Adebrelimab combined with anlotinib plus hepatic arterial infusion chemotherapy or intravenous chemotherapy for first-line treatment of advanced biliary tract cancer: protocol for a randomized open-label clinical study

Introduction

Malignancies of the biliary tract, commonly referred to as biliary tract carcinoma (BTC), primarily include gallbladder cancers (GBCs), which predominantly arise from the gallbladder fundus, and cholangiocarcinoma (CC). CC can be further classified pathologically and anatomically into extrahepatic cholangiocarcinoma (ECC) and intrahepatic cholangiocarcinoma (ICC). Together, these biliary tract-related tumors account for approximately 3% of digestive system malignancies (1). BTC is most frequently diagnosed at an advanced stage, at which point resection is no longer an option and systemic therapies are favored. Although a growing range of regimens has become available in recent years, the 5-year survival rate for patients with BTC remains low. Chemotherapy remains the therapeutic basis for patients with unresectable advanced CC. In recent years, immunotherapy, small-molecule tyrosine kinase inhibitors (TKIs), and precision medicine have improved the treatment for this disease. However, these strategies still fail to meet clinical demands, and limitations persist.

For unresectable and metastatic BTC, palliative chemotherapy may provide survival benefit. A phase III randomized controlled trial (ABC-02), published in The New England Journal of Medicine in 2010, reported that the median overall survival (mOS) was extended from 8.1 months with single-agent gemcitabine to 11.7 months with gemcitabine plus cisplatin [GC; hazard ratio (HR): 0.64, 95% confidence interval (CI): 0.52–0.80; P<0.001] (2). Adverse event profiles were similar between groups; except for a greater incidence of neutropenia in the combination group. Infection rates due to neutropenia were comparable between arms. This study established a foundation for the efficacy of chemotherapy in CC.

Immune checkpoint inhibitors (ICIs) have been subjected to numerous clinical investigations in a variety of advanced solid tumors. In the context of first-line treatment for advanced biliary tract malignancies, anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) agents combined with chemotherapy have shown therapeutic efficacy. TOPAZ-1 was a double-blind, placebo-controlled, phase III clinical trial that randomized previously untreated patients with unresectable or metastatic biliary malignancies. Patients were randomized 1:1 to receive either durvalumab or placebo after administration of GC (up to eight cycles) as the core treatment (3). The durvalumab group achieved a 24% reduction in the mortality risk as compared to the placebo group, and the mOS of the durvalumab and chemotherapy-alone group were 12.9 and 11.3 months, respectively (4). In the phase III KEYNOTE-966 trial investigating pembrolizumab combined with chemotherapy as a first-line treatment for advanced BTC, a median follow-up duration of 25.6 months was achieved. The mOS improved significantly in the pembrolizumab plus GC group as compared to the placebo plus GC group, with the mOS being 12.7 and 10.9 months, respectively. Moreover, the mortality risk was reduced by 17% in the pembrolizumab plus GC group: at 24 months, 25% of patients treated with pembrolizumab plus GC remained alive, as compared to 18% in the control group (5).

Adebrelimab, developed independently by Jiangsu Hengrui, is a recombinant humanized immunoglobulin G subclass 4 (IgG4) antibody for PD-L1. At the 2023 European Society for Medical Oncology (ESMO) Congress, the results of a phase II trial of using adebrelimab in combination with IBI310, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody, for patients with advanced ICC who had failed first-line therapy was reported. A total of 39 patients with ICC were enrolled in this phase II study. All had received prior systemic chemotherapy, 21 patients had received PD-1 antibody immunotherapy, and 26 had received small-molecule targeted therapy. Among the 25 evaluable patients, complete response was observed in two cases and partial response in three cases. Among the 13 patients previously treated with a PD-1 antibody, two achieved objective responses.

ICIs combined with antiangiogenic targeted drugs (AATDs) demonstrate synergistic effects. This combination can normalize the function of immune effector cells and improve the tumor immune microenvironment (6). AATDs can promote antitumor immune responses of T cells by inhibiting dendritic cell maturation disorders and reducing the activity of myeloid-derived suppressor cells. These actions help convert the tumor microenvironment from an immunosuppressive to a permissive state. Anti-VEGF therapies can also normalize tumor vasculature and increase T-cell infiltration within the tumor (7). Anlotinib is a multitarget receptor tyrosine kinase (RTK) inhibitor and has been demonstrated to exert a strong antitumor effect in ICC (8). A phase II trial investigating a regimen consisting of camrelizumab and anlotinib in the second-line setting for advanced BTC reported an objective response rate (ORR) of 30% and a disease control rate (DCR) of 95%. Th mOS was 12.3 months (95% CI: 10.1–14.5), with only 20% of patients experiencing grade 3 treatment-related adverse events (TRAEs), with no grade 4 or 5 TRAEs being observed (9).

Genetic mutations frequently occur in BTC. The variation in mutation rates across studies and anatomic sites is substantial, and the KRAS mutation rate in ICC may reach as high as 54%. A study conducted in China and published in Nature Genetics in 2014, used whole-exome and targeted gene sequencing to identify mutation rates in patients with gallbladder carcinoma. The rates observed for RAS (including KRAS, NRAS, and HRAS), BRAF, and PI3KCA mutations were 11.8%, 5.9%, and 5.9%, respectively (10). Targeted agents for the FGFR2 and IDH1 mutations are already available for the management of CC. However, the incidence of these two genetic mutations remains low.

Although advances have been made in immunotherapy, small-molecule TKI-targeted treatments, and precision medicine for CC in recent years, they do not satisfy clinical needs, and further development is needed. We thus devised a randomized open-label, multicenter phase II clinical trial to evaluate a therapeutic strategy that is potentially superior to conventional chemotherapy. This study aims to explore a combination of novel targeted and immunotherapy drugs, as well as new delivery methods, to explore a treatment plan that is superior to existing traditional therapies. This study also aims to demonstrate the efficacy and safety of adebrelimab combined with anlotinib and the GEMOX regimen in patients with advanced CC. We present this article in accordance with the SPIRIT reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-721/rc).

Methods

Study design

This study is organized as a randomized open-label, multicenter phase II clinical trial, with an enrollment goal of 60 participants. The participating research centers include The First Affiliated Hospital of Guangxi Medical University, The Affiliated Tumor Hospital of Guangxi Medical University, The Second People’s Hospital of Nanning, and The First Affiliated Hospital of Guangxi University of Chinese Medicine. Participants will be allocated to one of two cohorts. For cohort 1, it will be assumed that the 6-month progression-free survival rate (6-m PFS%) for patients with advanced BTC in China treated with GEMOX as first-line therapy is 40%. An increase in the 6-m PFS% to 65% is anticipated. The statistical test will one-sided, with the significance level (alpha) set to 0.05 and the study power (1−β) to 80%. At least 24 evaluable participants per cohort are required for analysis. To compensate for an estimated dropout rate as high as 20% during follow-up, 30 participants will be required for enrollment in each cohort. As with cohort 1, cohort 2 is expected to include 30 participants; therefore, the planned sample size for both cohorts is 60. The randomization system will assign individuals to cohort 1 or cohort 2 at a 1:1 ratio. Treatment cycles will span 21 days (3 weeks). Adebrelimab will be administered intravenously (1,200 mg or 20 mg/kg on day 1), and anlotinib will be administered orally at 12 mg once daily for 2 consecutive weeks, followed by 1 week off. The gemcitabine-oxaliplatin (GEMOX) chemotherapy regimen in cohort 1 will consist of one cycle of hepatic arterial infusion chemotherapy followed by one cycle of intravenous chemotherapy; meanwhile, in cohort 2, it will consist of two cycles of intravenous chemotherapy (total cycles ≤3), continuing until either six cycles are completed or an unacceptable adverse reaction arises. For any participants unable to complete six cycles due to toxicity, combination chemotherapy will be discontinued. After combination chemotherapy cessation, patients with complete response, partial response, or stable disease will continue to receive adebrelimab in combination with anlotinib. A schematic for the trial procedure is provided in Figure 1. Enrollment for this study commenced in June 2024 in China. Participant enrollment is projected to completed by December 2025. Sixteen months after the first dosing of the final participant, the research team will finalize data cleaning. During statistical analysis, two-sided P value <0.05 was set as the threshold for statistical significance for all primary analyses. With missing data, we will use multiple imputation. The study summary is scheduled to be completed by April 2027. The trial protocol has been registered with the Chinese Clinical Trial Registry (https://www.chictr.org.cn; unique identifier: ChiCTR2500102333).

Figure 1 Schematic for the trial procedure. Patients may continue to receive study medication if the investigator determines ongoing clinical benefit. ^†, efficacy assessed according to RECIST v. 1.1. BTC, biliary tract carcinoma; CT, computed tomography; DCR, disease control rate; ECOG PS, Eastern Cooperative Oncology Group performance status; GEMOX, gemcitabine-oxaliplatin; IV, intravenous; MRI, magnetic resonance imaging; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PO, peros; RECIST, Response Evaluation Criteria in Solid Tumors.

Objectives

This study primarily aims to determine whether adebrelimab combined with anlotinib plus hepatic arterial infusion chemotherapy is superior to traditional chemotherapy in the treatment of advanced CC and whether arterial infusion chemotherapy is superior to intravenous chemotherapy when using the same therapeutic drugs. Specifically, we will compare arterial infusion and alternating intravenous administration with conventional intravenos GEMOX under the same combination of adebrelimab and anlotinib and to determine whether the former outperforms the latter in terms efficacy and safety.

Endpoints

The primary endpoint will be the 6-m PFS%, as evaluated by investigators using the Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1 for solid tumors. Secondary endpoints, according to RECIST v. 1.1, will include progression-free survival (PFS), time to progression (TTP), ORR, DCR, duration of response (DoR), and overall survival (OS). The incidence and severity of adverse events (AEs) and serious adverse events (SAEs) will be determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v. 5.0. Exploratory endpoints will include the relationship of tumor PD-L1 expression levels and a strong PD-L1 positivity ratio with efficacy outcomes, such as, but not limited to, ORR and OS, of adebrelimab plus anlotinib combined with hepatic arterial infusion or intravenous chemotherapy. Moreover, the study will assess metrics for efficacy and safety, including but not limited to ORR and OS, of the chemotherapy drug delivery mode for the combination of adebrelimab and anlotinib in the first-line treatment of patients with advanced biliary malignancies.

Study procedure

Patient selection and screening

The inclusion criteria for patients in this study are as follows: age over 18 years, a diagnosis of advanced BTC, no previous systemic therapy, at least one measurable lesion evaluable by computed tomography or magnetic resonance imaging, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and essentially normal organ function. The detailed inclusion and exclusion criteria are provided in Table 1. Eligible patients will be randomly assigned to either cohorts 1 or 2.

Treatment

A total of 60 participants are planned for enrollment. The randomization system will assign participants to cohort 1 or cohort 2 at a 1:1 ratio. Treatment cycle will span 21 days (3 weeks). Adebrelimab will be administered intravenously (1,200 mg or 20 mg/kg on day 1), and anlotinib will be administered orally at 12 mg once daily for 2 consecutive weeks, followed by 1 week off. In cohort 1, the GEMOX chemotherapy will comprise one cycle of hepatic arterial infusion chemotherapy followed by one cycle of intravenous chemotherapy, and in cohort 2, it will comprise 2 cycles of intravenous chemotherapy (total cycles ≤3), continuing until either six cycles are completed or an unacceptable adverse reaction arises. For any participant unable to complete six cycles due to toxicity, combination chemotherapy will be discontinued. After discontinuation of combination chemotherapy, patients with complete response, partial response, or stable disease will continue to receive adebrelimab in combination with anlotinib.

Data collection

For clinical trial data management, the principal investigators and study team will complete the collection and management of research data. Completion of the case report form (CRF) will be carried out by investigators or data entry personnel. An overview of the results collection procedure is provided in Table 2.

Statistical analysis

Sample size calculation

Participants will be allocated to one of two cohorts. For cohort 1, it will be assumed that the 6-m PFS% for patients with advanced BTC in China treated with GEMOX as first-line therapy is 40%. An increase in the 6-m PFS% to 65% is anticipated. The statistical test will one-sided, with the significance level (alpha) set to 0.05 and the study power (1−β) to 80%. At least 24 evaluable participants per cohort are required for analysis. To compensate for an estimated dropout rate as high as 20% during follow-up, 30 participants will be required for enrollment in each cohort. As with cohort 1, cohort 2 is expected to include 30 participants; therefore, the planned sample size for both cohorts is 60.

Data analysis

Efficacy analysis will involve the full analysis set (FAS), which will include all enrolled participants who have received at least one dose of Adebrelimab combined with anlotinib plus GEMOX. Safety analyses will be based on the safety set, which will include all enrolled participants who have received at least one dose of study medication and completed at least one post-dose safety assessment. Primary endpoint efficacy analysis will be based on the evaluable set, which will include all enrolled participants who have received at least one dose of study medication, have a tumor baseline assessment, and have at least one postbaseline tumor efficacy assessment. . Continuous variables will be summarized as the mean and standard deviation, median, minimum, and maximum. Categorical variables will be summarized as the frequency and percentage. Time-to-event data (such as PFS and OS) will be analyzed via Kaplan-Meier estimation for survival rates and medians, and survival curves will be drawn. The proportion of assessable patients surviving at 6 months from trial initiation will be assessed according to RECIST v1.1. ORR calculation will be based on the FAS. The number of participants achieving an objective response and the ORR, with the corresponding Clopper-Pearson 95% CIs, will be reported. A summary of the best overall response will be provided. The calculation of the DCR will be the same as that for the ORR.

Data management

The detailed data obtained from each patient will be recorded in the CRF. All research records and source documents will be maintained and stored in accordance with applicable regulations, guidelines, or requirements of the research institution. Researchers seeking access to clinical trial source data will be required to review the CRFs. This process will determine the informational completeness, accuracy, and concordance with source documentation. A qualified and trained central monitoring team will be tasked with conducting regular visits to each participating site throughout the trial. These inspections will ensure data submission, participant eligibility, and compliance with protocol.

Ethics and dissemination

Ethical approval for this study was granted by the Medical Ethics Committee of The First Affiliated Hospital of Guangxi Medical University on June 26, 2024 (approval No. 2024-K229-1). All participating hospitals are informed and agree with this study. The study will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Informed consent will be obtained before each participant is enrolled, and participants will be free to withdraw at any time. Participants who sustain injuries as a result of trial involvement will receive compensation via insurance coverage. Since study enrollment and follow-up remain ongoing, findings will be released after the last enrolled participant completes the primary endpoint assessment. Results of trial analyses are to be disseminated at scientific and professional meetings, and the findings are expected to be published in a peer-reviewed journal.

Discussion

The objective of this study is to evaluate a strategy potentially superior to conventional chemotherapy that may have broader applicability in patients with advanced CC in China. A comparative analysis has been devised, with identical drug to compare hepatic arterial infusion with alternating intravenous administration to standard intravenous GEMOX. The data derived from this study will allow for a preliminary comparison of efficacy and safety and aid in determining whether arterial and intravenous alternation provides benefit over conventional intravenous therapy.

CC is a high-grade malignant disease. The ABC-02 study established gemcitabine-based combination chemotherapy as the standard treatment for this disease, with GC yielding a median PFS of 8 months and a median OS of 11.7 months (2). Fiteni et al. conducted a retrospective analysis comparing GC and GEMOX in 1,470 patients across 33 studies. In the cisplatin cohort, the mOS was 9.7 months and the PFS was 6.3 months; in the oxaliplatin cohort, the mOS reached 9.5 months and the median PFS 4.9 months. Cisplatin was associated with a modest survival extension but a notably higher frequency of grade 3–4 toxicity (11). A separate phase III trial published in the Journal of Clinical Oncology in 2010 demonstrated that GEMOX provide in a significant survival advantage over best supportive care (HR =0.44, 95% CI: 0.22–0.86; P=0.01) (12). In clinical practice in China, oxaliplatin is more frequently used for BTC than is cisplatin, and its safety outcomes are generally more favorable. These studies have established the standard front-line chemotherapy regimen for advanced BTC. Both GC and GEMOX remain the foundation of CC therapy. Our study protocol features a GEMOX regimen as it is associated with a relatively lower incidence of adverse events. Yet, chemotherapy alone continues to yield unsatisfactory outcomes. Therefore, combination regimens with a chemotherapy backbone have remained a principal focus of exploration.

With the advent of immunotherapy, ICIs have come to represent a new paradigm for cancer treatment. They function by activating a patient’s own T lymphocytes to restore or enhance antitumor immune responses. ICIs have already seen widespread clinical adoption owing to their ability to mediate tumor cell killing (13-17). Research on CC has also involved extensive investigations into immunotherapy combined with chemotherapy. For instance, the TOPAZ-1 trial—a double-blind, placebo-controlled, phase III study—randomized participants to receive either durvalumab or placebo, with both arms receiving GC in combination (3); the median follow-up durations reached 23.4 and 22.4 months, respectively. The updated survival data indicated a 24% reduction in mortality risk with durvalumab as compared to placebo; additionally, the mOS increased to 12.9 months in the durvalumab arm, in contrast to 11.3 months in chemotherapy-alone arm (4). Within 2 years, the number of surviving patients in the combination group was than double that of the chemotherapy-alone group (23.6% vs. 11.5%). Combination chemotherapy with durvalumab continues to be well tolerated. Moreover, 60.9% of patients in the durvalumab group and 63.5% in the chemotherapy-alone group experienced grade 3 or 4 TRAEs. The rate of treatment discontinuation due to TRAEs did not increase with durvalumab combination (8.9%) in comparison to that of chemotherapy alone (11.4%). Another representative trial, KEYNOTE-966, followed up patients for a median of 25.6 months. Pembrolizumab plus GC as first-line therapy for advanced BTC achieved an mOS of 12.7 (11.5–13.6) months, while that of placebo plus GC was 10.9 (9.9–11.6) months. The incidence rate of grade 3–4 AEs was 79% in the treatment group and 75% in the control group (5). These two studies firmly validate the survival benefit that immunotherapy offers to patients diagnosed with CC. However, the OS yielded by combined immunotherapy was less than 2 months, which is unsatisfactory. Moreover, it appears that durvalumab (targeting PD-L1) demonstrates a potential safety advantage over pembrolizumab (targeting PD-1) given the rates of grade 3 or 4 AEs. Adebrelimab, a recombinant humanized IgG4 anti-PD-L1 antibody developed by Jiangsu Hengrui, was therefore selected as the immunotherapeutic partner in our study.

Targeted therapies, particularly those for driver mutations, are also actively under investigation. Infigratinib and pemigatinib tablets for tumors harboring FGFR2 alterations have reached phase II in clinical studies (18,19). Infigratinib was administered in a cohort of 71 CC patients with FGFR2 fusions or translocations. The results indicated an ORR of 26.9% (95% CI: 16.8–39.1%; n=67) and a DCR of 83.6% in the patient cohort. In patients who had received one or more prior lines of therapy, the ORR reached 39.3% (n=28). Among those treated with two or more regimens, the mOS was 12.5 months, and the median PFS was 6.8 months, representing an ORR of 17.9% (18). A clinical trial of pemigatinib enrolled 107 patients, all previously treated and harboring FGFR2 gene fusion or rearrangement. Participants received oral pemigatinib at 13.5 mg once daily in 21-day cycles, and therapy continued until radiological disease progression or unacceptable toxicity occurred. The trial outcomes included (20) an ORR of 36% for pemigatinib, a complete response rate of 2.8%, a partial response rate of 33%, a median PFS of 9.2 months, and an mOS of 15.8 months. The ClarIDHy trial included 185 patients who were randomized to an ivosidenib arm (n=124) or a placebo arm (n=61), with a median follow-up period of 6.9 months. The median PFS was 2.7 months in the treatment group and 1.4 months in the placebo group (21). Based on these findings, the US Food and Drug Administration approved these agents for the treatment of advanced ICC harboring the FGFR2 mutation. However, the frequency of FGFR2 mutations in ICC is only about 15% (20), and IDH1 mutations are present in approximately 13% of these patients in China. Consequently, these precision therapies provide benefit for only a minority of patients. Our study was designed to assess a treatment strategy more broadly suitable for the CC population and therefore excluded agents with highly selective molecular targets.

Antiangiogenic drugs, such as lenvatinib, apatinib, and anlotinib, have also been investigated in the setting of BTC. A phase II study of lenvatinib combined with a PD-1 inhibitor (pembrolizumab/toripalimab/sintilimab/camrelizumab at 200 mg or toripalimab at 240 mg) as first-line therapy for BTC yielded an ORR of 42.1%, a DCR of 76.3%, and a 6-month OS rate of 87.1% (22). Apatinib combined with camrelizumab was evaluated as second-line therapy in CC in a trial with a median follow-up of 13.4 months. The ORR was 19%, the DCR was 71.4%, and the median treatment duration was 4.9 months. In the intention-to-treat population, the median OS was 13.1 months and the median PFS was 4.4 months (23). At the 2021 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, a portion of the results from a phase II trial on sintilimab plus anlotinib as second-line therapy for advanced BTC were released: the ORR was 31.58%, and the DCR was 82.35% (9). From these small-sample studies, it can be observed that combining antiangiogenic targeted therapy with immunotherapy demonstrates efficacy in the treatment of BTC. Given the higher DCR rate and better clinical safety profile, anlotinib was selected as the targeted therapy partner in our study.

Arterial infusion chemotherapy has achieved notable results in hepatocellular carcinoma. It has now become widely adopted, exhibiting a favorable safety profile. In CC, related studies have been conducted. Zhang et al. evaluated the efficacy and safety of lenvatinib combined with a PD-1 inhibitor plus GEMOX chemotherapy (the P-L-G group) with those of hepatic arterial infusion chemotherapy (the P-L-H group) in patients with advanced BTC. The median OS in the P-L-G group reached 23.8 months, whereas it was 11.6 months in the P-L-H group. The median PFS was 13.7 months in the P-L-G group and 6.0 months in the P-L-H group. Both the mOS and PFS were significantly prolonged in the P-L-G group as compared to the P-L-H group (24). Arterial infusion chemotherapy did not demonstrate benefit for these patients. Notably, at the 2024 ESMO Asia Congress, a study enrolling 41 patients with unresectable CC was presented. In this study, lenvatinib plus adebrelimab, combined with hepatic arterial infusion chemotherapy, yielded an ORR of 46.3% and a DCR of 78.0%. The median PFS was 6.1 months, and the mOS was 12.0 months. Grade 3 or 4 serious AEs were observed in 38.5% of the participants, with nausea, fever, and abdominal pain being the most common AEs. Findings from this study appear to contradict earlier results, and it remains uncertain whether differences in outcomes are due to the use of PD-1 versus PD-L1 inhibitors or to other factors. Determining the exact effect of arterial infusion chemotherapy in CC requires further investigation.

Taking all preceding experience into account, we added the PD-L1 inhibitor adebrelimab, which offers a superior safety profile, and anlotinib, which yields a high DCR, to a GEMOX-based chemotherapy backbone. Head-to-head comparisons between arterial and intravenous chemotherapy under identical dosing regimens will be conducted to identify differences in efficacy and safety for patients with CC.

This study may involve several limitations. As a phase II trial with a small sample size, prompt initiation of a large-scale, high-quality randomized controlled trial is indicated. Moreover, generalization of the results should be approached with caution. It is important to note that the participants in this study were exclusively recruited from China. While this homogeneous cohort strengthens the internal validity of our findings, it may limit the generalizability of the results to non-East Asian populations. Differences in genetic background, lifestyle, and healthcare systems could potentially influence the outcomes.

Acknowledgments

We thank Dr. Yutaka Midorikawa (Department of Surgery, Mombetsu General Hospital, Hokkaido, Japan) for the critical comments and valuable advice on this study.

Footnote

Reporting Checklist: The authors have completed the SPIRIT reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-721/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-721/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-721/coif). X.F. is from Jiangsu Hengrui Pharmaceuticals Co., Ltd. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Ethical approval for this study was granted by the Medical Ethics Committee of The First Affiliated Hospital of Guangxi Medical University on June 26, 2024 (approval No. 2024-K229-1). All participating hospitals are informed and agree with this study. The study will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Informed consent will be obtained before each participant is enrolled, and participants will be free to withdraw at any time.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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