Introduction

The incidence of and mortality rates for biliary tract cancer (BTC) have steadily increased over the past two decades [1,2]. BTC encompasses intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, distal extrahepatic cholangiocarcinoma, and gallbladder cancer, each of which is characterized by distinct anatomical and molecular features relative to other malignancies. Most patients present with unresectable advanced-stage disease at the time of diagnosis, resulting in limited therapeutic options and a poor overall prognosis [1-3]. However, recent advances in genomic analysis and related translational research have progressively elucidated the molecular mechanisms underlying BTC. Concurrent developments in immunological and molecular approaches have led to meaningful changes in diagnostic and therapeutic strategies [1]. In particular, growing insights into the immunological characteristics of BTC have redefined this disease as a tumor entity with a unique tumor microenvironment, underscoring the importance of understanding this microenvironment for the development and clinical application of immunotherapeutic agents [2].

In addition, emerging evidence regarding the heterogeneity and functional roles of cancer-associated fibroblasts, along with advances in circulating tumor DNA analysis, has expanded the potential applications of these approaches to early diagnosis and assessment of treatment response [2]. From a therapeutic perspective, agents targeting isocitrate dehydrogenase 1 (IDH1) mutations and fibroblast growth factor receptor 2 (FGFR2) fusions are used in clinical practice, and their indications continue to broaden. Furthermore, the combination of durvalumab or pembrolizumab with gemcitabine and cisplatin has demonstrated improved survival, thereby shifting the paradigm in first-line treatment for advanced BTC.

In this review, we summarize the most recent evidence regarding immunotherapy and targeted therapy for BTC to provide practical guidance for the development of treatment strategies in real-world practice.

Main subjects

In the clinical management of BTC, the role of systemic therapy is expanding beyond advanced-stage disease into the perioperative setting. For patients with resectable BTC, adjuvant capecitabine currently remains the standard of care based on the BILCAP trial, which demonstrated a significant survival benefit compared to observation. Although chemoimmunotherapy and targeted agents have not yet been established as standard adjuvant or neoadjuvant treatments, their clinical success in advanced settings has catalyzed investigations into their efficacy in earlier stages. Notably, induction therapy using these novel agents is being actively explored to improve resectability and long-term outcomes, potentially shifting the treatment paradigm across all stages of the disease.

1. Advances in targeted therapy for biliary tract cancer

Despite the recent increase in its incidence, BTC remains a malignancy with a poor prognosis and a 5-year survival rate of approximately 20%, largely due to challenges in early diagnosis and limited therapeutic options [2]. Over the past decade, the standard first-line treatment for unresectable advanced BTC has been a combination of gemcitabine and cisplatin; however, the reported median overall survival (OS) with this regimen remains less than 12 months, underscoring the ongoing need for improved therapeutic outcomes [4].

Molecular profiling studies using next-generation sequencing (NGS) have demonstrated that various anatomical subtypes of BTC possess distinct molecular characteristics that extend beyond mere differences in anatomical location [1].

Among intrahepatic cholangiocarcinomas, the mass-forming small duct-type subtype is characterized by a relatively high frequency of IDH1/2 mutations (10%–30%) and FGFR2 fusions (10%–20%). In contrast, the large duct subtype, which exhibits infiltrative growth along the bile ducts, is characterized by Kirsten rat sarcoma virus oncogene homolog (KRAS; 15%–30%) and tumor protein p53 (TP53) mutations (10%–40%) [2].

In perihilar cholangiocarcinoma, distal cholangiocarcinoma, and gallbladder cancer, KRAS mutations are observed at a high frequency (30%–50%), and erb-b2 receptor tyrosine kinase 2 (ERBB2) amplification (15%–20%) is also relatively more common than in intrahepatic cholangiocarcinoma. In contrast, IDH1/2 mutations and FGFR2 fusions are exceedingly rare in these subtypes, occurring in less than 1% of the cases [2,5].

This molecular heterogeneity not only underscores the importance of NGS-based genomic profiling at diagnosis but also supports the need for subtype-specific, precision-based therapeutic strategies. Indeed, according to a multicenter retrospective study conducted in Austria and published in 2023, among 159 patients with BTC harboring targetable molecular alterations, those who received targeted therapy after first-line treatment (n=36) demonstrated a significantly longer OS of 22.3 months compared with 17.5 months in those treated with cytotoxic chemotherapy (n=43) [3].

Although the currently available targeted therapeutic options for BTC remain limited, these findings indicate that targeted therapy is no longer merely a future possibility but has already emerged as an important treatment strategy in real-world clinical practice.

2. IDH mutation

IDH mutations convert α-ketoglutarate to 2-hydroxyglutarate (2-HG), leading to its intracellular accumulation. Elevated 2-HG functions as an oncometabolite that contributes to tumorigenesis. Based on this mechanism, IDH mutations are considered promising therapeutic targets for BTCs [6].

Ivosidenib, a mutant IDH1 inhibitor, significantly improved progression-free survival (PFS) in the phase III ClarIDHy trial, which enrolled 185 patients with previously treated BTC. In that study, median PFS was significantly longer in the ivosidenib group than in the placebo group (2.7 months vs. 1.4 months). However, no statistically significant difference in OS was observed [7]. Regarding the safety profile, common adverse events included fatigue and gastrointestinal symptoms such as nausea; notably, the approximately 7% incidence of corrected QT prolongation necessitates regular monitoring of electrocardiograms and electrolytes. To date, no additional IDH mutation-targeted inhibitors have been approved for use in the United States beyond ivosidenib.

3. FGFR2 fusions and rearrangements

FGFR2 fusions and rearrangements were first reported in BTC in 2013 and are currently considered among the most clinically actionable and targetable alterations.

Pemigatinib, a competitive inhibitor of FGFR1, FGFR2, and FGFR3, was the first FGFR inhibitor to receive regulatory approval for this indication. In the single-arm, phase II FIGHT-202 study of patients who had received at least one prior line of systemic therapy, 107 patients with FGFR2 fusions or rearrangements achieved an objective response rate of 35.5% and a disease control rate of 82%, with a median OS of 21.1 months [8]. In contrast, no meaningful therapeutic response was observed in patients harboring other FGF/FGFR alterations. Consequently, pemigatinib is currently approved only for patients with confirmed FGFR2 fusions or rearrangement.

The most common adverse event associated with pemigatinib treatment is hyperphosphatemia (approximately 60% of cases), which typically occurs during the early treatment phase. Other reported adverse events include arthralgia, stomatitis, nail disorders, hyponatremia, abdominal pain, fatigue, pyrexia, cholangitis, and pleural effusion [9].

Futibatinib, another FGFR inhibitor, has also been approved for the treatment of BTC based on data from a single-arm phase II study of patients with FGFR2 rearrangements, demonstrating an objective response rate of 42% and a median OS of 21.7 months [10]. Currently, both pemigatinib and futibatinib are approved for use as second-line or later therapies. However, phase III trials comparing these agents with conventional first-line standard regimens of gemcitabine and cisplatin are ongoing. The trials in question are NCT03656536 for pemigatinib and NCT04093362 for futibatinib.

Preclinical studies exploring mechanisms of resistance to FGFR2-targeted therapy may open new therapeutic avenues for the management of BTC.

4. Human epidermal growth factor receptor 2 overexpression or gene amplification

As noted above, IDH1/2 mutations and FGFR2 fusions have been predominantly identified in intrahepatic cholangiocarcinoma and are exceedingly rare in extrahepatic cholangiocarcinoma. In contrast, human epidermal growth factor receptor 2 (HER2; ERBB2) overexpression or amplification is common in extrahepatic cholangiocarcinoma and gallbladder cancer.

Clinical trials targeting HER2 have primarily enrolled patients who experienced disease progression after gemcitabine plus cisplatin therapy. In the phase IIa MyPathway basket study, the combination of trastuzumab and pertuzumab resulted in an objective response rate of 23% among 39 patients, with a median OS of 11 months [11].

A multicenter phase II study conducted in Korea evaluated trastuzumab in combination with 5-fluorouracil-leucovorin-oxaliplatin (FOLFOX) in 34 patients. The reported outcomes included an objective response rate of 29.4%, median PFS of 5.1 months, and median OS of 10.7 months [12].

Additionally, the phase II HERIZON-BTC-01 study evaluated zanidatamab, a bispecific antibody targeting two distinct HER2 epitopes. Among the 80 treated patients, the objective response rate was 41.3%. The median PFS and OS were 5.5 months and 9 months, respectively, demonstrating encouraging efficacy [13].

Major adverse events associated with HER2-targeted therapy include elevated liver function test results, diarrhea, infusion-related hypersensitivity reactions, and cardiotoxicity. Although the incidence of cardiotoxicity was relatively low (less than 3%), it may have significant clinical consequences. Therefore, baseline assessment of cardiac function before treatment initiation and regular cardiac monitoring during therapy are essential.

5. Other targetable genes

Therapies targeting relatively rare, actionable genetic alterations in BTCs are largely tumor-agnostic agents developed independently of a specific cancer type. These agents have received regulatory approval based on basket trials that enrolled patients with advanced solid tumors, and demonstrated meaningful clinical efficacy in a subset of patients with BTC.

B-type rapidly accelerated fibrosarcoma (BRAF) V600E mutations are observed primarily in intrahepatic cholangiocarcinoma and have been identified in approximately 5% of all BTCs. Combination therapy with the BRAF inhibitor dabrafenib and the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib demonstrated a clinically meaningful benefit in the BTC cohort, with an objective response rate of 47% and a median PFS of 9 months [14]. The combination of dabrafenib and trametinib was generally manageable, with pyrexia, fatigue, nausea, and rash being the most frequently reported treatment-related adverse events.

Neurotrophic tyrosine receptor kinase (NTRK) fusions are exceedingly rare in BTCs, occurring in approximately 0.7% of cases. The TRK inhibitors larotrectinib and entrectinib received tumor-agnostic approval after demonstrating high response rates of 75% and 57%, respectively, in clinical trials involving patients with various solid tumors [15,16].

Rearranged during transfection (RET) fusions are extremely uncommon and have been identified in less than 0.2% of all BTCs. In a phase I/II study of the RET inhibitor pralsetinib, two of three patients with metastatic BTC achieved partial responses, and one patient had stable disease [17,18]. Another RET inhibitor, selpercatinib, was evaluated in a study that included a variety of solid tumors. Among the 45 participants enrolled, two had BTC, and an overall response rate of 44% was reported for the entire study population [19].

Taken together, tumor-agnostic targeted therapies may represent an important therapeutic option for patients with BTC harboring rare, actionable genomic alterations. However, further well-designed studies are warranted to establish the optimal treatment strategies for this molecularly defined population.

6. Recent advances in immunotherapy for biliary tract cancer

The tumor microenvironment of BTC is characterized by immunosuppressive features. Compared to normal tissues, cytotoxic T lymphocytes and natural killer cells are decreased, while regulatory T cells tend to increase [20]. Additionally, the expression of immune checkpoint molecules, such programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), is upregulated [20]. The presence of various immunosuppressive cell populations also contributes to marked intratumoral transcriptomic heterogeneity. These characteristics promote tumor growth, immune evasion, and resistance to anticancer therapies [21], which may explain the generally low response rates observed with immune checkpoint inhibitor [21,22].

To overcome these limitations, combination strategies that incorporate immune checkpoint inhibitors and cytotoxic chemotherapy have been actively investigated. In the pivotal phase III TOPAZ-1 trial, the addition of the PD-L1 inhibitor durvalumab to gemcitabine-cisplatin demonstrated superiority over gemcitabine-cisplatin alone. In the updated analysis, the median OS in the combination group was 12.9 months (95% confidence interval [CI], 11.6–14.1), compared with 11.3 months (95% CI, 10.1–12.5) in the control group [23]. The 24-month OS rates were 23.6% and 11.5% (95% CI, 18.7–28.9; 7.6–16.2) in the combination group and control group, respectively. PFS and objective response rates were also significantly improved. No significant difference in treatment-related toxicity was observed between the two groups [23]. These findings demonstrate that durvalumab combination therapy provides a clinically significant long-term survival benefit and is currently considered an important first-line standard of care for advanced BTC.

Pembrolizumab, a PD-1 inhibitor, also demonstrated efficacy in the first-line setting in the phase III KEYNOTE-966 trial. Although pembrolizumab is primarily used as salvage therapy in patients with mismatch repair deficiency or high microsatellite instability, the KEYNOTE-966 trial showed that its combination with pembrolizumab, gemcitabine, – and cisplatin resulted in superior survival outcomes compared to chemotherapy alone [22,24]. The median OS was 12.7 months (95% CI, 11.5–13.6) in the combination group versus 10.9 months (95% CI, 9.9–11.6) in the control group, with a hazard ratio of 0.83 (95% CI, 0.72–0.95). Treatment-related toxicity did not differ significantly between the two groups [22,24].

Beyond combinations with cytotoxic chemotherapy, immune checkpoint inhibitors have also been explored in combination with targeted agents. In patients with BTC who had progressed on prior therapy, the combination of the tyrosine kinase inhibitor lenvatinib and pembrolizumab demonstrated response rates of 10%–25% and median OS ranging from 8.6 to 11 months [25]. This regimen may represent a potential therapeutic option in the context of limited alternatives following failure of first-line treatment.

However, because BTC is a relatively uncommon malignancy, many clinical studies have been limited to small cohorts or single-center studies. Therefore, large-scale, multicenter prospective studies are essential to establish immunotherapy as a more definitive standard of care for this disease. Furthermore, ongoing efforts are required to expand the current indications and develop treatment strategies applicable to a broader patient population.

Conclusions

Since the introduction of gemcitabine plus cisplatin in 2010, progress in the treatment of BTC remained limited for an extended period. However, recent advances in novel therapeutic strategies, particularly those involving immunotherapy and targeted agents, have marked a significant turning point in disease management (Fig. 1) Combination regimens that integrate immune checkpoint inhibitors and cytotoxic chemotherapy have helped overcome the limitations of conventional first-line therapies, leading to meaningful improvements in survival outcomes. Furthermore, precision-based treatments targeting specific molecular alterations, such as FGFR2 fusions, IDH mutations, and HER2 overexpression, have demonstrated clinically meaningful survival benefits in patients who have progressed after first-line therapy.

In the future, the application of targeted therapies is expected to expand into first-line settings. If optimal combination strategies that integrate cytotoxic chemotherapy, immunotherapy, and targeted agents can be established, further improvements in therapeutic efficacy may be achieved, with the potential to also minimize treatment-related toxicities.

Article information

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

None.

Author contributions

Conceptualization: JJH, JWL. Supervision: JWL. Visualization: JJH. Writing-original draft: JJH. Writing-review & editing: JJH, JWL. All authors have read and approved the final manuscript.

Fig. 1.

Treatment algorithm for biliary tract cancer (BTC). NGS, next-generation sequencing; IDH1, isocitrate dehydrogenase 1; FGFR2, fibroblast growth factor receptor 2; BRAF, b-type rapidly accelerated fibrosarcoma; MSI-H, microsatellite instability-high; dMMR, mismatch repair deficiency; HER2, human epidermal growth factor receptor 2; NTRK, neurotrophic tyrosine receptor kinase; RET, rearranged during transfection; FOLFOX, 5-fluorouracil-leucovorin-oxaliplatin; 5-FU, 5-fluorouracil.

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Figure & Data

References

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