come from the replacement of valine-600 by other amino acids (BRAF V600E), such as arginine, lysine, and aspartic acid [ 105 ]. Mutations in BRAF V600 are especially prevalent in melanoma (∼50%) [ 107 ], papillary thyroid cancer (36–83%) [ 108 , 109 ], colorectal cancer (12 – 27.8%) [ 110 , 111 ], and in NSCLC (2.2 - 8.9%) [ [112] , [113] , [114] ].

In cholangiocarcinoma, BRAF mutations occur almost exclusively in intrahepatic cholangiocarcinoma, with a controversial prevalence of CCA-BRAFV600E of 0–13% [ [115] , [116] , [117] , [118] , [119] , [120] , [121] ]. BRAF V600E mutation status is not correlated with statistically relevant differences in prognosis in patients with iCCA, just as it is not associated with other neoplasms [ 107 , 115 , 122 ].

Dabrafenib is a competitive RAF kinase inhibitor with high potency against mutations in BRAF V600E and was first approved by the FDA for treating patients with unresectable or metastatic melanoma with the mutation in 2013 [ 123 ]. The phase II, open-label, single-arm, multicenter basket trial “Dabrafenib plus trametinib in patients with BRAFV600E – mutated biliary tract cancer” (ROAR) ( NCT02034110 ) evaluated the extent of use of Dabrafenib and Trametinib for patients with mutated biliary tract cancer, finding an overall response rate of 56% (95% CI 38.1–72.1%), median PFS and OS at 6.7 months (95% CI 4.7–13.8 months) and 14.5 months (95% CI 6.8–23.2 months), respectively [ 124 ].

The Subprotocol H trial also evaluated the use of Dabrafenib and Trametinib, investigating it for solid tumors (except melanoma, CRC, NSCLC, and thyroid) with BRAF V600E mutation, finding OS 28.6 months, ORR 38% (90% CI, 22.9–54.9%, p < 0.0001) and PFS of 11.4 months (90% CI, 8.4–16.3 months) [ 125 ]. The NCCN nominally mentions both of these studies to indicate Dabrafenib plus oral Trametinib for selected patients with BRAF V600E mutation [ 15 ]. Since 2022 the combination has been cleared by the FDA for advanced solid tumors [ 126 ].

NTRK fusion

Tropomyosin receptor kinase (TRK) proteins TRKA, TRKB, and TRKC are encoded by the genes NTRK1, NTRK2, and NTRK3, respectively [ 127 ]. In early embryonic development, these proteins have a role in controlling pain, proprioception, appetite, and memory [ 128 ]. Fusion events in these proteins are drivers of oncogenesis, resulting in a variety of malignancies affecting both children and adults [ 129 ].

Chimeric proteins are formed and overexpressed, displaying constitutive, ligand-independent downstream signaling created because of the fusion events that follow [ 130 ]. Notable NTRK fusions include those seen in sarcomas, NSCLC, and mammary analog secretory carcinoma, occurring in approximately 0.3% of all solid tumors, with different frequencies per cancer type [ 131 ]. Furthermore, the corresponding abnormal expression of TRK proteins also varies across cancer types [ 132 ].

The NTRK gene encodes the membrane-bound receptor TRK, which, when activated, triggers the MAPK pathway [ 133 ]. The fusions involving NTRK can be specifically targeted for therapeutic interventions [ 134 ]. In fact, the application of tumor-agnostic approaches targeting NTRK fusions has yielded encouraging outcomes [ 135 ]. In a molecularly defined subgroup of cancer, targeted treatment has demonstrated histology-independent efficacy [ 136 ].

Currently, two TRK inhibitors, Entrectinib (STARTRK-1, STARTRK-2, EudraCT, ALKA-372–001), and Larotrectinib (LOXO-101) are approved by FDA [ 134 , 137 ]. LOXO-101 enrolled 55 patients in all, whose ages ranged from 4 months to 76 years, who received treatment. Patients had 17 different tumor types that exhibited TRK fusion. The total response rate was 75% (95% confidence interval [CI], 61–85%). At one year, 71% of responses were still ongoing, and 55% of patients remained progression-free and the median OS has not been reached [ 134 ].

In the studies for entrectinib the median follow-up was 12.9 months (IQR 8.77–18.76), 31 of 54 (57%; 95% CI 43.2–70.8) patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial responses. The median PFS was 11 months and the median OS was 21 months, while the median DOR was 10 months [ 137 ].

These inhibitors have demonstrated impressive overall response rates (ranging from 57% to 75%) in advanced solid tumors that have been previously treated, supporting the concept of targeting tumors regardless of their tissue of origin [ 136 ]. In addition to their role in various cancer types, NTRK fusions have been specifically identified in 3.5% of patients with iCCA [ 138 ].

RET fusion

Genetic anomalies known as Rearranged During Transfection (RET) fusions result in the constitutively active activation of the RET pathway, independent of regular ligand signaling [ [139] , [140] , [141] ]. These fusions occur most frequently in NSCLC and thyroid cancer, respectively, in 1–2% and 5–10% of instances [ 142 ]. Most RET fusion-positive tumors are NSCLC and thyroid cancer, but RET fusions have also been found in <1% of a variety of other tumor types, including breast, colon, esophagus, ovary, prostate, stomach, pancreas, salivary gland, connective tissues, and histiocytic neoplasms [ 131 , 135 , 136 ].

A highly selective RET kinase inhibitor called selpercatinib was created especially to treat people with malignancies who had RET mutations [ 143 ]. In preclinical models of lung, thyroid, and other malignancies with RET fusions, it has shown notable effectiveness [ 144 ]. As shown in the phase 1/2 study known as LIBRETTO-001, among 41 evaluable patients, ORR was 44% (95% CI: 28, 60) with a DOR of 24.5 months (95% CI: 9.2, not estimable). The median PFS per independent review committee and investigator assessment was 13.2 months (95% CI: 7.4, 26.2) and 11.1 months (95% CI: 5.6–19.1), respectively. The median OS was 18 months [ 145 ].

These findings prompted the FDA to approve selpercatinib for use in treating lung and thyroid malignancies that had RET fusions [ 146 ]. RET fusion-positive advanced solid tumors of all types were included in the trial, allowing for the investigation of selpercatinib's effectiveness in a tumor-agnostic scenario [ 145 ].

Pralsetinib, a similar selective RET inhibitor, also is shown to work well against RET kinases and RET fusion proteins, the phase I/II study (ARROW) [ 147 ]. In the 23 patients eligible for efficacy analyses, the ORR was 57% (95% CI, 35–77%); three (13%) had a confirmed complete response, and ten (43%) had a confirmed partial response. The clinical benefit rate was 70% (16/23 patients), and the disease control rate was 83% (19/23 patients). The PFS and OS found were, respectively, 7 and 14 months.

Pralsetinib was given regulatory clearance in a number of nations for the treatment of metastatic RET fusion-positive NSCLC, advanced or metastatic RET-mutant medullary thyroid cancer, RET fusion-positive thyroid cancer, and advanced RET fusion-positive NSCLC based on the findings from the ARROW research [ 147 , 148 ]. both target RET mutations in a variety of tumor types, which represents a substantial improvement in precision oncology [ [149] , [150] , [151] ].

MSI -H/dMMR

About 2% to 4% of all cancer diagnoses have dMMR [ 152 , 153 ]. The genomic profile of mismatch repair-deficient tumors is unique, with 10- to 100 times more mutations present than in mismatch repair-sufficient tumors [ 154 ]. These cancers have a high level of microsatellite instability (MSI-H), which is caused by mutations in repeated DNA sequences known as microsatellites [ 155 , 156 ]. The principal genes in controlling the mismatch repair are MLH1, MSH2, MSH6, and PMS2 [ 157 ].

According to research of Zang et al., there is a link between MSI-H and dMMR, with 32.14% of Chinese cancer patients displaying MSI-H also displaying dMMR [ 158 ]. Neoantigen levels in high MSI cancers are elevated, triggering potent local and systemic immune responses [ 159 ]. As a result, it is important to look at how MSI and TMB are related. The MSI-H, low MSI, and microsatellite stable groups' median TMB values, which demonstrate substantial differences between groups, were 1945, 408, and 90 nonsynonymous mutations per tumor, respectively [ 158 ]. About 89% of Chinese cancer patients with MSI-H status were categorized as belonging to the TMB-H category [ 158 ]. The study corroborated to demonstrate a strong link between MSI-H and TMB-H, high TMB has been linked to therapeutic benefits [ 160 ].

The KEYNOTE-164 ( NCT02460198 ) enrolled 124 patients with MSI-H CRC and evaluated the antitumor activity of pembrolizumab in these tumors [ 161 ]. The ORR in this study was 33% (95% CI, 21% - 46%), and PFS was 2.3 months (95% CI, 2.1 - 8.1 months) in Cohort A and 4.1 months (95% CI, 2.1 - 8.9 months) in Cohort B. The median overall survival was 31.4 months.

The KEYNOTE-158 had 351 enrolled patients with diverse tumor types and evaluated the efficacy of pembrolizumab [ 162 ]. The ORR was 30.8% (95% CI 25.8%−36.2%). Median PFS was 3.5 months (95% CI 2.3 - 4.2 months), and median OS was 20.1 months (95% CI 14.1–27.1 months). Both studies demonstrated a clinical benefit of therapy with pembrolizumab among patients with MSI-H.

Additionally, based on five clinical trials, the US FDA has authorized pembrolizumab therapy for unresectable or metastatic solid tumors in patients with MSI-H or dMMR [ 163 ]. These studies across 15 cancer types with 149 patients revealed full or partial response to pembrolizumab in 39.6% of patients with high MSI-H or dMMR [ 164 , 165 ]. Additionally, in 78% of the patients who responded, the reaction persisted for six months or longer [ 164 ]. Pembrolizumab is a recognized histology-independent cancer medication that bases treatment on a typical tumor biomarker rather than the tumor's anatomic origin [ 163 , 166 ].

TMB-H

Immune checkpoint inhibitor (ICI) therapy has significantly improved the treatment of advanced malignancies in recent years [ 167 ]. Although some patients get long-lasting advantages, just a small percentage of patients respond clinically to ICI treatment [ 168 , 169 ]. Better predictive biomarkers must be found in order to help in patient selection and treatment planning [ 170 , 171 ]. Numerous biomarkers, including cytotoxic T-lymphocyte antigen 4 (CTLA-4) or programmed cell death-ligand 1 (PD-L1) immunohistochemistry, T-cell infiltration levels, T-cell receptor clonality, gene expression patterns, and peripheral blood indicators, have been proposed as potential tools for predicting clinical response to ICI in earlier research [ 172 ].

The total number of somatic mutations per coding region of a tumor genome, or TMB is a measurement of all non-synonymous coding mutations in a tumor exome [ 173 ]. TMB has been found to vary significantly across patients and between tumor types [ 174 ]. TMB-H (at least 10 mutations per megabase) has been linked to therapeutic benefits in melanoma, NSCLC, and bladder cancer patients receiving ICI treatment (PD-1/PD-L1 inhibitors) [ 168 ]. Extensively modified tumors might create numerous neoantigens, some of which would boost T-cell reactivity [ 160 , 169 , [175] , [176] , [177] ]. TMB can be utilized as a biomarker to predict a patient's response to immunosuppressive therapy using ICI [ 174 , 178 , 179 ].

PD-L1 can be expressed on the membrane of cells from malignancies that lack mismatch repair [ 180 ]. Pembrolizumab, a humanized IgG4 monoclonal antibody, interacts with the inhibitory immune checkpoint receptor PD-1 expressed on the membrane and prevents the binding of its ligands, PD-L1 and PD-L2, reactivating T-cell-mediated tumor killing [ 158 ].

In the KEYNOTE-158 trial, which aimed to investigate pembrolizumab's effectiveness and safety in treating various cancers, 102 of the trial's 1073 enrolled patients had tumors with TMB-H status [ 160 ]. This group experienced objective radiographic responses in 29% of cases (95% CI, 21–39%) as opposed to only 6% of cases (95% CI, 5–8%) in the non-TMB-H group. The PFS was found to be 2.1 months, been equal between the TMB-H and non-TMB-H group, and the OS in the TMB-H group was 11.7 while in non-TMB-H group was 12.8 months, Even though no TMB-H tumors were discovered in any of the 63 biliary cancer patients in the KEYNOTE-158 TMB cohort, previous studies have revealed that about 4% of advanced biliary tract malignancies contain TMB-H tumors, justifying testing for TMB in this group [ 158 , 160 ]. The FDA approved pembrolizumab based on these findings, for patients with TMB-H advanced solid tumors that have progressed after prior treatment and who have no suitable alternative treatment choices.

Discussion

Precision medicine has profound implications in the context of cholangiocarcinoma, a cancer characterized by its aggressive nature and diverse genetic profiles. In this review, we have outlined the molecular landscape of CCA, focusing on key genetic aberrations that can be used as targets for treatments. By considering each person’s unique genetic environment, precision medicine transforms the way that cancer is treated.

A key component of this approach is the genomic profiling, which makes it possible to pinpoint the precise genetic changes that can be actioned by different treatments and drugs. Oncogenic driver alterations (HER2, IDH1, FGFR2, BRAF, NTRK, and RET) along with the immunotherapy-predictive biomarkers TMB-H and MSI-H/dMMR, are among the molecular features guiding precision therapy in CCA.

HER2 overexpression is prevalent across multiple cancers, including CCA. While earlier HER-2 targeted regimens such as Pertuzumab+Trastuzumab showed modest activity (ORR 23%), zanidatamab, a bispecific antibody, achieved an ORR of 52% and was granted FDA accelerated approval in November 2024. This makes it the first HER2-targeted therapy approved specifically for biliary tract cancer. This substantially higher response rate underscores the mechanistic advantage of simultaneous dual-domain HER2 blockade. IDH1 mutation is targeted by Ivosidenib, which showed improved outcomes in advanced CCA in the phase III ClarIDHy trial. It remains the only FDA-approved IDH1-targeted therapy for CCA. Importantly, the ORR was only 2%, highlighting that disease stabilization, not necessarily tumor regression, is the primary mechanism of clinical benefit. For BRAF V600E-mutated CCA, the combination of Dabrafenib+Trametinib has shown promise (ORR 56% in ROAR) and has received FDA approval for advanced solid tumors with BRAF V600E mutations. Notably, FGFR2 and IDH1 mutations are mutually exclusive in iCCA, with important implications for therapeutic sequencing; two FDA-approved selective FGFR inhibitors (Pemigatinib and Futibatinib) are now available for FGFR2-rearranged iCCA. Infigratinib was previously approved but was withdrawn in May 2024 by the FDA. For tumor-agnostic targets (NTRK fusions, RET fusions, TMB-H, and MSI-H/dMMR), approved agents (Larotrectinib, Entrectinib, Selpercatinib, Pralsetinib, and Pembrolizumab) can be applied regardless of histology, though the prevalence of each target in CCA is low (<5%), reinforcing the need for comprehensive molecular profiling panels rather than sequential single-gene testing.

Beyond targeting the disease at the molecular level, precision medicine emphasizes the importance of comprehensive patient care, integrating individual differences in lifestyle, environmental factors, and concurrent medical conditions. This represents a paradigm change in the treatment of cancer by providing individualized treatment plans based on each patient’s unique molecular profile.

Precision medicine has great potential to change the way CCA is treated, improve diagnosis and patients’ outcomes as the understanding of CCA biology expands and technology advances. Research efforts and clinical trials are necessary to validate and investigate new biomarkers. This will open the door to customized methods to CCA management in the era of precision oncology.

Future perspectives and unmet needs

Despite the significant advances reviewed here, important unmet needs remain. First, the majority of CCA patients lack a currently targetable genotype and continue to depend on systemic chemotherapy plus immunotherapy (e.g., gemcitabine, cisplatin, and durvalumab) as first-line treatment [ 181 ]. For these patients, novel strategies are urgently needed. Second, acquired resistance to approved targeted agents is nearly universal. Documented resistance mechanisms include secondary FGFR2 kinase domain mutations (V564F, N549K, E565A) emerging on Pemigatinib or Infigratinib, and secondary IDH2 mutations or IDH1 D279N mutations arising under Ivosidenib therapy. Next-generation inhibitors in clinical development (e.g., Lirafugratinib/RLY-4008 for FGFR2 resistance) offer hope [ 182 ], but the field requires systematic resistance profiling and rational therapeutic sequencing. Third, for tumor-agnostic targets such as NTRK fusions, RET fusions, TMB-H, and MSI-H/dMMR, CCA-specific prevalence is low (<5% each), which underscores the practical importance of comprehensive molecular profiling panels (rather than sequential single-gene testing) to efficiently identify actionable alterations. Fourth, nearly all current targeted therapy approvals in CCA are based on single-arm phase II data; phase III confirmatory studies with overall survival endpoints are needed—a limitation already apparent for Zanidatamab, whose accelerated approval awaits confirmation from the HERIZON-BTC-302 phase III trial. Fifth, combination strategies that address the immunosuppressive CCA tumor microenvironment, for example, pairing targeted therapy with immune checkpoint inhibitors, are an emerging area of investigation that may broaden the proportion of patients benefiting from precision approaches. Finally, the integration of liquid biopsy and cfDNA monitoring into clinical practice holds promise for real-time assessment of molecular response, early detection of emerging resistance, and longitudinal management of advanced CCA.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CRediT authorship contribution statement

Augusto Almeida: Writing – original draft, Investigation, Formal analysis. Joao Manzi: Writing – original draft, Investigation, Conceptualization. Camila Hoff: Writing – original draft. Haaris Kadri: Writing – review & editing, Visualization. Alan Livingstone: Writing – review & editing. Ana Gleisner: Writing – review & editing. Emily Baiyee Toegel: Writing – review & editing. Richard Schulick: Writing – review & editing. Paulo M Hoff: Writing – review & editing. Rodrigo Vianna: Writing – review & editing. Phillipe Abreu: Writing – review & editing, Writing – original draft, Supervision, Project administration, Methodology, Investigation, Conceptualization.

Declaration of competing interest

The author(s) declare(s) that there is no conflict of interest.

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