Recent advancements in systemic therapy for biliary tract cancers: a literature review

Introduction

Biliary tract cancers (BTCs) are a diverse and anatomically complex group of malignancies arising from the epithelial lining of the biliary system and include gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (iCCA), perihilar cholangiocarcinoma (Klatskin tumors), extrahepatic cholangiocarcinoma (eCCA), and, occasionally, ampullary cancers (1,2). Among these, GBC is the most common subtype, followed by eCCA and iCCA; however, precision in epidemiology has been historically hindered by the frequent misclassification of perihilar tumors as iCCAs (3,4). BTCs impose a substantial global health burden and were responsible for more than 211,000 new diagnoses and approximately 174,000 deaths worldwide in 2017 (5). Although BTCs are considered rare on a global scale, their incidence has been rising steadily over recent decades, with Southeast Asia reporting the highest regional burden (6,7). Incidence rates vary dramatically by geography, ranging from 0.3 to 6 per 100,000 individuals; for example, in South Korea, the reported rate is 3.0 per 100,000, while in the United Kingdom, it is 0.66 per 100,000 (8). Despite constituting only about 15% of all primary liver tumors, BTCs are notoriously aggressive and confer a poor prognosis, with the 5-year overall survival (OS) rate remaining below 10% and the recurrence rate exceeding 50% even among early-stage cases (9-11). Numerous risk factors have been implicated in the pathogenesis of BTCs, including hepatobiliary infections, gallstones, liver cirrhosis, diabetes mellitus, obesity, chronic hepatitis B and C infections, and, notably, primary sclerosing cholangitis (PSC), which is particularly prevalent in Asian populations (9). Due to nonspecific symptoms and inherent biological heterogeneity, the majority of patients with BTCs are diagnosed at advanced or metastatic stages, limiting the opportunity for systemic treatment, participation in clinical trials, or palliative care (12). In this challenging context, the identification of reliable prognostic and predictive biomarkers is essential for guiding personalized treatment approaches. Inflammatory indices derived from routine blood parameters such as the neutrophil-to-lymphocyte ratio (NLR) and the emerging neutrophil-to-eosinophil ratio (NER) have demonstrated significant prognostic relevance across various malignancies, including BTCs (13). The Royal Marsden Hospital (RMH) prognostic score, although originally developed for patients in early-phase clinical trials, has proven useful in BTC cohorts. It integrates serum albumin levels, lactate dehydrogenase (LDH), and the number of metastatic sites to stratify patients according to risk and assist with trial enrollment and treatment planning (14). Molecular profiling has identified several actionable genetic alterations in BTCs. Up to 15–20% of iCCA tumors harbor isocitrate dehydrogenase 1 (IDH1) mutations or fusions involving the fibroblast growth factor receptor (FGFR) family, both of which are being actively targeted in ongoing clinical trials. Additionally, B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E mutations are found in approximately 5% of iCCA cases and represent a promising target for genotype-directed therapies involving dual BRAF and MEK inhibition (15). Although human epidermal growth factor receptor 2 (HER2) amplification or overexpression is rare in iCCA, it is observed in up to 15–20% of GBCs and eCCAs, which forms the rationale for anti-HER2 therapeutic strategies in these subsets (15-17). Support for the targeting of BRAF is primarily derived from a phase II multicenter basket trial, which demonstrated the clinical benefit of combined BRAF-MAPK/ERK pathway inhibition in patients with BRAF V600E-mutated tumors. Approximately 5% of iCCA cases carry this activating mutation in the BRAF gene, which drives tumorigenesis through the MAPK pathway (18). HER2 activation is also present in a subset of BTC cases. Although rare in iCCA, HER2 overexpression or gene amplification is present in 15–20% of eCCA and GBC cases, providing further justification for the application of HER2-targeted therapy in these populations (19). However, HER2 alterations are relatively uncommon in BTCs overall, occurring in just 1–2% of cases. In contrast, they are more prevalent in ampullary cancers, with reported rates of up to 7% (20). Alterations in neurotrophic receptor tyrosine kinase (NTRK) genes 1–3 are exceedingly rare in BTCs but are considered actionable targets when present, given the efficacy of NTRK inhibitors in fusion-positive cancers (21). Similarly, a small subset of patients with BTC, approximately 1% harbor high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR), forming a rare but therapeutically relevant population that may benefit from immunotherapy (22). Given the predominance of late-stage diagnoses, BTCs are often associated with poor clinical outcomes, and current treatment strategies are largely limited to systemic therapies, investigational agents in clinical trials, or supportive care (12).

The therapeutic approaches that are presently in use or that are being considered by clinicians for the systemic treatment of BTCs are summarized in the sections below. We present this article in accordance with the Narrative Review reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-83/rc).

Methods

Google Scholar, PubMed, EMBASE, and the Cochrane Library were searched for recent literature via the following search terms: bile duct cancer, systemic therapy, adjuvant therapy, chemotherapy, cholangiocarcinoma, extrahepatic cholangiocarcinoma, intrahepatic cholangiocarcinoma, distal cholangiocarcinoma, common bile duct cancer, gallbladder cancer, targeted therapy, immunotherapy, and similar terms.

Literature selection

The inclusion criteria for the literature were as follows: (I) English-language literature; (II) extensive studies; (III) a topic related to recent advancements in BTCs, and (IV) publication in peer-reviewed journals. Meanwhile, the exclusion criteria for the literature were as follows: (I) inadequate data for BTCs; (II) similar studies from the same institute or sharing the same patient sample; and (III) languages other than English (see Table 1).

Treatment

Systemic treatments in the advanced setting are based on three main pillars: cytotoxic chemotherapy, the addition of immunotherapy to chemotherapy, and targeted therapies. Targeted therapies are based on several promising targets, including IDH1 mutations, FGFR2 fusions, BRAF-V600E mutations, and HER2 amplifications (23).

Adjuvant therapies

Adjuvant therapy represents one of the most effective approaches in improving patients’ outcomes in systemic therapy. However, several issues exist, and the results from trials are equivocal, most likely due to the diversity of BTCs observed in terms of prognosis, etiology, epidemiology, and molecular characteristics. The only effective treatment available remains radical surgical resection; unfortunately, however, only 35% patients at diagnosis have resectable disease, and postoperative recurrence is common (50–70%) (24-27). Therefore, there is a critical need to develop effective adjuvant therapy. In the PRODIGE 12 ACCORD 18 clinical trial and BCAT trial (28), two recent observation-controlled phase III trials, adjuvant gemcitabine-based chemotherapy was not found to be effective in treating surgically removed biliary tract malignancies (29). Perioperative chemotherapy may thus be necessary to improve survival, but as BTCs are relatively uncommon, few randomized phase III clinical study trials on perioperative chemotherapy have been conducted. For advanced BTCs, gemcitabine combined with cisplatin plus S-1 (GCS) has become the preferred chemotherapeutic regimen. In addition to increasing OS, GCS is associated with a high response rate. A phase III randomized clinical trial (JCOG1920) conducted in Japan examined the effectiveness of GCS in preoperative neoadjuvant chemotherapy for resectable BTCs (30), yet clinical studies that have assessed the value of adjuvant systemic treatment for patients with BTCs are rare (Tables 2,3).

Depending on these findings, the American Society of Clinical Oncology (ASCO) guidelines recommend adjuvant capecitabine for approximately 6 months after curative surgical resection of BTCs, including CCA and GBC (34). Clinicians agree that after surgery, patients should recover for 12 to 16 weeks before beginning optimal therapy. In addition, chemotherapy should be administered for a limited time (rather than waiting until the disease relapses) because it is considered a routine practice in optimal conditions and has been observed to be safe. Finally, fluoropyrimidine-based therapy seems to be preferred (26).

Palliative therapy

Chemotherapy remains the cornerstone of treatment for most newly diagnosed patients with advanced BTCs, including those with unresectable or metastatic disease. Cytotoxic drugs have been observed to be effective in a number of randomized controlled trials in patients with advanced BTCs. Combination chemotherapy is currently recommended for patients with sufficient organ function and good performance status, as it is generally associated with superior responsiveness, OS, and progression-free survival (PFS) than is single-agent chemotherapy (35).

First-line palliative treatment

Standard first-line chemotherapy with cisplatin and gemcitabine has been practiced for over the past 10 years, with the ABC 02 study in the United Kingdom reporting a median survival of 11.7 months and a PFS of 8.0 months under this regimen (36). Another phase II study (37) examined the combination of gemcitabine, cisplatin, and nab-paclitaxel (GCNP) in patients with BTCs and found it conferred a higher response rate and longer survival. From January 2018 to August 2022, patients with locally advanced, inoperable, and metastatic liver disease receiving first-line chemotherapy for GCNP at a multidisciplinary joint clinic (MDJC) were evaluated, with the objective response rate (ORR) being the primary endpoint and event-free survival (EFS) being the secondary endpoint. A total of 142 patients received GCNP at baseline. Men accounted for 81.7% and women for 18.3% of the cohort, with a mean age of 52 years (range, 21–79 years). A total of 137 patients were included in the response rate calculation, with 9 (6.3%), 87 (61.3%), and 24 (16.9%) patients exhibiting CR, partial response, and stable disease, respectively, representing an ORR of 67.6% and a clinical benefit rate of 84.5%. A median EFS of 9.92 [95% confidence interval (CI): 7.69–12.14] per month was achieved. Surgery was performed in 17 of 52 (34%) patients, with neoadjuvant chemotherapy-targeted GCNP being administered for locally advanced GBC (37). The efficacy of folinic acid plus fluorouracil (5-FU) and gemcitabine plus oxaliplatin (GEMOX) versus that of best supportive care (BSC) was evaluated in 81 patients with advanced GBC. The median OS was 9.5 months for patients receiving GEMOX, 4.6 months for those treated with 5-FU plus folinic acid, and 4.5 months for those treated with BSC (P=0.039) (38).

The TOPAZ-1 trial demonstrated that compared to GC alone, durvalumab with GC provides markedly longer OS [12.8 vs. 11.5 months; hazard ratio (HR) =0.80, 95% CI: 0.66–0.97; P=0.021] (39). These OS results support the National Comprehensive Cancer Network Guidelines (NCCN) 2022 (40) recommendation that durvalumab with GC be used as one of the first-line treatments for metastatic and incurable BTC. These immune checkpoint inhibitors (ICIs), however, target programmed cell death ligand 1 (PD-L1), and have a distinct safety profile and efficacy as compared to ICIs targeting programmed cell death protein 1 (PD-1) (41). A 2019 Japanese phase III trial included 354 patients with advanced BTC and examined the noninferiority of gemcitabine plus S-1 (GS) to oral fluoropyrimidine with gemcitabine and cisplatin (GC). GS was found to be noninferior to GC. The response rate was 29.8% with GS and 32.4% with GC. The median PFS was 6.8 months for the GS group and 5.8 months for the GC group (HR =0.86, 95% CI: 0.70–1.07), while the median OS was 15.1 months for the GS group and 13.4 months for the GC group (HR =0.94, 95% CI: 0.78–1.15; P=0.046 for noninferiority). However, North America and Europe currently do not have access to S-1 (42). Another common regimen for treating BTC is GEMOX, which replaces cisplatin and oxaliplatin when combined with gemcitabine. GEMOX was evaluated in a phase II trial (43) for patients with advanced BTC not receiving chemotherapy. The results showed that the median PFS ranged from 3.4 to 5.7 months, the median OS ranged from 8.8 to 15.4 months, and the ORR ranged from 14.9% to 41% (42,44-47). There are only a few phase III clinical trials (Table 4) that have evaluated the efficacy of chemotherapy for patients with advanced BTC.

KEYNOTE-966, a double-blind, placebo-controlled, randomized phase III trial, was conducted in 175 medical institutions across the world. Eligible individuals were required to be least 18 years of age and have untreated, incurable, locally advanced, or metastatic lung disease. Between October 4, 2019 and June 8, 2021, 1,564 patients were examined, of whom 1,069 were randomized to receive GC (n=536) or pembrolizumab plus GC (n=533). The median follow-up at the time of the final analysis was 25.6 months (IQR, 21.7–30.4 months). The pembrolizumab group had a median OS of 12.7 months (95% CI: 11.5–13.6), and the placebo group had a median OS of 10.9 months (IQR, 9.9–11.6 months) (HR =0.83, 95% CI: 0.72–0.95; one-sided P=0.003; limit-of-significance P=0.020). The findings indicated that pembrolizumab in combination with GC is a promising new treatment option for patients with metastatic or unresectable BTC (50). A number of clinical investigations on GTC are still in progress, and further developments are anticipated.

Second-line palliative treatment

A few second-line therapeutic options are available for patients with advanced BTC (51). However, there has been a lack of definitive findings indicating that second-line chemotherapy increases survival in those with advanced BTC. A review of 25 publications, most of which were phase II trials published before 2015, and included a total of 761 patients with advanced BTC who had progressed on first-line chemotherapy, concluded that there was insufficient evidence to support a general recommendation for second-line therapy in this setting (52). However, the efficacy of second-line treatment may vary depending on the tumor’s mutational profile. For patients without contraindications to targeted therapies and without actionable mutations, chemotherapy remains the preferred option (53).

The present standard of care for patients with advanced BTCs is second-line therapy with 5-FU plus oxaliplatin (FOLFOX) after first-line GC. The ABC 06 trial on patients progressing after GC showed that FOLFOX improved OS against active symptom control alone (median OS: 6.2 vs. 5.3 months; P=0.031; HR =0.69, 95% CI: 0.50–0.97); this advantage was also seen at 6 months (35.5% vs. 50.6%) and 12 months (11.4% vs. 25.9%). Recent results from phase II of the NIFTY trial (45) comparing patients treated with 5-FU and nanoliposomal irinotecan (nal-IRI) to those with 5-FU alone who have progressed after receiving GC therapy show promise. The median PFS in the combination arm was 7.1 months, while that in the 5-FU-alone arm was 1.4 months (HR =0.56; 95% CI: 0.39–0.81; P=0.0019), suggesting that the actual goal of the study has been met. Early-phase data from the ongoing phase III SWOG S1815 clinical trial indicated increases in median PFS and OS from the combination of GC with nab-paclitaxel used in first-line treatment (54). The NIFTY trial demonstrated that second-line treatment with nanoliposomal irinotecan combined with 5-FU and leucovorin significantly improved PFS compared to 5-FU and leucovorin alone in patients who had progressed after first-line gemcitabine-cisplatin (55). The NapaSinti trial (56), a prospective, randomized, open-label, phase II study, was recently conducted at a tertiary care hospital in Chengdu, China. It evaluated the safety and efficacy of sintilimab plus nab-paclitaxel as second-line therapy for advanced BTC. The ongoing Brightline-2 clinical trial is examining the safety and efficacy of brigimadlin (also known as BI 907828), an experimental medication, in patients with advanced or metastatic malignancies. This trial aims to evaluate brigimadlin’s potential as a novel therapy option for individuals with lung adenocarcinoma, pancreatic ductal adenocarcinoma (PDAC), bladder cancer, or advanced BTC (34). Nonetheless, only a few significant trials (Table 5) on second-line treatment in patients with advanced BTC have been completed.

A phase II trial on the efficacy of anlotinib and sintilimab as second-line therapy for patients with advanced BTC was conducted, with the primary endpoint being the OS rate. The treatment for this study was administered to 20 consecutively enrolled patients. The median OS for the trial was 12.3 months (95% CI: 10.1–14.5), there were no grade 4 or 5 treatment-related adverse events (TRAEs), and only 4 patients (20%) had grade 3 TRAEs. Sintilimab and sintilimab demonstrated a manageable safety profile and promising antitumor efficacy (57). FOLFOX is currently the recommended second-line treatment for unselected patients without advanced BTC. For those with advanced BTC, the focus should be shifted to immunotherapy and targeted therapy.

Targeted therapy for BTCs

To be able to treat patients with advanced BTCs successfully and improve their outcomes, new therapeutic approaches must be developed. Novel research on BTC therapies has included a focus on tyrosine kinase receptor-related pathways, epigenetic silencing, and certain gene alterations (58). By identifying potential genetic alterations, deep sequencing studies have shed light on the complicated molecular biology involved in BTCs (59,60). There is a comparatively high prevalence of druggable genetic modification in patients with advanced BTC, and they have demonstrated encouraging responses to molecular-targeted treatments for gene abnormalities such as FGFR2 fusions and rearrangements, IDH1 mutations, and HER2 overexpression and amplification (61). A comprehensive analysis found that approximately 40% of patients with BTC harbor potentially actionable genetic alterations. Notably, the distribution of driver mutations varies among the different subtypes of cholangiocarcinoma (62). Targeted therapy is used to treat BTCs in most cases that are resistant to chemotherapy. BTCs have been linked to several carcinogenic pathways, especially in iCCAs, which show more aggressive changes than do eCCAs, and exhibit more effective mutations than do GBCs (63). Targeted therapies have significantly extended the array of possible treatment choices for individuals with refractory illness and prolonged survival in those with advanced BTCs. The NER may serve as a prognostic biomarker in BTs, aiding treatment stratification in immunotherapy and targeted therapy settings (13). Given the advancements in the diagnosis of genetic changes, the treatment landscape for patients with advanced BTCs remains dynamic (64).

Isocitrate dehydrogenase inhibitor

IDH is an enzyme that transforms isocitrate to α-ketoglutarate in the citric acid cycle. Mutant IDH1, along with IDH2, then converts α-ketoglutarate to the carcinogenic metabolite, 2-hydroxyglutarate (2-HG). The buildup of 2-HG causes the disruption of cellular metabolism. IDH1 mutations are far less rare than are IDH2 mutations (21,65,66), and a common mutation in patients with cholangiocarcinoma involves the IDH, the metabolic enzyme (67,68). About 20% of those with iCCA have IDH1 mutations. In the phase III ClarIDHy trial, the median PFS was 5.1 months (95% CI: 3.8–7.6) with ivosidenib and 1.6 months (95% CI: 1.4–1.8) with placebo, while the median OS was 10.3 months (95% CI: 7.8–12.4) and 7.5 months (95% CI: 6.2–8.3), respectively (69). IDH1, IDH2, and pan-IDH1/2 inhibitors are among the various IDH inhibitors that are being tested in clinical trials for the treatment of iCCA. Early-phase clinical trials have produced the first encouraging results. For instance, a phase I research applied a 500-mg daily dose of ivosidenib, an IDH1 inhibitor, and successfully assessed 77 individuals with CCA who had previously received treatment but had IDH1 mutations (67). The phase III ClarIDHy trial enrolled 185 patients with metastatic IDH1-mutated cholangiocarcinoma and compared ivosidenib to placebo as second- or third-line therapy, with PFS as the primary endpoint. Overall, 230 participants were evaluated between February 20, 2017 and January 31, 2019. At the cutoff date, 185 patients were randomized to receive either placebo (n=61) or ivosidenib (n=124). The median PFS of the ivosidenib group was 6.9 months (IQR, 2.8–10.9 months), representing a considerable improvement as compared with the placebo group [one-sided P<0.0001; median OS 2.7 months (95% CI: 1.6–4.2) vs. 1. 4 months (95% CI: 1.4–.6); HR =0.37, 95%: CI 0.25–0.54], Ascites occurred in 4 of 59 patients receiving placebo and 9 of 121 patients receiving ivosidenib (7%), with grade-3-or-beyond ascites being the most common grade in both treatment groups. Moreover, 36 of 121 (30%) patients receiving ivocidinib and 13 of 49 (22%) receiving placebo experienced adverse events (AEs). Overall, ivosidenib was well tolerated and provided prolonged PFS as compared to placebo. Overall, targeting IDH1 mutations in patients with advanced IDH1-mutant cholangiocarcinoma has shown therapeutic benefit.

Common AEs of ivosidenib include severe fatigue, diarrhea, and nausea, while serious AEs include diarrhea, bleeding, elevated blood bilirubin level, and hyponatremia (70). Currently, the NCCN guidelines suggest oral IDH1 inhibitor ivosidenib as a second-line therapy for advanced, unresectable, and metastatic BTCs with mutations (71). This recommendation was made after the US Food and Drug Administration (FDA) approved the drug based on the above-mentioned phase III randomized controlled ClarlDHy trial (70). Ivosidenib is currently being evaluated in an ongoing phase I study (NCT04088188) as a component of first-line combination therapy along with GC, which is expected to be finished in 2025. Early-phase trials are also being conducted on additional IDH inhibitors. LY3410738, an oral medication that is already thought to be more effective and perhaps more long-lasting than ivosidenib, is presently being studied in a phase I trial (NCT04521686) for certain BTC IDH variants (IDH2-R140, IDH1-R132, and IDH2-R172). Trials investigating the tolerability of IDH305, an investigational oral drug reserved only for malignancies containing IDH1-R132 mutations, are now underway (NCT02381886). According to preliminary evidence, the oral inhibitor of mutant IDH1, olinusidenib, has shown modest clinical activity, safety, and tolerability, with 23% of treated iCCA patients exhibiting stable disease (72,73). An oral dual IDH1 and IDH2 inhibitor, voracidenib, is also under development, and although its clinical activity in gliomas has been demonstrated in preliminary trials, its effect in BTC has not yet been established (24,74). FDA approved ivosidenib in August 2021 for previously treated patients with CCA and who had a confirmed IDH1 mutation according to an FDA-approved test and who were either locally progressed or metastatic. Moreover, ivosidenib and nivolumab were both tested in combination in a phase II trial for advanced solid tumors with IDH1 mutations (NCT04056910). Regarding IDH2 inhibition, a number of drugs are presently under investigation in early-phase trials, including AG-881 (NCT02481154), which is examining IDH1/2 inhibitors (75).

FGFR inhibitor

The four receptor tyrosine kinases (FGFR 1 to 4) that make up the family known as FGFRs are encoded by the same gene. This receptor exerts several biological functions through several signaling pathways, including the RAS/MAPK and PI3K.AKT pathways (76). This family of oncogenic changes (mutations, fusions, amplifications, or rearrangements) is observed in 7% of solid tumors and is linked to aberrant activation of FGFR, which causes angiogenesis, cell division, and immune escape (76,77). iCCA with FGFR2 fusion has been associated with female gender, young age, and the presence of a concurrent BAP1 mutation (59,78). Approximately 15% of individuals with iCCA have FGFR2 rearrangements or fusions. TAS-120, pemigatinib, infigratinib, and Debio 1347 are among the FGFR inhibitors being investigated in the treatment of BTCs (17,79-81). The FGFR inhibitor infigratinib was assessed in 71 patients with advanced BTCs in a phase II trial. With infigratinib, the ORR was 31%, the median time frame of response was 5.4 months, the median PFS was 6.8 months, the median OS was 12.5 (95% CI: 9.9–16.6) months, and the disease control rate (DCR) was 83.6% (80). Pemigatinib, a selective reversal inhibitor of FIGR 1–3 was approved for treating advanced BTCs after the phase II FIGHT 202 trial demonstrated its efficacy, with an ORR of 35.5% (95% CI: 26.5–45.4%) and with three patients who were unresponsive to previous treatment achieving CR. (82). The highly anticipated phase III Fight 302 (NCT03656536) randomized controlled trial comparing pemigatinib with GC as first-line therapy in advanced BTC is currently underway. Futibatinib is a unique, extra-potent oral drug that acts as an irreversible, covalent pan-inhibitor of FGFR 1–4. In the phase II FOENIX CCA2 trial, it yielded a 12-month survival rate of 73% and an ORR of 41.7% (83). The ongoing FOENIX CCA3 trial (NCT04093362) is currently investigating the efficacy and safety profile of futibatinib as compared to GC as first-line therapy. The first selective FGFR2 inhibitor, RLY-4008, was designed to reduce on-target toxicity and bypass the polyclonal FGFR2 resistance pathway (66). Evidence from the phase I/II ReFocus trial (NCT04526106), presented at the European Society for Medical Oncology (ESMO) Congress 2022, indicated that RLY-4008 has strong efficacy, with an ORR of 88% (95% CI: 63.6–98.5%) in the first 17 patients with FGFR-naïve BTC who received the recommended phase II treatment (66). Enrollment in additional cohorts consisting of patients with BTCs exposed to FGFR inhibitors and all solid tumors is also ongoing (66). Table 6 provides a summary of the completed and ongoing trials for FGFR inhibitors.

HER2

The overexpression of HER2 (also known as ERBB2) occurs in 15% to 20% of BTC cases, especially in eCCA and GBC (84). The combination of the monoclonal antibodies pertuzumab, along with trastuzumab, has been extensively investigated. Although it has not received FDA approval, it is included in the NCCN guidelines as a treatment option for patients with malignancies that are positive for HER2 after first-line therapy (71). A large multibatch phase II clinical trial, MyPathway (NCT02091141), is assessing the efficacy of trastuzumab and pertuzumab in the treatment of patients with metastatic biliary tract tumors with HER2 overexpression and amplification that have not responded to prior therapies. Although the initial results were unsatisfactory, further updates with additional enrollment include an ORR of 23% (95% CI: 11–39%) (85,86). Trastuzumab deruxtecan (T-DXd) is being assessed in the prospective HERB 2 trial in Japan for the treatment of patients with HER2-mutant cholangiocarcinoma who are intolerant or unresponsive to gemcitabine as first-line therapy (87). T-DXd is an antibody drug combination composed of deruxtecan, a topoisomerase inhibitor, a cleavable linker, and the anti-HER2 antibody trastuzumab. The preliminary data presented at the 2022 ASCO Annual Meeting 202 2are promising, with a DCR of 81.8% (95% CI: 59.7–94.8%) and an ORR of 36.4% (95% CI: 19.6–56.1%). However, major side effects were noted, with 25% of patients developing interstitial lung disease, severe gastrointestinal toxicity, and myelosuppression, all of which require further investigation and observation (88). SGNTUC-019 (NCT04579380) was an open-label phase II trial aimed at assessing the safety and efficacy of trastuzumab and tucatinib in patients with advanced malignancies harboring HER2 mutations. Among the 30 included patients, the median follow-up period was 10.8 months, with the data cutoff date being January 30, 2023. Patients were treated with trastuzumab (8 mg/kg intravenously and then 6 mg/kg every 3 weeks) and tucatinib (300 mg orally twice a day) in a 21-day cycle. Among 76.7% of patients (90% CI: 60.6–88.5%), the DCR was 46.7% (90% CI: 30.8–63.0%), the PFS was 5.5 months (90% CI: 3.9–8.1), and the median duration of response was 6.0 months (90% CI: 5.5–6.9). The 12-month OS rate at the data cutoff point was 53.6% (90% CI: 36.8–67.8%), and 15 patients (50.0%) died. The most common treatment-emergent adverse events (TEAEs) were diarrhea (40.0%) and pyrexia (43.3%). Eighteen patients (60.0%) had grade ≥3 TEAEs, most of which included fatigue, cholangitis, and nausea (10.0%), all of which were unrelated to the drug. One patient’s treatment regimen was discontinued due to a TEAE, but the TEAE did not result in the patient’s death. The results showed that previously treated HER2-positive patients with BTC responded to tutunitinib and trastuzumab, demonstrating the clinically significant anticancer activity of this regimen (89). There remain numerous challenges related to HER2-targeted therapy for BTC. It is interesting to note that, in contrast to FGFR and IDH, HER2 amplification is not relatively uncommon in patients with BTCs. Consequently, only a small number of these patients are suitable for clinical study trials, and more research is needed to gain insights into HER2 therapies in clinical settings (90).

B-raf kinase

The B-RAF protein encoded by BRAF is a member of the RAF family of serine threonine protein kinases. In the RAF, MEK, and ERK pathways, this protein functions as a primary enzyme, with tumorigenesis being associated with the dysregulation of these pathways.

Among patients with iCCA, 4% have BRAF mutations, representing the most common mutation type (91-93). Meanwhile, the BRAF V600E mutation is present in approximately 5% of patients with BTC. Combination therapy has considerably potential in the first-line treatment of patients with the BRAF V600E mutation. The Rare Oncology Agnostic Research (ROAR) trial (NCT02034110), a phase II, open-label, multicenter trial, evaluated the safety and efficacy of trametinib (an oral MEK inhibitor) and dabrafenib (an oral BRAF inhibitor) in the treatment of 43 patients with BTC and BRAF mutations who had progressed after chemotherapy (18). According to an independent observer evaluation, BTC-related cases had an ORR of 47%, a median PFS of 9 months, and a median OS of 14 months. Reported AEs included fatigue, flushing, nausea/vomiting, and pyrexia (18).

Vemurafenib is an oral selective RAF inhibitor for BRAF V600 mutations. In a multicenter basket study of 172 patients with BRAF V600-mutant solid tumors excluding melanoma, 9 of the patients had BTCs, and 99% of the patients had BRAF V600E mutations. An ORR of 33.3% was recorded among the patients with BTCs (94,95). In June 2022, the US FDA approved dabrafenib in combination with trametinib for the treatment of patients with advanced solid tumors and the BRAF V600E mutation (96). ABM 1310, a novel small oral molecule inhibitor of BRAF V600E, is presently being evaluated in phase I trials for its safety and potential antitumor efficacy. Concurrently, studies are being carried out for ABM 1310’s combination with the MEK inhibitor cobimetinib (NCT04190628) and monotherapy (NCT05501912). Drugs targeting non-BRAF V600E-mutant melanoma are also being evaluated, with the FDA-approved BRAF-MMEK inhibitor combination yielding promising results (97).

Neurotrophic tropomyosin receptor kinase (TRKs) inhibitors

The NTRK genes, NTRK1, NTRK2, and NTRK3, encode the TRKs, TRKA, TRKB, and TRKC, respectively. These tyrosine kinase receptors are critical to the proper development of the nervous system (98). NTRK gene rearrangements occur in about 3% of patients with iCCA (99). With an overall 75% response rate and prolonged remission, the TRK inhibitor larotrectinib has yielded encouraging results in TRK fusion-positive patients with advanced malignancies, such as BTCs (100). Neurotrophins normally activate TRK receptors and, through ERK signaling, promote cellular growth and multiplication. Meanwhile, fusion rearrangements create hybrid genes by placing constitutively active genes adjacent to NTRK sequences. This results in uncontrollably activated ERKs and ligand-independent TRK receptor signaling (101). Through this key mechanism, TRK-binding proteins are recognized as oncogenic drivers in many tumors. They are more common in rare cancers such as secretory breast carcinoma, where they appear in over 90% of cases, as compared to in fewer than 1% cases of common cancers such as lung and colorectal cancer. The incidence of TRK-binding proteins in bile duct carcinoma is estimated to be around 0.25% (102). A phase I–II trial evaluated larotrectinib treatment in 159 patients with NTRK fusion-positive solid tumors who had previously received conventional therapy. The ORR was 79%, the CR rate was 16%, the median PFS was 28.3 months, and the OS was 44.4 months. One of the two patients with BTC exhibited a limited response, while the other’s disease worsened over time (103). Larotrectinib is an encouraging alternative treatment for patients with BTCs and the NTRK fusion, although NTRK fusion has been documented in only 0.2–0.7% of patients with this disease (102,104).

Immunotherapy

Immunotherapy mainly consists of ICIs that target cytotoxic T-lymphocyte antigens, PD-1, and PD-L1, as well as cancer vaccines and CTLA-4 cell transplants. Immunotherapy has been applied in treating various solid tumors, such as breast cancer, colon cancer, and non-small cell lung cancer. Immunotherapy is currently gaining popularity as a potent therapeutic approach for cancer and is a crucial component of systemic treatment for BTCs and other cancers. In immunotherapy trials, pembrolizumab, nivolumab, and durvalumab monotherapies have shown encouraging outcomes for patients with advanced BTC. Thus, combining immunotherapy with other treatments could be a useful strategy for increasing antitumor efficacy (90). ICIs, as one of the most common forms of immunotherapy, have been well researched in GBC, iCCA, and eCCA. In tumor immunotherapy, endogenous anticancer activity is primarily enhanced by monoclonal antibodies. The majority of the targets of these monoclonal antibodies are immunological checkpoint regulators, also known as ICIs (105). The most studied ICI targets are CTLA-4 and PD-1, as these are the most common T-cell immune checkpoints. In addition, ICIs that directly target other immunological checkpoints, such as LAG-3, TIM-3, TIGIT, and B7-HH3 are being developed (106). ICIs have demonstrated favorable treatment responses across a variety of tumor types (107-109). The US FDA has approved pembrolizumab and nivolumab for the treatment of advanced-stage cancers (110,111). Moreover, cytokine treatment and adoptive cell therapy (ACT) primarily target iCCA and have a moderate impact, but for GBC and eCCA, the efficacy is less conclusive (112). The 2022 phase III TOPAZ 1 trial assessed the efficacy of durvalumab immunotherapy in addition to standard GC chemotherapy in treating patients with recurrent BTC. The median OS increased from 11.5 to 12.8 months, and the ORR increased from 18.7% to 26.7% (39). A single-arm multicenter phase II trial assessed the efficacy of the PD-1 inhibitor nivolumab in the treatment of 54 patients with advanced BTC who had not responded to one or three lines of therapy. The DCR was 59%, and the investigator-assessed response rate was 22%. Patients who responded to therapy did not reach the median duration of treatment. The OS was 14.2 months, and the PFS was 3.7 months. Notably, the long PFS was associated with PD-L1 expression in tumor cells (HR =0.23, 95% CI: 0.10–0.51; P<0.001) (113).

A case report was published that indicated the potential of immunotherapy conversion for tumors that were initially considered incurable. The report described a patient with iCCA who underwent successful surgery following six cycles of ICI plus GEMOX, which decreased tumor size and enabled surgical resection (114). PD-L1 is the most common therapeutic target for cancer immunotherapy. Solid tumors with MSI-H status respond well to immunotherapy consisting of PD-L1 inhibitors (115,116). Pembrolizumab, which binds to and inactivates PD-1, has been approved for the treatment of various solid cancers with microsatellite instability. The safety and efficacy of pembrolizumab in the treatment of advanced BTCs were evaluated in the KEYNOTE 158 (phase II) and KEYNOTE 028 (phase Ib) trials. In 6% to 13% of patients with advanced BTC, monoclonal antibodies, independent of PD-L1 expression, demonstrated moderate toxicity and long-lasting anticancer activity (117). Several phase II trials have investigated another PD-L1 blocker, nivolumab, reporting encouraging results and a reasonable safety profile, both alone and with GC (118). In a phase II trial that enrolled 46 patients with advanced BTC who received at least first-line chemotherapy, nivolumab treatment yielded an ORR of 11% overall, a PFS of 3.7 months, and an OS of 14.2 months (113). Clinical trials are currently being conducted on the anti-CTLA-4 medication ipilimumab to evaluate its efficacy in treating various solid cancers. The CA209-538 (phase II) clinical trial reported that a combination of nivolumab and ipilimumab yielded favorable results in patients with advanced BTC. Compared to single-agent anti-PD-1 therapy, this combination was associated with higher response rates, with a 23% ORR among patients with GBC or iCCA; however, patients with eCCA did not respond to this treatment. The OS was 5.7 months (95% CI: 2.7–11.9). However, further trials are needed to determine if this combination immunotherapy regimen can provide superior therapeutic effect for patients with advanced BTC as compared to single-agent anti-PD-1 treatment (119).

The efficacy of immunotherapy as a first-line treatment has been evaluated in chemotherapy-naïve patients with BTC. Patients with a histologically confirmed diagnosis of advanced or unresectable BTCs were enrolled in the phase III KEYNOTE-966 trial (NCT04003636), and the OS of patients treated with GC plus pembrolizumab was compared with that in patients treated with GC alone. Although definitive findings are still expected, the preliminary results are encouraging, as GC plus pembrolizumab yielded a statistically significant increase in survival as compared to chemotherapy alone. The TOPAZ 1 trial (NCT03875235) was a double blind, placebo-controlled study that examined the effects of GC and durvalumab, an anti–PD L1 agent, in chemotherapy-naïve patients with advanced BTC. Patients who received durvalumab also showed significant improvements in PFS (HR =0.75, 95% CI: 0.64–0.89) and OS (HR =0.80, 95% CI: 0.66–0.97). Moreover, those who received durvalumab had an ORR of 26.7%, while those who received placebo had an ORR of 18.7% (39). Based on the results of the TOPAZ 1 trial, the US FDA approved durvalumab for the treatment of locally advanced or metastatic BTC in older patients in combination with GC chemotherapy. Additionally, the NCCN guidelines now recommend this regimen as first-line therapy for patients with metastatic, locally advanced or unresectable cancers.

Immunotherapy has emerged as a promising strategy in the treatment of BTCs, particularly with the introduction of ICIs such as durvalumab and pembrolizumab. Phase III trials such as TOPAZ-1 and KEYNOTE-966 have demonstrated improved survival outcomes when these agents were combined with chemotherapy. Despite this progress, the lack of reliable predictive biomarkers remains a substantial challenge, highlighting the need for further research into personalized treatment strategies (120).

ICI monotherapy

Novel approaches to therapy are being developed. For instance, the ICIs durvalumab or pembrolizumab have been added to GC as a first-line systemic treatment, providing prolonged survival as compared to GC alone (121).

In one clinical trial (NCT01876511), pembrolizumab treatment resulted in satisfactory results for 86 patients with dMMR or MSI-H (including those with cholangiocarcinoma) (116). In one phase Ib clinical trial, 228 patients with high-grade cholangiocarcinoma and 4 patients with high-grade GBC, all of whom were PD-L1-positive—received pembrolizumab monotherapy. Three of the patients with cholangiocarcinoma and one with GBC achieved stable disease. Grade 3 toxicity was observed in 17% of cases, but no grade 4 events occurred. Moreover, the ORR was 17%, the median PFS was 1.8 months, and the median OS was 6.2 months. Of note, this trial confirmed that pembrolizumab exerts anticancer activity, is well tolerated, and provides satisfactory safety and efficacy (117). In a phase II study, 54 patients with advanced refractory BTC who had received at least one line of systemic therapy but no more than three lines were treated with nivolumab. More than half of patients with well-controlled disease had a median PFS of 3.68 months and a median OS of 14.22 months (113).

In addition to immune-specific ICIs, immune-simulating ICIs have also garnered considerable attention. An encouraging example is ABL501, which has stronger antibody efficacy than does anti-LAG-3 and anti-PD-L1 combination therapy because it can inhibit LAG-3 and PD-L1 simultaneously. ABL501 is currently undergoing first-in-human trials (NCT05101109) and has emerged as one of the viable options for cancer immunotherapy (122). Another emerging agent is M7824, a unique bifunctional fusion protein. M7824 is a monoclonal antibody against PD-L1 fused to the extracellular domain of human TGF-β receptor II. Due to its unique structure, M7824 can inhibit TGF-β and PD-L1 simultaneously (123). One study examined M7824’s response in Asian patients with cholangiocarcinoma. It yielded an ORR of 23%, but 63% of the patients experienced TRAEs (124). Sex-based differences in immune-related adverse events (irAEs) may influence BTC management, particularly as ICIs are increasingly used in the treatment of advanced BTC. Understanding sex-specific toxicity profiles could help tailor immunotherapy strategies for patients with BTC receiving ICIs (125). However, more research is needed to evaluate the general safety and efficacy of this strategy in immunotherapies.

Dual-ICI combination therapy

Given the limited efficacy of ICI monotherapy, combination immunotherapy is increasingly being studied in its ability to improve therapeutic response and elicit an immune response. Two ICIs combined in combination therapy have shown encouraging results in various solid cancers. In one phase II trial, 39 patients with advanced BTC were treated a combination of nivolumab and ipilimumab. The trial reported a 44% DCR and a 23% ORR, demonstrating the considerable benefit of dual combination ICI therapy over monotherapy (119). In an advanced-stage phase I trial, the combination of durvalumab and tremelimumab was examined in 65 patients with BTC (126), yielding an ORR of 10.8%, a median OS of 10.1 months, and a median PFS of 1.6 months. However, 23.1% of patients experienced TRAEs of grade 3 or above. Meanwhile, in a study of Japanese patients with hepatocellular carcinoma (HCC) and BTC, durvalumab-tremelimumab combination therapy provided the least encouraging response rates and survival results (127). Because these studies involved small sample sizes, care should be taken in interpreting these findings. Consequently, even while combination immunotherapies appear promising, especially those involving dual ICIs, further studies including larger and more varied patient groups are necessary to determine the actual efficacy and safety of these strategies in the management of BTCs.

Chemotherapy combined with ICIs

According to one trial (NCT03046862), which divided 124 patients with advanced-stage BTC into three treatment groups (GC → GC + durvalumab, GC + durvalumab, and GC + durvalumab + tremelimumab), the combination of GC with ICIs may provide therapeutic benefit (128). Oh et al. (129) examined the combination of immunotherapy and GC in treating BTC in a phase III TOPAZ 1 trial. They further investigated the use of PD-L1 inhibitors in combination with chemotherapy for the treatment of advanced CCA. In this trial, 685 participants were randomized to undergo durvalumab plus GC or placebo plus GC. The durvalumab-plus-GC group had a median OS of 12.8 months and a median PFS of 7.2 months, while in the GC-placebo group, the median OS and PFS were 11.5 and 5.7 months, respectively. Interestingly, although TRAEs were found in 64.9% patients in the control group (placebo + GC) and 62.7% patients in the treatment group (durvalumab + GC). The combination of chemotherapy and ICIs for advanced BTCs did not greatly improve survival, while other combinations—such as ICIs with targeted therapies or dual immunotherapy—have shown more promising outcomes. This suggests that exploring alternative combination strategies beyond chemotherapy may offer a more effective approach to improving treatment efficacy in advanced BTCs (129). Furthermore, numerous studies have evaluated the safety and therapeutic efficacy of GC in conjunction with nivolumab (118,130,131), capecitabine and oxaliplatin combined with pembrolizumab (CAPOX), and paclitaxel combined with tremelimumab and durvalumab for treating BTCs (132). These trials have yielded consistently positive outcomes, with the exception of one (NCT03704480). Taken together, these studies indicate that ICIs combined with chemotherapy may be a valuable approach for treating individuals with BTC, providing both a respectable safety profile and improved efficacy.

ICIs combined with targeted therapy

It has been shown that the combination of immunotherapy and molecular targeted therapy is highly effective. Immunotherapy’s ability to reverse immunosuppression can prolong the subsidence effect that targeted molecular therapy induces, increasing targeted therapy’s overall efficacy.

In one trial (NCT02443324), the efficacy of pembrolizumab in combination with ramucirumab (a VEGFR 2 monoclonal antibody) was evaluated in 26 patients with locally advanced, unresectable or metastatic BTC. Only 1 patient experienced a limited response, and the median OS was 6.4 months, a very poor outcome (133). Another trial (NCT03201458) compared atezolizumab monotherapy with the MEK inhibitor cobimetinib in patients with BTC who had not responded to first- or second-line therapy (134). Both therapy groups had very low ORRs; however, the combination group had a slightly improved median PFS. In a similar setting, a single-arm study investigated the safety and efficacy of pembrolizumab combined with lenvatinib in the management of patients with BTCs who had not responded to prior systemic therapy. In this trial, 25% of patients responded to treatment, the DCR was 78.1%, and clinical benefit rate was 40.5% (135,136). The clinical trials examining the immunotherapy regimens for BTC are summarized in Table 7.

ACT

The term ACT describes the intravenous administration of immune cells that have been altered in the tumor or peripheral blood to patients with cancer in order to mediate an anticancer effect (137). Autologous tumor-infiltrating lymphocyte (TIL) infusion, chimeric antigen receptor T-cell (CAR-T) therapy aimed against particular surface tumor antigens, and genetically modified T-cell receptor (TCR) T-cell therapy are examples of such treatments (138). In 2006, a case report proposed the therapeutic efficacy of ACT in BTCs. A patient with iCCA who had lymph node involvement had extensive resection and was treated with adjuvant CD3-activated T cells with tumor lysate- or peptide-pulsed dendritic cells (DCs). He lived for more than 3.5 years after therapy (139).

Chimeric antigen receptor T cells and genetically modified TCRs

CAR-T cells are T cells produced from patients that have been genetically modified with exogenous receptors that identify tumor-expressing antigens. Technologies such as viral vector-mediated gene therapy and CRISPR/Cas9-mediated genome editing enable the insertion of recombinant DNA that codes CAR and the elimination of TCR gene expression. The patient is then administered CAR-T cells to destroy cancerous cells. Genetically engineered TCR treatments modify T-cell specificity by expressing particular TCR α and β chains, which facilitate antigen recognition. Tumor-specific TCR α and β chains are identified, extracted, and cloned into transduction vectors. T cells are then transduced to produce tumor-antigen-specific lymphocytes (140).

A number of phase I and II clinical studies of CAR-T treatment for advanced BTCs have now been completed (112). In a phase I clinical study of CAR-T-cell therapy targeting HER2 in nine patients with advanced BT, one had a partial response (141). As of this writing, three patients are in good physical health, indicating that CAR-T therapy may be a viable strategy for increasing the longevity of patients with BTC and expressing HER2. Another clinical study evaluated CAR-T treatment for patients with advanced BTC and overexpression of epidermal growth factor receptor (EGFR). Ten patients experienced disease control, and one patient was in total remission (142). Several countries have conducted clinical trials on CAR-T and TCR therapy (Table 8).

TILs

In TIL therapy, specific effector T cells are extracted from tumor tissue via TILs, cultivated in vitro, and subsequently administered to patients. Research has indicated that TILs may benefit patients with distant organ metastasis or locally progressed BTC (112). In a clinical experiment, TILs significantly inhibited BTC in a patient with an ERBB2-interacting protein mutation (144). Additionally, in 2012, a clinical trial (UMIN000005820) involving 62 BTC cases reported that the PFS of 36 patients with iCCA treated with surgery, DC vaccination, and TILs was 18.3 months, which was significantly longer than the 7.7 months of PFS observed in the 26 patients treated with surgery alone (P<0.05) (145).

Cytokine-induced killer (CIK) cell therapy

For CIK cell therapy, peripheral blood lymphocytes from patients are cultured in vitro and subsequently reinfused into the body to produce antitumor effects. In a clinical trial, 2 out of 85 patients achieved complete response (CR), 14 had partial response, and 54 had good curative outcomes when CIK cell therapy and DC vaccination were administered to patients with BTC (146).

Radiotherapy

Radiotherapy may be recommended for certain patients with BTC. However, according to the ESMO guidelines, there is little clinical evidence to support its efficacy. Radiotherapy can be used to ameliorate a number of the signs and symptoms of stomach cancer via the shrinking of tumors that block the bile ducts, blood vessels, or nerves (2). A retrospective analysis of patients with inoperable iCCA who underwent final radiation therapy revealed that the long-term survival rates appear to be comparable to resection at a biologically effective dosage (BED) of >80.5 Gy (147). Manterola et al. (148) conducted a review of the literature on radiotherapy alone or in combination with chemoradiotherapy (CRT) and fluoropyrimidines in an adjuvant setting as a radiosensitizer for resected GBC. Although adjuvant CRT’s efficacy remains controversial, the SWOG080 trial examined gemcitabine combined with capecitabine (Gem-cape) plus concomitant computed tomography-guided chemoradiation, which produced an excellent 2-year OS rate of 65% (95% CI: 53–74%) for 79 patients, regardless of the condition of resection limits (149). Unfortunately, a consensus definitive conclusion could not be reached regarding the radiation mode, dosage, or appropriate administration time due to the lack of direct comparisons and the poor quality and scarcity of data. Given that CRT involves modest radiation doses, it can be speculated that it will benefit OS more than other adjuvant treatments that have less harmful consequences (149). In the ASCO guidelines (150), the role of CRT is not specified, but some research suggests that it should be restricted to patients with eCCAs who have undergone R1 resection or who have other high-risk factors (151).

Local treatment

Transarterial chemoembolization (TACE)

TACE involves the administration of chemotherapeutic drugs directly into the arteries that feed the tumor. TACE increases the concentration of chemotherapeutic agents in the tumor while decreasing the concentration in normal tissues. As a result, TACE can enhance therapeutic efficacy while minimizing systemic toxicity. In recent years, research on the efficacy of TACE in patients with unresectable BTC has produced encouraging findings (152,153). TACE is a popular, minimally invasive treatment for patients with HCC, particularly those with intermediate-stage illness and a strong liver functional reserve (154). Furthermore, TACE has been assessed as a downstaging therapy for lowering tumor burden in order to transform previously unresectable HCC to possibly resectable illness (155). TACE has two tumor-suppressive functions: embolizing the branches of arteries feeding HCC to cause ischemic tumor necrosis and releasing chemotherapeutic medicines in a regulated and sustained manner to eliminate residual cancer cells (156). TACE has recently emerged as an effective postoperative adjuvant therapy for patients with HCC. A prospective randomized controlled trial found that postoperative TACE substantially reduced tumor recurrence, resulting in a longer OS and disease-free survival (DFS) for patients with hepatitis B virus-related HCC with an intermediate or high risk of recurrence. Importantly, the therapy was shown to be both safe and well-tolerated (157). In the TACTICS trial (NCT01217034), a randomized, prospective trial comparing TACE plus sorafenib to TACE alone in patients with unresectable HCC, TACE plus sorafenib did not show a significant OS (36.2 months) benefit over TACE alone (30.8 months); however, there was clinically meaningful OS prolongation and significantly improved PFS (22.8 months). Thus, the TACE with sorafenib might be considered a therapeutic option in intermediate-stage HCC, especially in patients with substantial tumor burden (158). Another phase III, randomized controlled trial (NCT03905967) aimed to evaluate clinical results of lenvatinib coupled with TACE (LEN-TACE) compared to lenvatinib monotherapy in patients with advanced HCC. Of the 338 patients, 170 were randomly assigned to receive LEN-TACE and 168 to receive lenvatinib monotherapy. Following a median follow-up of 17.0 months, the LEN-TACE group had a substantially longer median OS compared to the lenvatinib-alone group (17.8 vs. 11.5 months; HR=0.45; P<0.001). The median PFS in the LEN-TACE group was 10.6 months compared to 6.4 months in the lenvatinib-alone group (HR =0.43; P<0.001), and the LEN-TACE group had a significantly higher ORR (54.1% vs. 25.0%; P<0.001). These findings suggest that the addition of TACE to lenvatinib enhances clinical outcomes and might be effective as a first-line therapy for individuals with advanced HCC (159).

Transarterial radioembolization (TARE)

TARE, also known as selective internal radiation treatment (SIRT), is used to treat primary tumors and liver metastases. The treatment is based on the fact that tumors have greater arterial vascularization than does nontumor liver tissue. When microspheres containing beta-emitting nuclides are administered via a microcatheter into the artery supplying the tumor-containing liver tissue, the tumor dosages are greater than those supplied to nontumor liver tissue (160,161). Furthermore, TARE can be used as a bridge therapy to slow hepatic tumor growth and guarantee that patients survive the waiting period for liver transplantation without acquiring contraindications to this procedure (162,163). Y90 is the most commonly applied radioactive element in radioembolization. The unstable Y90 radioisotope decays into the stable element zirconium-90 via logarithmic beta decay, with a half-life of 2.67 days (64.2 hours). In doing so, it produces a high-speed electron, a beta particle, which causes direct cytotoxic annihilation of the target tumor. The tissue penetration of Y90 varies from 2.5 to 11 mm, and a radiation dosage of up to 170 Gy may be delivered (164).

Hepatic artery infusion (HAI)

The combination of HAI and systemic chemotherapy has demonstrated clinical benefit in extending OS in patients with unresectable iCCA, and it has been used as a therapeutic option in a minority of patients. However, the lack of surgeons and oncologists with extensive expertise in using HAI chemotherapy limits its application (165). Poor hepatic function, extended systemic chemotherapy, substantial liver tumor burden, portal hypertension, portal vein thrombosis, and hepatic artery blockage are all absolute contraindications to HAI treatment (166). HAI chemotherapy was first designed to treat colorectal liver metastases (167,168). However, over the past two decades, additional data have been published regarding iCCA therapy (Table 9).

There is little information on the use of localized treatment in unresectable iCCA in the current guidelines due to a paucity of prospective studies. The rigorous examination of these techniques in clinical trials is critical, and future research should examine tailoring chemotherapy and regimens to selected targets in mutant iCCA.

Thermal ablation

With the development of advanced clinical technology, minimally invasive thermal ablation of tumors has become common practice. Percutaneous radiofrequency ablation, microwave ablation, cryoablation, and irreversible electroporation are being increasingly applied in the treatment of solid neoplasms, from the ablation of tiny, unresectable tumors to experimental treatments (174). Thermal ablation involves the breakdown of tissue via severe hyperthermia (high tissue temperatures) or hypothermia (low tissue temperatures). The temperature change is limited to a specific area in and around the tumor. Ablation procedures using both heat and cold can be administered, and there is no one best therapy for all clinical presentations. Thus far, radiofrequency ablation has been the predominant energy type used for hyperthermic ablation, but microwave ablation may eventually take its place. Laser ablation allows for accurate thermal monitoring via magnetic resonance imaging (MRI), whereas high-intensity focused ultrasound ablation allows for external energy delivery as well as MRI compatibility. Cryoablation is used to treat many of the same malignancies and is more evident on CT and ultrasound than is hyperthermic ablation, although it may not be appropriate for other cancers due to a lack of coagulation. Despite several years of clinical practice, the majority of ablation systems are in their first or second generation of development. Thermal tumor ablation is likely to become increasingly common as energy delivery technology improves (175).

Future steps and discussion

The treatment landscape for BTCs has undergone significant transformations, yet challenges remain in improving patient survival rates. BTCs are aggressive malignancies, often diagnosed at advanced stages, which severely limit the effectiveness of traditional therapies. Surgical resection offers the best opportunity for a cure; however, only a small subset of patients are eligible for this approach due to late-stage diagnoses. As a result, the focus has shifted toward systemic therapies aimed at prolonging survival and improving quality of life for patients with metastatic or unresectable BTCs.

Chemotherapy, particularly the combination of GC has long been the cornerstone of treatment. The establishment of GC as the first-line therapy has significantly improved survival outcomes. However, resistance to therapy and the inherent toxicity associated with chemotherapy remain considerable hurdles. Advancements in the molecular understanding of BTCs have led to the identification of key genetic mutations and alterations, such as IDH1 mutations, FGFR2 fusions, and HER2 overexpression, that drive tumor progression. These insights have paved the way for targeted therapies that offer more personalized treatment options.

In addition, immunotherapy has emerged as a groundbreaking approach in BTC treatment, offering new hope for patients whose options were previously limited. The incorporation of ICIs such as pembrolizumab and durvalumab in combination with chemotherapy has yielded promising results in clinical trials, prolonging PFS and offering more durable responses. Although these combination therapies hold immense promise, challenges remain in identifying the specific patient populations who will benefit the most and in managing irAEs.

The evolution of second-line therapies, such as FOLFOX and nal-IRI, has expanded treatment options for patients who have failed first-line therapies. These therapies, when used in combination with other agents, have shown significant efficacy in extending survival, but patient selection remains key to achieving optimal outcomes. The ongoing exploration of combination therapies, involving cytotoxic agents, targeted therapies, and immunotherapy, represents a promising direction for improving outcomes among patients with BTC. Moreover, while substantial progress has been made in treating advanced BTC, the complexity of its biology necessitates continued research into novel therapeutic agents and the development of biomarkers that can predict treatment responses and guide clinical decision-making.

One of the most promising areas in the treatment of BTCs is the reconsideration of dosing strategies, particularly in the combination of cytotoxic chemotherapy with targeted therapies and immunotherapies. Recent studies have reevaluated the dosing of chemotherapy and radiotherapy in combination therapies to optimize efficacy and reduce toxicity, resulting in noninferior or even improved outcomes in various cancers, including BTCs. For example, the combination of gemcitabine with nab-paclitaxel has shown promising results, facilitating the adjustment of dosing schedules to minimize toxicity while maintaining therapeutic efficacy. Similarly, lower doses of cytotoxic agents combined with ICIs have demonstrated improved survival outcomes without the severe side effects traditionally associated with chemotherapy. The TOPAZ-1 and KEYNOTE-966 trials investigating the addition of durvalumab and pembrolizumab to GC chemotherapy, respectively, showed that immune checkpoint inhibition combined with chemotherapy could offer a durable response.

Radiotherapy, traditionally used in the palliative setting, has also undergone advances in its integration with systemic therapies. Stereotactic body radiation therapy combined with chemotherapy or immunotherapy has shown promising results, particularly in select patients with BTC and oligometastatic disease. Future clinical trials should continue to investigate the optimal timing, dosing, and sequencing of radiotherapy to maximize its synergy with novel therapies.

Looking ahead, the future of BTC therapy lies in personalized treatment regimens, in which therapy is tailored based on the individual’s tumor profile, genetic mutations, and molecular markers. Clinical trials will continue to refine these treatment approaches, with a focus on optimizing the dosing and sequencing of chemotherapy, targeted agents, and immunotherapies. The identification and validation of biomarkers such as MSI-H, dMMR, and IDH1 mutations will enable more precise therapy and improve clinical outcomes.

The continued development of targeted agents, particularly those focused on genetic alterations such as IDH1 mutations, FGFR2 fusions, and HER2 overexpression, will further personalize BTC treatment. Precision medicine, guided by comprehensive genomic profiling, will allow clinicians to identify better which patients are most likely to respond to certain therapies. Additionally, the expansion of immune-based therapies, such as bispecific antibodies and novel immune modulators, will further enhance the antitumor activity of immunotherapy in BTCs.

In conclusion, while significant progress has been made in the treatment of BTCs, the future holds even more promise, with advancements in combination therapies, personalized medicine, and immunotherapy driving improved outcomes. The integration of optimized dosing strategies for chemotherapy and radiotherapy in combination with targeted therapies and immunotherapies will be key to improving survival rates and minimizing side effects. However, challenges remain, and ongoing clinical trials and translational research will be essential in shaping the next generation of treatments for this challenging and often deadly disease.

Conclusions

BTCs remain among the most aggressive and challenging malignancies, with historically limited treatment options and poor survival outcomes. However, the therapeutic landscape is rapidly evolving. Advances in molecular profiling have enabled the identification of actionable mutations, driving the development of targeted therapies that offer personalized, mutation-specific treatment strategies. Meanwhile, the integration of immunotherapy, particularly ICIs, with traditional chemotherapy regimens has yielded meaningful survival benefits in several landmark trials. As precision oncology gains momentum, the future of BTC management lies in biomarker-driven approaches, rational combination therapies, and individualized care models. Continued research into resistance mechanisms, novel molecular targets, and predictive biomarkers is essential to optimizing outcomes. A multidisciplinary, patient-centered approach will be critical in translating these scientific advances into real-world clinical success.

Acknowledgments

The authors sincerely thank the referenced studies and consortiums for contributing open-access datasets for this analysis.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-83/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-83/prf

Funding: This study was supported by the 1·3·5 Project for Disciplines of Excellence-Clinical Research Incubation Project, West China Hospital, Sichuan University (No. 2021HXFH001); the 1·3·5 Project for Artificial Intelligence West China Hospital, Sichuan University (No. ZYAI24030); the National Natural Science Foundation of China for Young Scientists Fund (No. 82203782); the Sichuan Natural Science Foundation (Nos. 2024NSFSC0742 and 2024NSFSC1949); the Lanzhou Science and Technology Development Guiding Plan Project (No. 2023-ZD-143); the Sichuan Science and Technology Program (Nos. 2024YFFK0384 and 2024YFFK0385); the Sichuan University-Sui Ning School-Local Cooperation Project (No. 2022CDSN-18); the Postdoctorate Research Fund of West China Hospital, Sichuan University (No. 2024HXBH134); and the Clinical Research of Sichuan Anticancer Association (Nos. XH2023-032 and XH2023-502).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-83/coif). The authors have no conflicts of interest to declare.

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(English Language Editor: J. Gray)