The prevalence of intrahepatic cholangiocarcinoma (ICC) is increasing globally. Despite advancements in comprehending this intricate malignancy and formulating novel therapeutic approaches over the past few decades, the prognosis for ICC remains poor. Owing to the high degree of malignancy and insidious onset of ICC, numerous cases are detected at intermediate or advanced stages of the disease, hence eliminating the chance for surgical intervention. Moreover, because of the highly invasive characteristics of ICC, recurrence and metastasis postresection are prevalent, leading to a 5-year survival rate of only 20%-35% following surgery. In the past decade, different methods of treatment have been investigated, including transarterial chemoembolization, transarterial radioembolization, radiotherapy, systemic therapy, and combination therapies. For certain patients with advanced ICC, conversion treatment may be utilized to facilitate surgical resection and manage disease progression. This review summarizes the definition of downstaging conversion treatment and presents the clinical experience and evidence concerning conversion treatment for advanced ICC.

Biliary tract cancer (BTC) remains among the most challenging malignancies with a poor prognosis and limited treatment options, particularly in pretreated patients. As most patients experience disease progression after first-line treatment, effective second-line and subsequent treatments are required. Although the addition of modified FOLFOX (fluorouracil, leucovorin, and oxaliplatin) to active symptom control improved the overall survival of patients with progressing advanced BTC despite gemcitabine plus cisplatin treatment, its efficacy was modest. Moreover, most clinical trials demonstrated modest efficacy of molecular-targeted agents for molecularly unselected pretreated advanced BTC. Patients with advanced BTC carry a relatively high druggable genetic alteration rate and have shown promising responses to molecular-matched therapies targeting gene alterations such as FGFR2 fusions/rearrangements, IDH1 mutation, and HER2 overexpression/amplification. Additionally, tumor-agnostic approaches, including BRAF V600E, NTRK fusion, and RET fusion, have expanded the treatment options for some patients. Immune checkpoint inhibitors have shown limited efficacy as mono- or combination therapy in patients with pretreated advanced BTC. Therefore, developmental efforts have shifted to immune checkpoint inhibitor and other combinations such as vascular endothelial growth factor receptor inhibitors or radiation. In addition to refining combination strategies to enhance the therapeutic potential of immune checkpoint inhibitor, future research should focus on elucidating the tumor microenvironment. This review delineates the evolution of systemic therapies in patients with pretreated advanced BTC. By examining past developments and recent advances through prospective trials, it highlights novel approaches that may improve outcomes in this challenging disease.

The purpose of this review is to summarize the current knowledge of cholangiocarcinoma molecular biology and to suggest a framework for implementation of next-generation sequencing in all stages of liver transplantation. This is timely as recent guidelines recommend increased use of these technologies with promising results.

The main themes covered here address germline and somatic genetic alterations recently discovered in cholangiocarcinoma, particularly those associated with prognosis and treatment responses, and nascent efforts to translate these into contemporary practice in the peri-liver transplantation period.

Early efforts to translate molecular profiling to cholangiocarcinoma care demonstrate a growing number of potentially actionable alterations. Still lacking is a consensus on what biomarkers and technologies to adopt, at what scale and cost, and how to integrate them most effectively into care with the ambition of increasing the number of patients eligible for liver transplantation and improving their long-term outcomes.

Biliary tract cancer (BTC) is a highly heterogeneous aggressive tumor, and advanced patients have poor prognosis. This work aimed to evaluate the efficacy and safety of camrelizumab combined with chemotherapy in treating advanced BTC, and to explore predictive biomarkers for distinguishing effective population.

183 advanced BTC patients admitted from September 2018 to September 2021 were retrospectively selected. 93 patients were treated with camrelizumab combined with chemotherapy (C+C group) and 90 patients were treated with chemotherapy alone (C group). Objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), and median overall survival (mOS) were analyzed between two groups. Peripheral blood lymphocyte subsets were assessed by flow cytometry pre- and post-treatment.

The mPFS (6.9 months) and mOS (12.1 months) in the C+C group were significantly longer than those in the C group, which were 5.2 months and 9.8 months respectively (HR 0.46, 95% CI 0.38-0.54, p=0.017; HR 0.39, 95% CI 0.32-0.47, p=0.033). The percentage of Total T, CD4+T, natural killer (NK) cells, lymphocyte, and CD4+/CD8+ cell ratios were significantly increased in effective patients after C+C treatment, but didn't increase in progressive disease (PD) patients. Higher percentage of Total T, CD4+T, and higher CD4+/CD8+ cell ratios post-treatment were associated with longer OS.

Camrelizumab combining chemotherapy significantly prolonged the mPFS and mOS of advanced BTC patients. Immunotherapy may improve the immune status of advanced patients, and immunotherapy efficacy might be predicted based on the peripheral blood lymphocyte subsets.

Immune checkpoint inhibitors (ICIs) combined with gemcitabine and cisplatin chemotherapy have become the standard first-line treatment for advanced biliary tract cancer (BTC). However, real-world evidence on domestic ICIs widely used in China and the therapeutic outcomes across treatment lines remains limited. This study aimed to assess the real-world effectiveness and safety profiles of ICIs in advanced BTC patients, while concurrently elucidating potential efficacy variations among distinct ICI subtypes.

We analyzed patients with unresectable, locally advanced, or metastatic BTC treated with ICIs at West China Hospital (January 2019-October 2023). Primary endpoint was overall survival (OS), while secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Kaplan-Meier survival curves, propensity score matching (PSM), and Cox proportional hazards regression analyzed treatment efficacy.

A total of 221 advanced BTC patients were enrolled. Among them, 137 patients received ICIs treatment in the first line, while 84 patients in the second or later lines. For patients treated with ICIs as first-line therapy, the median OS was 15.7 months (95% CI: 13.1-19.8) and PFS was 8.4 months (95% CI: 7.6-10.3). In contrast, patients treated in second or later lines had shorter median OS of 9.8 months (95% CI: 8.1-12.3) and median PFS of 5.6 months (95% CI: 4.2-6.8). The reduced efficacy in later-line treatments may reflect prior therapeutic resistance and generally poorer patient conditions compared to first-line recipients. 211 (95.5%) patients experienced at least one adverse event (AE), and 93 (42.1%) of them experienced grade 3 or higher AEs. The incidence of immune-related adverse events (irAEs) was 35.8%, with 8.6% of patients experiencing grade 3-4 irAEs. The most common ICI treatments are with Durvalumab or Sintilimab, which we are interested in comparing. Durvalumab showed numerically superior OS vs Sintilimab (19.3 vs 10.2 months, p<0.001) in unmatched analysis, though significance attenuated after PSM (16.1 vs 13.1 months, p=0.299).

ICIs demonstrate robust efficacy and manageable toxicity in real-world settings, supporting their use in both first- and later-line treatments for advanced BTC. However, whether domestic ICI alternatives remain viable options warranting further validation.

The Eastern Canadian Gastrointestinal Cancer Consensus Conference was an annual meeting that was held in St. John's, Newfoundland and Labrador, from 26 to 28 September 2024. This included experts in medical oncology, radiation oncology, surgical oncology, nuclear medicine, and general practitioners in oncology (GPO) from across the eastern Canadian provinces who are involved in the management of patients with gastrointestinal malignancies. This consensus statement generated by the conference addresses multiple topics, including the management of localized rectal cancer, liver-limited colorectal cancer, systemic therapy for advanced biliary tract cancers, radioligand therapy for gastroenteropancreatic neuroendocrine tumors (GEP-NETs), systemic therapy for pancreatic and midgut well-differentiated NETs, and systemic therapy for HER2-positive gastroesophageal cancers.

A clinical trial of nab-paclitaxel plus capecitabine as a first-line treatment for advanced biliary tract cancers was conducted. We analyzed the development of systemic therapy recommended by the National Comprehensive Cancer Network guidelines and the development of nab-paclitaxel combination chemotherapy for advanced biliary tract cancers (BTCs) and concluded that nab-paclitaxel plus capecitabine is a promising first-line regimen for advanced BTCs.

Due to the limited efficacy of chemotherapy alone in the treatment of unresectable biliary tract cancer, we performed conversion surgery in patients with unresectable biliary tract cancer who responded to down-staging chemotherapy.

Patients with unresectable biliary tract cancer who initiated chemotherapy between 2007 and 2018 were included in this study. We evaluated the short- and long-term outcomes of patients with initially unresectable biliary tract cancer who underwent conversion surgery.

A total of 101 patients with unresectable biliary tract cancers treated with chemotherapy were eligible for the present study. A total of 20 patients eventually underwent conversion surgery; these patients had locally advanced disease in 6 cases, liver metastasis in 6 cases, para-aortic lymph node metastasis in 5 cases, and peritoneal dissemination in 3 cases. The mean operative time was 823 min, and the mean intraoperative blood loss was 1902 mL. Histological R0 resections were performed in 17 patients. Postoperative complications of Clavien-Dindo grade IIIa or higher occurred in 10 patients, with no surgery-associated deaths. The 5-year survival rate was significantly higher in patients who underwent conversion surgery (65.0%) than in those who did not (4.3%, p < 0.001).

Conversion surgery for initially unresectable biliary tract cancer resulted in favorable overall survival and was safely performed despite its high surgical invasiveness. Conversion surgery for an initially unresectable biliary tract cancer is worth considering.

The Tumor Microenvironment (TME) in classical Hodgkin Lymphoma (HL) contains abundant immune cells and only few neoplastic Hodgkin and Reed-Sternberg cells (HRSC). We analyzed the T-cell receptor (TCR) repertoire to detect T-cell expansion in the TME and blood. In contrast to solid cancer tissue, T-cells in the TME of HL are highly polyclonal at first diagnosis and show only minor clonal expansion during anti-PD1 immune checkpoint blockade (ICB). At relapse and during ICB, pre-amplified T-cell populations increase in the TME of solid cancers but to a much lesser extent in HL. In contrast, T-cell populations in the peripheral blood of HL patients display higher clonality than healthy controls reaching clonality levels comparable to solid cancer. However, pre-amplified blood T-cells in HL patients show only minor additional clonal expansion during ICB. Moreover, blood-derived T-cells do not repopulate the TME of HL to the same extent as observed in solid cancers. Thus, the T-cell repertoire in the TME of HL appears unique by a relatively low clonal T-cell content and the exclusion of clonally expanded T-cells from the peripheral blood. Exclusion of clonally expanded tumor-specific T-cells from the TME may present a novel mechanism of immune evasion in HL.

In recent years, treatment options for patients with advanced biliary tract cancer (BTC) have increased significantly due to the positive results from phase 2/3 clinical trials of immune checkpoint inhibitors, combined with chemotherapy, and molecularly targeted agents. These advances have led to the need for molecular testing to identify actionable alterations and patients amenable to targeted therapies. However, these improvements have brought with them many questions and challenges, including the identification of resistance mechanisms and therapeutic sequences. In this Series paper we aim to provide an overview of the current systemic treatment options for patients with BTC, highlighting disparities in access to innovative treatments and molecular testing across European countries, which lead to inequalities in the possibilities of treating patients with advanced BTC. We also discuss how ongoing European collaborative projects, such as the COST Action Precision-BTC-Network CA22125, supported by COST (European Cooperation in Science and Technology), linked to the European Network for the Study of Cholangiocarcinoma (ENSCCA), can help overcome these disparities and improve the current scenario.

The administration of second-line or subsequent immune checkpoint inhibitors (ICIs) in previously treated patients with advanced solid cancers has been clinically investigated. However, previous clinical trials lacked an appropriate primary endpoint for efficacy assessment. This systematic review aimed to explore the most optimal early efficacy endpoint for such trials.

Phase 2 or 3 clinical trials involving patients with advanced solid cancers with disease progression following standard first-line therapy receiving second-line or subsequent ICI administration, with adequate survival outcome data, were included from PubMed, Embase, Web of Science, and Cochrane Library databases before February 2023. Quality assessment was conducted using the Cochrane tool and Newcastle-Ottawa Quality Assessment Scale for Cohort Studies for randomized controlled trials (RCTs) and non-randomized trials, respectively. Objective response rate (ORR) and progression-free survival (PFS) at 3, 6, and 9 months were investigated as potential early efficacy endpoint candidates for 12-month overall survival (OS), with a strong correlation defined as Pearson's correlation coefficient r ≥ 0.8.

A total of 64 RCTs comprising 22,725 patients and 106 non-randomized prospective trials involving 10,608 participants were eligible for modeling and external validation, respectively. RCTs examined 15 different cancer types, predominantly non-small-cell lung cancer (NSCLC) (17, 28%), melanoma (9, 14%), and esophageal squamous cell carcinoma (5, 8%). The median sample size of RCTs was 124 patients, and the median follow-up time was 3.2-57.7 months. The ORR (r = 0.38; 95% confidence interval [CI], 0.18-0.54) and PFS (r = 0.42; 95% CI, 0.14-0.64) exhibited weak trial-level correlations with OS. Within ICI treatment arms, the r values of ORR and 3-, 6-, and 9-month PFS with 12-month OS were 0.61 (95% CI, 0.37-0.79), 0.78 (95% CI, 0.62-0.88), 0.84 (95% CI, 0.77-0.90), and 0.86 (95% CI, 0.79-0.90), respectively. External validation of 6-month PFS indicated an acceptable discrepancy between actual and predicted 12-month OS.

In non-randomized phase 2 trials on second-line or subsequent ICI therapy in patients with advanced solid cancers, 6-month PFS could serve as an early efficacy endpoint. However, early efficacy endpoints are not recommended in RCTs to replace OS.

Biliary tract cancer (BTC), encompassing diseases such as intrahepatic (ICC), extrahepatic cholangiocarcinoma (ECC), and gallbladder cancer, is not only increasing but also poses a significant and urgent health threat due to its high malignancy. Genomic differences point to the possibility that these subtypes represent distinct diseases. Elucidation of the specific distribution of T-cell subsets, critical to cancer immunity, across these diseases could provide better insights into the unique biology of BTC subtypes and help identify potential precision medicine strategies. To address this, we conducted single-cell RNA sequencing and T-cell receptor sequencing on CD3+ T cells from 36 samples from 16 patients with BTC across all subtypes and analyzed 355 pathologic slides to examine the spatial distribution of T cells and tertiary lymphoid structures. Compared with ICC and gallbladder cancer, ECC possessed a unique immune profile characterized by T-cell exhaustion, elevated CXCL13 expression in CD4+ T helper-like and CD8+CXCL13+ exhausted T cells, more mature tertiary lymphoid structures, and fewer desert immunophenotypes. Conversely, ICC displayed an inflamed immunophenotype with an enrichment of IFN-related pathways and high expression of LGALS1 in activated regulatory T cells, associated with immunosuppression. Inhibition of LGALS1 reduced tumor growth and regulatory T-cell prevalence in ICC mouse models. Overall, this study unveils T-cell diversity across BTC subtypes at the single-cell and spatial level that could open paths for tailored immunotherapies. Significance: Single-cell and spatial analyses detailed the T-cell characteristics specific to anatomic subtypes of biliary tract cancer, identifying unique immunologic features that could potentially be harnessed to improve patient outcomes.

Objectives: Although systemic chemotherapy (SC) is the mainstay for treating unresectable intrahepatic cholangiocarcinoma (ICC), its efficacy is limited and it causes severe systemic side effects. This study focuses on evaluating the effectiveness and safety of hepatic arterial infusion chemotherapy (HAIC) in combination with lenvatinib plus programmed death-1 (PD-1) inhibitors (HLP), compared to SC in combination with lenvatinib plus PD-1 inhibitors (SCLP) for unresectable ICC. Methods: We analyzed patients initially diagnosed with unresectable ICC at our center between March 2021 and December 2023, classifying them into HLP and SCLP groups according to treatment regimen. This study assessed and compared overall survival (OS), progression-free survival (PFS), tumor response, and safety outcomes across the two treatment groups. Results: This study enrolled 53 subjects in total; 25 were treated with HLP and 28 with SCLP. The two groups showed well-matched baseline characteristics. The HLP group reported an extended median OS (12.8 vs. 11.0 months, p = 0.310) and a prolonged median PFS (8.8 vs. 6.4 months, p = 0.043), compared to the SCLP group. The HLP group had a better objective response rate (ORR) (52% vs. 25%, p = 0.043) and disease control rate (DCR) (96% vs. 78.6%, p = 0.104). Based on OS (p = 0.019) and PFS (p = 0.032) results, those without extrahepatic metastasis seemed to benefit more significantly from the HLP regimen than from the SCLP regimen. The HLP group experienced fewer grade 3-4 adverse events (AEs) than the SCLP group. Conclusions: The HLP regimen for unresectable ICC is an effective and safe strategy and is potentially better suited for patients without extrahepatic metastases.

This was the first phase 1 study conducted in the United States. It consisted of dose-escalation (part A) and multiple indication-specific cohort expansion (part B), investigating the safety and preliminary efficacy of toripalimab (anti-programmed cell death-1 inhibitor) in patients with advanced malignancies.

Patients with advanced malignancies that progressed after treatment with at least one prior line of standard systemic therapy, including the patients with advanced/recurrent cholangiocarcinoma (CCA), received toripalimab 240 mg every 3 weeks in part B. The primary endpoint was safety assessment. Efficacy endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS) as assessed by the investigators according to Response Evaluation Criteria in Solid Tumors (version 1.1) and overall survival (OS).

In part B, 166 patients, including the 42 patients with CCA, were enrolled and received toripalimab. Among the 166 patients, treatment-emergent adverse events (TEAEs) of any grade occurred in 158 (95.2%) patients, and 97 (58.4%) patients experienced TEAEs of Grade 3 or greater. The most common TEAE was fatigue (42.2%). Seven (4.2%) patients experienced TEAEs with a fatal outcome, none of which were identified by investigators as related to toripalimab. Investigator-assessed immune-related adverse events (irAE) of Grade 3 or higher occurred in 7 (4.2%) patients. In the CCA cohort, with the median follow-up of 4.4 months, the ORR and DCR were 4.8% (95% CI: 0.58, 16.16) and 40.5% (95% CI: 25.63, 56.72), respectively; median DoR was 7.8 (range 4.4+ to 7.8) months; median PFS was 2.1 (95% CI: 1.91, 3.88) months; median OS was not estimable.

Toripalimab had manageable side effects in patients with refractory cholangiocarcinoma and exhibited preliminary evidence of anti-tumor activity. However, further information regarding biomarkers is needed. ClinicalTrials.gov ID: NCT03474640.

Background: Biliary tract cancers (BTCs), including gallbladder and bile duct cancers, have a poor prognosis. Recent advances in chemotherapy, such as using targeted drugs for specific gene mutations, have improved outcomes. Gemcitabine plus cisplatin chemotherapy has been the standard of care for the primary treatment of BTCs, but secondary treatment had not been established until recently. In recent years, durvalumab plus gemcitabine and cisplatin (GCD) chemotherapy is emerging as a promising regimen, although more evidence is needed for its effectiveness. Methods: This retrospective single-center study involved 44 patients receiving GCD treatment between January 2023 and March 2024 with a median follow-up of 10 months. Outcomes focused on overall survival (OS), progression-free survival (PFS), response rates, and adverse events (AEs). Results: The overall response rate (ORR) was 23%, and the disease control rate (DCR) was 82%. The overall median OS and PFS were 15.3 and 8.0 months, respectively, with patients receiving primary chemotherapy experiencing longer survival compared to a control group. Patients who did not undergo bile duct drainage had statistically different better OS and PFS. Grade 3 or higher AEs occurred in 54.5% of patients, with neutropenia and biliary infections being common. Conclusions: GCD chemotherapy shows potential as an effective treatment for BTCs. The favorable treatment outcome was the response rate, particularly in primary therapy or those cases with no metastasis. Bile duct management is crucial for improving patient outcomes. GCD chemotherapy has a high response rate, PFS, and OS compared to other forms of chemotherapy.

The current state of systemic therapy for advanced biliary tract cancer (BTC) has undergone significant changes. Currently, there are no clinical trials directly comparing various first-line systemic therapy regimens to each other, and these trials are unlikely to be conducted in the future. In this systematic review, after various abstracts and full-text articles published from the establishment of the database until October 2024 were searched, we included and analysed phase 3 clinical trials to evaluate the efficacy of different first-line systemic treatment regimens in advanced BTC. We used the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines and a random effects model to pool the overall effects. Finally, seven low-risk-of-bias trials (with all of the trials representing first-line trials) were included. A total of 4033 patients were included in seven first-line trials. In terms of progression-free survival (PFS), network meta-analysis revealed that durvalumab + gemcitabine + cisplatin (GemCis) triple therapy, S-1 + GemCis triple therapy, and pembrolizumab + GemCis triple therapy were superior to GemCis. In terms of overall survival (OS), network meta-analysis revealed that durvalumab + GemCis triple therapy and pembrolizumab + GemCis triple therapy outperformed GemCis. According to the ranking of the P scores, durvalumab + GemCis triple therapy ranked first in PFS and second in OS. Therefore, the advantages of molecular immunotherapy have gradually become known, which suggests that future trials should focus on other potential combinations and molecular immunotargeted therapies.

The efficacy of combined chemotherapy and immunotherapy has previously been demonstrated in patients with biliary tract cancer. The aim of this study was to assess the efficacy and safety of camrelizumab in combination with gemcitabine and apatinib as a first- or second-line treatment for advanced programmed death-ligand 1 (PD-L1)-positive biliary tract cancer. This prospective, single-arm, and exploratory clinical trial aimed at recruiting 20 PD-L1-positive patients (tumor proportion score ≥1% or combined positive score ≥1) who met the inclusion criteria. Camrelizumab (200 mg) was administered in combination with gemcitabine (800 mg/m2) and apatinib (250 mg). The primary endpoint was the objective response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Fourteen patients were enrolled between September 2, 2020, and December 15, 2022. At the data cutoff on August 16, 2023, the median follow-up time was 11.4 months (interquartile range, 4.5-15.4), with one patient still undergoing treatment. Among the enrolled patients, six achieved a partial response, and four had stable disease. The ORR was 42.9% (95% confidence interval [CI], 17.7-71.1), and the DCR was 71.4% (95% CI, 41.9-91.6). The median PFS was 5.4 months (95% CI, 2.8-not reached), and the median OS was 13.5 months (95% CI, 5.7-not reached). The most frequent grade 3 or 4 treatment-related adverse event was neutropenia (n = 4, 29%). The combination of camrelizumab, gemcitabine, and apatinib showed promising efficacy and acceptable safety in patients with advanced PD-L1-positive biliary tract cancer.

Biliary tract cancers (BTC) are a highly heterogeneous group of cancers at the genomic, epigenetic and molecular levels. The vast majority of patients initially present at an advanced (unresectable) disease stage due to a lack of symptoms and an aggressive tumour biology. Chemotherapy has been the mainstay of treatment in patients with advanced BTC but the survival outcomes and prognosis remain poor. The addition of immune checkpoint inhibitors (ICI) to chemotherapy have shown only a marginal benefit over chemotherapy alone due to the complex tumour immune microenvironment of these cancers. This review appraises our current understanding of the immune landscape of advanced BTC, including emerging transcriptome-based classifications, highlighting the mechanisms of immune evasion and resistance to ICI and their therapeutic implications. It describes the shifting treatment paradigm from traditional chemotherapy to immunotherapy combinations as well as the potential biomarkers for predicting response to ICI.

Circadian rhythms in the immune system and anti-tumor responses are underexplored in cancer immunotherapy. Despite the success of immune checkpoint inhibitors (ICIs) in treating advanced biliary tract cancers (BTCs), not all patients benefit. This study examined whether the timing of ICI administration affects outcomes in advanced BTC patients.

We included advanced BTC patients from West China Hospital of Sichuan University who received ≥2 ICI treatments from October 2019 to September 2023, with follow-up until May 2024. Primary outcome was overall survival (OS), with secondary outcomes including progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). Propensity score matching (1:2 ratio, caliper width 0.1) mitigated confounding factors. Cox proportional hazards regression analyzed the impact of ICI timing (post-16:30) on OS and PFS. Chi-square test assessed ORR and AE differences.

Among 221 patients, 51 received ≥20% of ICIs after 16:30; 170 received <20%. Post-matching, 49 late-infusion patients had significantly shorter OS (median 10.1 vs. 14.5 months, HR=1.80, P=0.012) compared to 90 early-infusion patients. Pre-matching, late-infusion patients also had shorter OS (median 9.8 vs. 13.7 months, HR=1.68, P=0.010) and PFS (median 4.9 vs. 8.1 months, HR=1.62, P=0.006). Multivariate analysis confirmed these results. No significant differences were found in ORR (χ^2 = 1.53, P=0.215) or AEs (all P>0.050). Sensitivity analyses supported these findings.

Timing of ICI administration affects efficacy in advanced BTC, with pre-16:30 infusions linked to better survival. Larger, prospective studies are needed to validate these results.

Recently, immunotherapy has offered new hope for treating biliary tract cancer (BTC). However, several issues are to be considered, including the lack of validated predictive biomarkers that could help to identify patient groups which are most likely to benefit from such therapeutic approaches.

In the current article, we will provide an overview of recent results and ongoing and future research directions of immunotherapy in BTC, with a special focus on recently published, practice-changing data, and ongoing active and recruiting clinical trials.

At this moment, dozens of clinical trials in phases I to III are evaluating the role of cancer immunotherapy in this setting, with the hope of adding more therapeutic options for BTC patients. Future research must focus on the development of novel agents and combinations, but the validation of biomarkers remains an urgent need. As more research results emerge, novel combinatorial strategies are destined to further transform the treatment paradigm for this heterogeneous and aggressive tumor type.

Biliary tract cancer (BTC) is an aggressive biliary tract cancer, arising from the bile ducts and gallbladder, with a poor prognosis. The TOPAZ-1 trial of durvalumab plus first-line chemotherapy (gemcitabine plus cisplatin) showed improved survival vs chemotherapy alone. This real-world study aimed to confirm the effectiveness of this regimen.

This retrospective, multicenter study included patients with advanced BTC treated with first-line durvalumab plus platinum chemotherapy at the Linkou, Taoyuan, and Tucheng branches of Chang Gung Memorial Hospital as well as at Taipei Veterans General Hospital between August 2021 and June 2023.

Among the 45 patients with advanced biliary tree cancer treated with durvalumab plus cisplatin and gemcitabine as first-line treatment, the objective response rate was 31.1% (14 partial responses). An additional 40% (18 patients) had stable disease. The median progression-free survival was 5.6 months (95%CI, 4.4-6.9) and median overall survival was 15.8 months (95%CI, 7.9-23.8). Responders had significantly longer survival than non-responders (15.8 vs 3.3 months). Although higher durvalumab doses (1000-1500 mg) appeared to have improved efficacy compared to lower doses (<1000 mg), the difference was not statistically significant. On multivariate analysis, poor ECOG performance status (≥2) and a high neutrophil-lymphocyte ratio were independent prognostic factors for shorter overall survival.

This real-world study demonstrated the comparable efficacy of durvalumab plus chemotherapy to the TOPAZ-1 trial for patients with advanced BTC and identified prognostic factors. There was a trend toward improved efficacy with higher durvalumab dosing (1000-1500 mg) vs lower dosing, though further research is needed to confirm this relationship.

Cholangiocarcinoma (CCA) presents a formidable therapeutic challenge due to its extensive heterogeneity and plasticity, which inevitably lead to acquired resistance to current treatments. However, recent evidence suggests that acquired drug resistance is associated with a fitness cost resulting from the myriad of acquired alterations under the selective pressure of the primary treatment. Consequently, CCA patients with acquired resistance are more susceptible to alternative therapies that are ineffective as monotherapies. This phenomenon, termed "acquired vulnerability," has garnered significant interest in drug development, as the acquired alterations could potentially be exploited therapeutically. This review elucidates the modes of acquired vulnerability, methods for identifying and exploiting acquired vulnerabilities in cancer (particularly in CCA), and strategies to enhance the clinical efficacy of drug combinations by leveraging the principle of acquired vulnerability. Identifying acquired vulnerabilities may pave the way for novel drug combinations to effectively treat highly heterogeneous and adaptable malignancies such as CCA.

The response of patients with biliary tract carcinoma (BTC) to immunotherapy varies widely, and there is an urgent need for biological indicators. The predictive value of inflammation based score (IBS) for the efficacy of immunotherapy in patients with BTC remains unclear, as the evidence is inconsistent. This study aimed to comprehensively examine the predictive value of IBS in peripheral blood on the survival of BTC patients receiving immunotherapy.

We retrospectively assessed 118 patients with advanced BTC who received anti-PD-1 therapy in the first or second line in two medical centers. The Kaplan-Meier, time-dependent ROC, and Harrell's concordance index (C-index) were applied to analyze the predictive value of 13 reported peripheral blood IBS.

All 13 IBS were identified as significant prognostic factors for OS in univariate analysis. Pan-immune-inflammation value (PIV) (p=0.005), PILE (composed of PIV, lactate dehydrogenase and Eastern Cooperative Oncology Group performance status) (p=0.033), neutrophil-to-lymphocyte ratio (NLR) (p=0.003), platelet-to-lymphocyte ratio (PLR) (p<0.001), lymphocyte-to-monocyte ratio (LMR) (p=0.006), systemic immune inflammation index (SII) (p=0.039), CRP-to-albumin ratio (CAR) (p=0.025), and Albumin-NLR (p=0.008) were identified as independent prognostic factors for OS in multivariate analysis. PIV and PILE scores were superior to other scores, according to time-dependent ROC curves, and their superiority became more pronounced after the 12-month time point. C-index analysis showed PIV (C-index 0.62, 95% CI: 0.55, 0.68) and PILE (C-index 0.62, 95% CI: 0.55, 0.70), both superior to other IBS.

PIV and PILE scores are independent predictors of OS in patients with BTC after immunotherapy and are superior to other IBS. PIV and PILE may be able to help screen out patients with advanced BTC who are less likely to benefit from anti-PD-1 monotherapy. Due to the retrospective nature of this analysis, the predictive value of PIV and PILE require validation in further prospective studies.

Biliary tract carcinoma (BTC) is relatively rare and comprises a spectrum of invasive tumors arising from the biliary tree. The prognosis is extremely poor. The incidence of BTC is relatively high in Asian countries, and a high number of cases are diagnosed annually in China owing to the large population. Therefore, it is necessary to clarify the epidemiology and high-risk factors for BTC in China. The signs associated with BTC are complex, often require collaborative treatment from surgeons, endoscopists, oncologists, and radiation therapists. Thus, it is necessary to develop a comprehensive Chinese guideline for BTC.

This clinical practice guideline (CPG) was developed following the process recommended by the World Health Organization. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to assess the certainty of evidence and make recommendations. The full CPG report was reviewed by external guideline methodologists and clinicians with no direct involvement in the development of this CPG. Two guideline reporting checklists have been adhered to: Appraisal of Guidelines for Research and Evaluation (AGREE) and Reporting Items for practice Guidelines in Healthcare (RIGHT).

The guideline development group, which comprised 85 multidisciplinary clinical experts across China. After a controversies conference, 17 clinical questions concerning the prevention, diagnosis, and treatment of BTC were proposed. Additionally, detailed descriptions of the surgical principles, perioperative management, chemotherapy, immunotherapy, targeted therapy, radiotherapy, and endoscopic management were proposed.

The guideline development group created a comprehensive Chinese guideline for the diagnosis and treatment of BTC, covering various aspects of epidemiology, diagnosis, and treatment. The 17 clinical questions have important reference value for the management of BTC.

The tumorigenesis of intrahepatic cholangiocarcinoma (ICC) has been identified to be exceptionally involved in dysregulated Hippo/Yes-associated protein (YAP) signaling pathway (Hippo/YAP). Hippo/YAP functions as a master regulator engaged in a plethora of physiological and oncogenic processes as well. Therefore, the aberrant Hippo/YAP could serve as an Achilles' heel regarding the molecular therapeutic avenues for ICC patients. Herein, we comprehensively review the recent studies about the underlying mechanism of disrupted Hippo/YAP in ICC, how diagnostic values could be utilized upon the critical genes in this pathway, and what opportunities could be given upon this target pathway.

As a second-line therapy, oxaliplatin/fluorouracil/leucovorin (FOLFOX) remains the standard of care for patients with biliary tract cancer (BTC); however, its efficacy is suboptimal. The aim of this study was to evaluate whether, compared with chemotherapy alone, the immune checkpoint inhibitor (ICI) combination regimen improved the overall survival (OS) in patients with advanced BTC.

Patients diagnosed with advanced BTC who received chemotherapy or ICI combination therapy as second-line (L2) treatment between January 1, 2018, and April 1, 2022, were retrospectively identified.

A total of 98 patients with BTCs were reviewed and recruited: the chemotherapy group (cohort A, n = 40), the chemotherapy plus ICIs group (cohort B, n = 27), and the tyrosine kinase inhibitor (TKIs) plus ICIs group (cohort C, n = 31). The median progression-free survival (PFS) and median OS were 2.6 months (95% confidence interval [CI]: 1.7-4.2) and 7.8 months (95% CI: 5.9-12.0) for cohort A, 4.3 months (95% CI: 2.9-8.4) and 10.9 months (95% CI: 7.67-NA) for cohort B, 5.1 months (95% CI: 4.0-8.3) and 10.1 months (95% CI: 8.23-NA) for cohort C, respectively. The confirmed overall response rates were 7.5% (3/40, cohort A), 22.2% (6/27, cohort B), and 19.4% (6/31, cohort C), whereas the disease control rates were 47.5% (19/40, cohort A), 77.8% (21/27, cohort B), and 77.4% (24/31, cohort C). Grade 3 or higher treatment-related adverse reaction were reported in 20.0% (cohort A), 37.0% (cohort B), and 41.9% (cohort C) of the patients.

The ICI combination strategy beyond first-line (L1) systemic chemotherapy plays a positive role in advanced BTCs. Both TKIs plus ICIs and chemotherapy plus ICIs could be considered candidates for trials and applied as competitive L2 treatment regimens for advanced BTCs in clinical practice.

Pancreaticobiliary cancer, encompassing malignancies of both the pancreatic and biliary tract, presents a formidable clinical challenge marked by a uniformly bleak prognosis. The asymptomatic nature of its early stages often leads to delayed detection, contributing to an unfavorable 5-year overall survival rate. Conventional treatment modalities have shown limited efficacy, underscoring the urgent need for alternative therapeutic approaches. In recent years, immunotherapy has emerged as a promising avenue in the fight against pancreaticobiliary cancer. Strategies such as therapeutic vaccines and the use of tumor-infiltrating lymphocytes have garnered attention for their potential to elicit more robust and durable responses. This review seeks to illuminate the landscape of emerging immunotherapeutic interventions, offering insights from both clinical and research perspectives. By deepening our understanding of pancreaticobiliary cancer and exploring innovative treatment modalities, we aim to catalyze improvements in patient outcomes and quality of life.

The anti-PD-L1 antibody durvalumab has been approved for use in first-line advanced biliary duct cancer (ABC). So far, predictive biomarkers of efficacy are lacking.

ABC patients who underwent gemcitabine-based chemotherapy with or without durvalumab were retrospectively enrolled, and their baseline clinical pathological indices were retrieved from medical records. Overall (OS) and progression free survival (PFS) were calculated and analyzed. The levels of peripheral biomarkers from 48 patients were detected with assay kits including enzyme-linked immunosorbent assay. Genomic alterations in 27 patients whose tumor tissues were available were depicted via targeted next-generation sequencing.

A total of 186 ABC patients met the inclusion criteria between January 2020 and December 2022 were finally enrolled in this study. Of these, 93 patients received chemotherapy with durvalumab and the rest received chemotherapy alone. Durvalumab plus chemotherapy demonstrated significant improvements in PFS (6.77 vs. 4.99 months; hazard ratio 0.65 [95% CI 0.48-0.88]; P = 0.005), but not OS (14.29 vs. 13.24 months; hazard ratio 0.91 [95% CI 0.62-1.32]; P = 0.608) vs. chemotherapy alone in previously untreated ABC patients. The objective response rate (ORR) in patients receiving chemotherapy with and without durvalumab was 19.1% and 7.8%, respectively. Pretreatment sPD-L1, CSF1R and OPG were identified as significant prognosis predictors in patients receiving durvalumab. ADGRB3 and RNF43 mutations were enriched in patients who responded to chemotherapy plus durvalumab and correlated with superior survival.

This retrospective real-world study confirmed the clinical benefit of durvalumab plus chemotherapy in treatment-naïve ABC patients. Peripheral sPD-L1 and CSF1R are promising prognostic biomarkers for this therapeutic strategy. Presence of ADGRB3 or RNF43 mutations could improve the stratification of immunotherapy outcomes, but further studies are warranted to explore the underlying mechanisms.

Cholangiocarcinoma (CCA) is a rare and aggressive cancer, mostly diagnosed at advanced or metastatic stage, at which point systemic treatment represents the only therapeutic option. Chemotherapy has been the backbone of advanced CCA treatment. More recently, immunotherapy has changed the therapeutic landscape, as immune checkpoint inhibitors have yielded the first improvement in survival and currently, the addition of either durvalumab or pembrolizumab to standard of care cisplatin plus gemcitabine represents the new first-line treatment option. However, the use of immunotherapy in subsequent lines has not demonstrated its efficacy and therefore, it is not approved, except for pembrolizumab in the selected microsatellite instability-high population. In addition, advances in comprehensive genomic profiling have led to the identification of targetable genetic alterations, such as isocitrate dehydrogenase 1 (IDH1), fibroblast growth factor receptor 2 (FGFR2), human epidermal growth factor receptor 2 (HER2), proto-oncogene B-Raf (BRAF), neurotrophic tropomyosin receptor kinase (NTRK), rearranged during transfection (RET), Kirsten rat sarcoma virus (KRAS), and mouse double minute 2 homolog (MDM2), thus favoring the development of a precision medicine approach in previously treated patients. Despite these advances, the use of molecularly driven agents is limited to a subgroup of patients. This review aims to provide an overview of the newly approved systemic therapies, the ongoing studies, and future research challenges in advanced CCA management.

Most patients with advanced gallbladder cancer are treated with multiagent chemotherapy. Immune checkpoint inhibitors offer the possibility of a durable response with less toxicity. This prospective, multicenter, open-label study was designed to evaluate the anticancer activity of nivolumab plus ipilimumab in patients with advanced gallbladder cancer.

Nineteen patients with advanced gallbladder cancer refractory to ≥1 previous therapy received nivolumab 240 mg intravenously every 2 weeks and ipilimumab 1 mg/kg intravenously every 6 weeks until disease progression or unacceptable toxicity. The primary end point was confirmed radiographic overall response rate (ORR) (complete response [CR] + partial response [PR] confirmed on subsequent scan); secondary end points included unconfirmed overall response, clinical benefit rate (confirmed and unconfirmed responses + stable disease >6 months), progression-free survival, overall survival, and toxicity.

The confirmed ORR was 16% (CR, n = 1 [5%]; PR, n = 2 [11%]); all were microsatellite stable, and the confirmed CR had undetectable programmed death-ligand 1 by immunohistochemistry. The unconfirmed ORR and clinical benefit rates were both 32%. The median duration of response was 14.8 months (range, 4-35.1+ months). The 6-month progression-free survival was 26% (95% CI, 12-55). The median overall survival was 7.0 months (95% CI, 3.9-19.1). The most common toxicities were fatigue (32%), anemia (26%), and anorexia (26%). Aspartate aminotransferase elevation was the most common grade 3/4 toxicity (11%). There was 1 possibly related death (sepsis with attendant hepatic failure).

Ipilimumab plus nivolumab was well tolerated and showed modest efficacy with durable responses in previously treated patients with advanced gallbladder cancer.

NCT02834013 (ClincialTrials.gov).

This prospective study assessed the efficacy and safety of nivolumab plus ipilimumab in 19 patients with advanced gallbladder cancer refractory to previous therapy. The combination demonstrated modest efficacy with a 16% confirmed overall response rate, durable responses, and manageable toxicities, suggesting potential benefits for this challenging patient population.

Immune checkpoint blockade (ICB)-based immunotherapy has inspired new hope for advanced biliary tract cancer (BTC) treatment; however, there are no prior studies that primarily focus on different anatomical types of unresectable BTCs reacting differently to ICB.

We retrospectively collected data on advanced BTC patients who received anti-programmed cell death protein 1 (anti-PD1) therapy from two affiliated hospitals of Sun Yat-Sen university. The effects of anti-PD1 were compared for different anatomical sites. The GSE32225 and GSE132305 datasets were used to further analyze differences in the immune microenvironments between intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC).

A total of 198 advanced BTC patients were enrolled in this study, comprising 142 patients with ICC and 56 with other cancer types ("Others" group), including ECC and gallbladder cancer. In the anti-PD1 treated patients, the ICC group (n = 90) achieved longer median progression-free survival (mPFS) (9.5 vs. 6.2 months, p = 0.02) and median overall survival (mOS) (15.1 vs. 10.7 months, p = 0.02) than the Others group (n = 26). However, chemotherapy did not show different effects between the two groups (mOS: 10.6 vs. 12.1 months, p = 0.20; mPFS: 4.9 vs. 5.7 months, p = 0.83). For the first-line anti-PD1 therapy, the ICC group (n = 70) achieved higher mOS (16.0 vs. 11.8 months, p = 0.04) than the Others group (n = 19). Moreover, most chemokines, chemokine receptors, major histocompatibility complex molecules, immunostimulators, and immunoinhibitors were stronger in ICC than ECC; furthermore, CD8+ T cells and M1 macrophages were higher in ICC than ECC for most algorithms. The immune differential genes were mainly enriched in antigen processing and presentation as well as the cytokine receptors.

This study shows that the efficacy of anti-PD1 therapy was higher in ICC than in other types of BTCs. Differences in the immune-related molecules and cells between ICC and ECC indicate that ICC could benefit more from immunotherapy.

The purpose of this study was to evaluate the clinical benefits of nivolumab with/without ipilimumab combined with stereotactic body radiotherapy (SBRT) in patients with pretreated metastatic biliary tract cancer (mBTC).

The study was a phase 2 randomized trial with Simon's optimal two-stage design requiring 36 evaluable patients per group after second stage. Sixty-one patients were included from September 2018 to January 2022 and randomized (1:1) to receive SBRT (15 Gy × 1 on day 1 to a primary or metastatic lesion) and nivolumab (3 mg/kg intravenously on day 1 and every 2 weeks) with/without ipilimumab (1 mg/kg intravenously on day 1 and every 6 weeks). Primary endpoint was clinical benefit rate (CBR), defined as the percentage of patients with complete response, partial response, or stable disease. Decision to continue accrual into the second stage depended on the CBR from the first stage.

Forty-two patients received SBRT/nivolumab/ipilimumab with a CBR of 31.0% [95% confidence interval (CI), 17.6-47.1]. Five patients (11.9%) achieved partial response with median duration of 4.4 months (range, 1.1-21.5). Nineteen patients received SBRT/nivolumab. This group was closed after the initial stage based on a CBR of 10.5% (95% CI, 1.3-33.1). Adverse events were graded with National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Grade ≥3 treatment-related adverse events occurred in 13 (31%) and 3 (16%) patients in the SBRT/nivolumab/ipilimumab and SBRT/nivolumab groups, respectively. One patient died from immune-related hepatitis in the SBRT/nivolumab/ipilimumab group.

Combining SBRT, nivolumab, and ipilimumab is well tolerated, feasible, and shows response in a subgroup of patients with mBTC.