Biliary Tract Cancer Patients Research Articles

5-Fluorouracil metabolic pathway genes predict recurrence risk following adjuvant S-1 therapy: Results of an ancillary analysis from a phase III trial of resected biliary tract cancer (JCOG1202A1).

S-1, an oral fluoropyrimidine derivative, is standard adjuvant therapy for resected biliary tract cancer (BTC), based on the results of the JCOG1202, a phase III trial evaluating the survival benefit with adjuvant S-1 following curative resection for BTC compared to surgery alone. This multicenter ancillary study of the JCOG1202 aimed to evaluate the prognostic impact of the 5-fluorouracil (5-FU) metabolic pathway genes including thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD). The 5-FU metabolic pathway genes were measured in tumor cells from formalin-fixed paraffin-embedded resected specimens from 183 patients (surgery alone: n = 94; adjuvant S-1: n = 89). We randomly divided them into training (n = 96) and validation sets (n = 87) for evaluating the interaction between gene levels and RFS benefits in the treatment arm. RFS benefits of adjuvant S-1 were observed in the low DPD (HR = 0.440 and 0.748, respectively in the training and validation sets) and the low TP groups (HR = 0.709 and 0.602, respectively). Clinicopathological characteristics were well balanced between low and high DPD populations. More advanced stage tumors were observed in high TP populations as compared to those in low TP populations (p = .0332). The results suggest the RFS benefit of adjuvant S-1 in resected BTC patients with low DPD and low TP gene expressions.

Efficacy and safety of camrelizumab combined with chemotherapy in the treatment of advanced biliary malignancy and associations between peripheral blood lymphocyte subsets and clinical 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.

Diffusion-Weighted Magnetic Resonance Imaging for the Diagnosis of Lymph Node Metastasis in Patients with Biliary Tract Cancer.

Objective: The diagnostic efficacy of the apparent diffusion coefficient (ADC) in diffusion-weighted magnetic resonance imaging (DW-MRI) for lymph node metastasis in biliary tract cancer was investigated in the present study. Methods: In total, 112 surgically resected lymph nodes from 35 biliary tract cancer patients were examined in this study. The mean and minimum ADC values of the lymph nodes as well as the long-axis and short-axis diameters of the lymph nodes were assessed by computed tomography (CT). The relationship between these parameters and the presence of histological lymph node metastasis was evaluated. Results: Histological lymph node metastasis was detected in 31 (27.7%) out of 112 lymph nodes. Metastatic lymph nodes had a significantly larger short-axis diameter compared with non-metastatic lymph nodes (p = 0.002), but the long-axis diameter was not significantly different between metastatic and non-metastatic lymph nodes. The mean and minimum ADC values for metastatic lymph nodes were significantly reduced compared with those for non-metastatic lymph nodes (p < 0.001 for both). However, the minimum ADC value showed the highest accuracy for the diagnosis of histological lymph node metastasis, with an area under the curve of 0.877, sensitivity of 87.1%, specificity of 82.7%, and accuracy of 83.9%. Conclusions: The minimum ADC value in DW-MRI is highly effective for the diagnosis of lymph node metastasis in biliary tract cancer. Accurate preoperative diagnosis of lymph node metastasis in biliary tract cancer should enable the establishment of more appropriate treatment strategies.

Safety of pressurized intraperitoneal aerosolized chemotherapy in biliary cancer patients with peritoneal metastases.

Biliary tract cancers are a rare diagnosis with a rising incidence. Up to 20% of patients have peritoneal metastases, resulting in symptoms of ascites, abdominal pain and potential bowel obstruction. A standard of care systemic treatment comprises gemcitabine, cisplatin and durvalumab (gem/cis/durva). However, the clinical benefit among patients with peritoneal metastases remains unknown. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) delivers chemotherapy directly to the peritoneal space, which could potentially improve efficacy with minimal systemic toxicity. We describe the design of a Phase I study investigating PIPAC with nab-paclitaxel plus systemic gem/cis/durva among biliary tract cancer patients with peritoneal metastases who have not received prior systemic treatment. The primary end point is safety of PIPAC with nab-paclitaxel in combination with systemic gem/cis/durva.Clinical Trial Registration: NCT05285358 (ClinicalTrials.gov).

Artificial intelligence-powered spatial analysis of tumor-infiltrating lymphocytes as a predictive biomarker for immune checkpoint inhibitors in biliary tract cancer.

Anti-PD-1/L1 has been demonstrated for its efficacy when combined with cytotoxic chemotherapy in randomized phase 3 trials for advanced biliary tract cancer (BTC). However, no biomarker predictive of benefit has been established for anti-PD-1/L1 in BTC. Here, we evaluated tumor-infiltrating lymphocytes (TILs) using artificial intelligence-powered immune phenotype (AI-IP) analysis in advanced BTC treated with anti-PD-1. Pre-treatment H&E-stained whole-slide images from 339 advanced BTC patients who received anti-PD-1 as second-line treatment or beyond, were utilized for AI-IP analysis and correlative analysis between AI-IP and efficacy outcomes with anti-PD-1. Next, data and images of BTC cohort from The Cancer Genome Atlas (TCGA) were additionally analyzed to evaluate the transcriptomic and mutational characteristics of various AI-IPs in BTC. Overall, AI-IPs were classified as inflamed (high intratumoral TIL [iTIL]) in 40 patients (11.8%), immune-excluded (low iTIL and high stromal TIL) in 167 (49.3%), and immune-deserted (low TIL overall) in 132 (38.9%). The inflamed IP group showed a significantly higher overall response rate compared to the non-inflamed IP groups (27.5% vs. 7.7%, P<0.001). Median overall survival and progression-free survival were significantly longer in the inflamed IP group than in the non-inflamed IP group (OS: 12.6 vs. 5.1 months, P=0.002; PFS: 4.5 vs. 1.9 months, P<0.001). In the analysis using TCGA cohort, the inflamed IP showed increased cytolytic activity scores and an interferon-gamma signature compared to the non-inflamed IP. AI-powered IP based on spatial TIL analysis was effective in predicting the efficacy outcomes in patients with BTC treated with anti-PD-1.

Liver Oligometastasis in Biliary Tract Cancer and Impact on Survival Outcomes.

Outcomes of unresectable biliary tract cancer (BTC) with varying extents of liver involvement remain unclear. We evaluated characteristics and outcomes of BTC patients with liver metastases who underwent chemotherapy. We retrospectively reviewed consecutive BTC patients with synchronous or metachronous intrahepatic metastases who started first-line chemotherapy at our institution between January 2016 and December 2021. Ninety-six patients were included, of which 57 only had liver metastases and 39 had multiorgan involvement. The liver only group had longer median overall survival (OS) (11.8 vs. 7.4months, P = 0.006) and median progression-free survival (PFS) (4.1 vs. 2.7months, P = 0.035) than the multiorgan group. Patients with oligometastases (defined as no more than three liver metastases) achieved longer OS than those with polymetastases (four or more liver metastases) in the entire cohort. Within the liver only group, there were no significant differences in OS or PFS between the oligometastasis and polymetastasis groups. Patients who underwent subsequent surgery had significantly longer median OS than those who did not (44.4 vs. 7.7months, P < 0.001). Age ≥ 75years, liver-only metastasis, modified Glasgow prognostic score ≥ 1 carcinoembryonic antigen ≥ 5μg/L, and subsequent surgery were independent predictors of OS. Liver oligometastasis was only a significant predictor of longer OS in univariate Cox analysis. Outcomes in BTC patients with metastases limited to the liver, particularly those with oligometastasis, were more favorable than those with multiorgan metastases. Selected cases, generally with liver oligometastases, may achieve prolonged OS through subsequent surgery.

Cost-effectiveness of pembrolizumab plus chemotherapy vs. chemotherapy as first-line treatment for advanced biliary tract cancer in China and the US.

Background: Pembrolizumab is a potentially valuable treatment. However, patients, doctors, and healthcare decision-makers are uncertain about its cost-effectiveness and an appropriate pricing for this new therapy. This study aims to appraise the cost-effectiveness of pembrolizumab as a first-line treatment for advanced biliary tract cancer (BTC) patients in China and the United States (US). Methods: A Markov model was constructed from the perspectives of healthcare systems in both China and the US for pharmacoeconomic evaluation. Patient baseline characteristics and key clinical data were sourced from the KEYNOTE-966 trial (ClinicalTrials.gov, NCT04003636). Costs and utilities were collected from drug cost websites and published literature. Cumulative costs (in USD), life years (LYs), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were measured and compared. Price simulations were conducted under given willingness-to-pay (WTP) thresholds to provide pricing scheme references. The model's robustness was analyzed through one-way sensitivity analysis and probabilistic sensitivity analysis. Results: Basic data analysis illustrates that pembrolizumab ($2662.41/100mg) in combination with chemotherapy regimen was not cost-effective relative to chemotherapy regimens at the WTP threshold of $38,201.19 in China, and the additional cost relative to chemotherapy regimens was $77,114.94 (ICER $556,689.47/QALY) while increasing 0.14 QALYs. Pembrolizumab ($54.71/1mg) also increased efficacy by 0.14 QALYs in the US, but remained also not cost-effective at the US WTP threshold of $229,044, and the total cost increased by $160,425.24 (ICER $1,109,462.92/QALY). Conclusion: Compared with chemotherapy, pembrolizumab plus chemotherapy reduces the disease of burden. However, at its current price, it may not be a cost-effective treatment for advanced BTC in both China and the US. This study can aid decision-makers in making optimal choices.

Trends in megestrol acetate prescription among Korean patients with biliary-pancreatic cancer and their impact.

85 Background: Chemotherapy-induced anorexia poses a significant challenge for cancer patients, particularly in biliary tract cancer (BTC) and pancreatic ductal adenocarcinoma (PDAC), known for their poor response to treatment. Megestrol acetate (MA), a commonly prescribed appetite stimulant, is associated with concerns regarding thrombosis and polypharmacy. Understanding the trends in MA prescription and its cascade effects is essential for optimizing cancer care. Methods: We conducted a retrospective cohort study using data from the Health Insurance and Review Assessment Service (HIRA) database in South Korea. The study included patients diagnosed with BTC and PDAC between 2008 and 2017. Prescription trends for MA, thrombosis events, anticoagulant prescriptions, and total parenteral nutrition (TPN) were analyzed. Statistical analysis included Chi-square tests and Kaplan-Meier estimates. Results: In our analysis of 41,670 patients with BTC and PDAC between 2008 and 2017, MA prescriptions increased notably, with PDAC patients rising from 7.85% to 51.84%. TPN prescriptions remained consistently high, especially among patients prescribed MA. For instance, in 2008, 94.71% of BTC patients prescribed MA received TPN, compared to 70.34% without MA. Similarly, in 2017, 87.56% of those prescribed MA received TPN, compared to 61.63% without MA. Among BTC patients with long-term MA prescriptions, 16.34% received anticoagulants, compared to 4.92% without MA (p&lt;0.001). Among PDAC patients, 18.3% with long-term MA prescriptions received anticoagulants, compared to 7.12% without MA (p&lt;0.001). Conclusions: The study highlights the escalating trend in MA prescriptions among BTC and PDAC patients, along with increased thrombosis diagnoses and anticoagulant prescriptions. These findings underscore the importance of understanding and managing the cascade effects of MA use and associated polypharmacy in optimizing cancer care and improving patient outcomes.

Identification of PANoptosis-relevant subgroups and predicting signature to evaluate the prognosis and immune landscape of patients with biliary tract cancer.

This study conducted molecular subtyping of biliary tract cancer patients based on 19 PANoptosis-related gene signatures. Through consensus clustering, patients were categorized into two subtypes, A and B. By integrating multi-omics data and clinical information from different cohorts, we elucidated the association between different subtypes of biliary tract cancer and patient prognosis, which correlated with the immune infiltration characteristics of patients. LASSO regression analysis was performed on the 19 gene signatures, and we constructed and validated a 9-gene risk score prognostic model that accurately predicts the overall survival rate of different biliary tract cancer patients. Additionally, we developed a predictive nomogram demonstrating the clinical utility and robustness of our model. Further analysis of the risk score-based immune landscape highlighted potential associations with immune cell infiltration, chemotherapy, and immune therapy response. Our study provides valuable insights into personalized treatment strategies for biliary tract cancer, which are crucial for improving patient prognosis and guiding treatment decisions in clinical practice.

N-glycan signatures identified in the serum from biliary tract cancer patients: Association with clinical diagnosis and prognosis.

Changes in the expression of genes related to glycosyltransferases may lead to alterations in N-glycan structure abundance, potentially acting as markers for diagnosis and prognosis in biliary tract cancer (BTC). This study was divided into cross-sectional and longitudinal approaches. The cross-sectional study included 316 BTC and 301 non-BTC. Propensity score matching was applied to adjust for sex and age differences between BTC and non-BTC. Univariate and multivariate logistic regression identified independent risk factors for BTC and constructed the BTC-G model. The ROC curve was used to validate the diagnostic performance of BTC-G. Longitudinal follow-up studies included postoperative (N = 50) and immunotherapy (N = 43) follow-up cohorts. Cox regression analysis identified N-glycan structures impacting BTC prognosis postoperative and immunotherapy, with further confirmation through Kaplan-Meier curves. Univariate and multivariate analyses identified Peak3 (OR: 0.790, 95% CI: 0.658-0.949), Peak9 (OR: 1.646, 95% CI: 1.409-1.922), and Peak9p (OR: 2.467, 95% CI: 1.267-4.804) as independent BTC risk factors, leading to the creation of the BTC-G. The ROC curve confirmed that BTC-G performed well in training (AUC: 0.753, 95% CI: 0.703-0.799), validation (AUC: 0.811, 95% CI: 0.740-0.870), and CA19-9 negative cohorts (AUC: 0.717, 95% CI: 0.664-0.767). Cox regression analysis and Kaplan-Meier curves established that Peak12 (HR: 5.578, 95% CI: 1.145-27.170) and Peak11 (HR: 1.104, 95% CI: 0.611-1.994) are independent risk factors for BTC prognosis following surgery and immunotherapy, respectively. Our NGFP technology supplements BTC diagnostics, distinguishing survival and recurrence subtypes for postoperative and immunotherapy, thereby supporting the development of treatment strategies.

Network meta-analysis of adjuvant chemotherapy in biliary tract cancers: Setting the scene for new randomized evidence.

The best adjuvant chemotherapy for resected biliary tract cancer (BTC) is under debate, with capecitabine supported by weak evidence. Aim of this network meta-analysis is to estimate the efficacy of different phase II/III regimens, comparing monotherapies (gemcitabine or fluoropyrimidines) head-to-head, against observation and combination regimens. A comprehensive literature search was conducted on PubMed and EMBASE for phase II/III randomized clinical trials (RCTs) available as of December 2023, reporting hazard ratios (HRs) of overall survival (OS) and event-free survival (EFS). A frequentist framework employing a random-effects model was applied; treatment rankings were outlined according to P-score, based on direct and indirect evidence. Exploratory subgroup analyses for OS were also performed (primary site, resected margin status and nodal involvement). Six RCTs (1979 total patients) were identified. Fluoropyrimidine monotherapy showed significantly better OS (HR .84 [.72-.97]) and EFS (HR .79 [.69-.91]) than observation, as any monotherapy did (HR .84 [.74-.96]; HR .79 [.70-.89]). In the head-to-head comparison for OS, only S1 confirmed to be superior to observation alone (HR .69 [.49-.98]) while fluoropyrimidines achieved the best P score (.81), similarly to any monotherapy (0.92). Combinations failed to prove superior to monotherapies with respect both to OS and EFS. Subgroup analyses were inconclusive due to results' inconsistency and limited sample size. Our work confirmed that adjuvant chemotherapy grants OS and EFS benefit for resected BTC patients. Fluoropyrimidines appeared the most effective option, confirming capecitabine as the preferred choice for the Western population.

Efficacy and biomarker analysis of second-line nab-paclitaxel plus sintilimab in patients with advanced biliary tract cancer.

Biliary tract cancer (BTC) is a highly aggressive malignancy with limited second-line therapy. We conducted this phase 2 trial to evaluate the efficacy and safety of second-line nab-paclitaxel plus sintilimab in advanced BTC. Histologically confirmed advanced BTC patients with documented disease progression after first-line chemotherapy were enrolled. Subjects received nab-paclitaxel 125 mg/m2 on days 1 and 8 plus sintilimab 200 mg on day 1, administered every 3 weeks. The primary end point was the objective response rate (ORR). The secondary end points were progression-free survival (PFS), overall survival (OS), and adverse reactions. Simultaneously, next-generation sequencing, programmed cell death ligand 1 immunohistochemistry and multiplex immunofluorescence of tumor-infiltrating lymphocytes were applied to explore potential biomarkers. Twenty-six subjects were consecutively enrolled. The ORR was 26.9% (7/26), including two complete responses and five partial responses, which met the primary end point. The disease control rate was 61.5% (16/26). The median PFS was 169 days (about 5.6 months, 95% confidence interval [CI] 60-278 days). The median OS was 442 days (about 14.7 months, 95% CI 298-586 days). Grade 3 treatment-related adverse events (TRAEs) were mainly anemia (27%), leukopenia (23%), neutropenia (19%), and peripheral sensory neuropathy (8%). No grade 4 or 5 TRAEs occurred. Biomarker analysis suggested that positive PD-L1 and high proportions of CD8+ T-cell infiltration were correlated with improved clinical outcome. Nab-paclitaxel plus sintilimab is a potentially effective and tolerable second-line regimen for advanced BTC that deserves to be studied in large-scale trials. PD-L1 status and CD8+ T cell infiltration might be promising biomarkers for efficacy prediction.

Treatment Outcomes in Advanced Biliary Tract Cancers: Single Institution Retrospective Analysis

Abstract Purpose Biliary tract cancers (BTCs), particularly gallbladder cancers (GBCs), are prevalent in India. Yet there are limited data on treatment outcomes. To bridge this gap, we performed an analysis of advanced BTC treatment outcomes at our institute, seeking to offer insights into real-world scenario. Materials and Methods This is a retrospective study comprising advanced BTC patients treated at our institute from January 2015 to March 2023. We assessed demographics, treatment approaches, progression-free survival (PFS), overall survival (OS), and associated toxicities. Results Of the 411 patients analyzed, the majority were GBC (67.3%, n = 277), while the rest were cholangiocarcinoma (CCA) (32.6%, n = 134). The median age of study population was 56 years. Palliative chemotherapy was administered in 85% (n = 349) of all patients. Gemcitabine–cisplatin doublet was the most commonly used chemotherapy regimen (80.2%, n = 280). Platinum doublets yielded higher response rates compared with single-agent/nonplatinum chemotherapy (60 vs. 30%, n = 133). The median PFS was 4 months. The median OS was 8 months with platinum doublets and 5 months with single-agent/nonplatinum chemotherapy (hazard ratio [HR]: 0.60, 95% confidence interval: [CI] 0.43–0.84, p = 0.0001). OS was no different based on the type of platinum agent used. Patients receiving multiple lines of treatment lived longer compared with those who received single line only (14 vs. 6 months, respectively, HR: 0.36, 95% CI: 0.28–0.45, p &lt; 0.0001). Significant prognostic factors for OS were treatment with chemotherapy, platinum doublets, platinum exposure in first line, and treatment beyond first line. Grade 3 or 4 adverse effects seen were anemia (13.9%, n = 36), vomiting (4.2%, n = 11), diarrhea (3.4%, n = 9), thrombocytopenia (3.4%, n = 9), and febrile neutropenia (3.1%, n = 8). Conclusion This analysis confirms that chemotherapy is beneficial for advanced BTC. Platinum-based doublets are more effective than single agents. There is no significant difference between cisplatin and oxaliplatin. Patients who received multiple lines of treatment had better OS.

Diagnostic value of carbohydrate antigen 50 in biliary tract cancer: A large-scale multicenter study.

To date, carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) have been widely used for the screening, diagnosis and prediction of biliary tract cancer (BTC) patients. However, few studies with large sample sizes of carbohydrate antigen 50 (CA50) were reported in BTC patients. A total of 1121 patients from the Liver Cancer Clin-Bio Databank of Anhui Hepatobiliary Surgery Union between January 2017 and December 2022 were included in this study (673 in the training cohort and 448 in the validation cohort): among them, 458 with BTC, 178 with hepatocellular carcinoma (HCC), 23 with combined hepatocellular-cholangiocarcinoma, and 462 with nontumor patients. Receiver operating characteristic (ROC) curves and decision curve analysis (DCA) were used to evaluate the diagnostic efficacy and clinical usefulness. ROC curves obtained by combining CA50, CA19-9, and AFP showed that the AUC value of the diagnostic MODEL 1 was 0.885 (95% CI 0.856-0.885, specificity 70.3%, and sensitivity 84.0%) in the training cohort and 0.879 (0.841-0.917, 76.7%, and 84.3%) in the validation cohort. In addition, comparing iCCA and HCC (235 in the training cohort, 157 in the validation cohort), the AUC values of the diagnostic MODEL 2 were 0.893 (95% CI 0.853-0.933, specificity 96%, and sensitivity 68.6%) in the training cohort and 0.872 (95% CI 0.818-0.927, 94.2%, and 64.6%) in the validation cohort. The model combining CA50, CA19-9, and AFP not only has good diagnostic value for BTC but also has good diagnostic value for distinguishing iCCA and HCC.

Adjuvant tislelizumab combined with capecitabine for patients with biliary tract cancer with high risk of postoperative relapse (ACTIVE): Primary analysis from a prospective cohort study.

e16248 Background: Only 20% of biliary tract cancer (BTC) patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. This rate is even lower in patients with high-risk features. Capecitabine as an adjuvant therapy in biliary tract cancer has been verified to improve overall survival, however, the efficacy still remains limited. PD-1/L1 antibody combined with chemotherapy have been demonstrated to improve survival in advanced biliary tract cancer. This study aimed to evaluate the efficacy and safety of adjuvant tislelizumab and capecitabine following surgery for biliary tract cancer with high risk of recurrence. Methods: This was a single-center, prospective cohort phase II study. BTC patients (pts) underwent R0/R1 resection with high postoperative recurrence risk were eligible. The high-risk factors included positive resection margins, positive lymph nodes, positive perineural invasion, and tumor &gt; 5cm in diameter. The patients were divided into two groups, the tislelizumab (TIS 200 mg Q3W for 1 year )+capecitabine (CAP D1-14, 1500mg/m2 for eight 3-weekly cycles) group and the capecitabine group. The primary endpoint was DFS (disease free survival). The second endpoints was OS (overall survival) and adverse event (AE). Results: A total of 37 pts were enrolled into the study, while 22 pts in the TIS+CAP group and 15 in CAP group, 23 males and 14 females with a median age of 66 years. According to the location of the tumor, 37.8% pts were intrahepatic cholangiocarcinoma, 21.6% were gallbladder cancer, 5.4% were distal cholangiocarcinoma and 35.1% were hilar cholangiocarcinoma. The median DFS was 16.2 months (95% CI, 8.1-26.2) in the TIS+CAP group, which was longer than CAP group (11.4 months, 95% CI 4.2-27.1). 12-month RFS rates were 56.5% and 36.6% , respectively. The most common adverse events (AEs, any grade) were rash (18.2%), vomiting (13.6%), neutropenia (13.6%) and anorexia (13.6%) in the TIS+CAP group. Conclusions: Tislelizumab in combination with capecitabine were effective and safe as adjuvant therapy, which can prolong the DFS of BTC patients with high recurrence risk after resection. Clinical trial information: NCT04782804 .

Cadonilimab in combined with gemcitabine and cisplatin in advanced biliary tract cancer (BicureX): A phase II, single-arm clinical trial.

e16158 Background: PD-1 or PD-L1 inhibitors plus chemotherapy as the first-line treatment has been proven to be effective in improving the prognosis of advanced biliary tract cancer (BTC) patients. However, there is still considerable demand for further improvement of BTC patients’ prognosis. This trial aims to evaluate the efficacy and safety of Cadonilimab (PD-1/CTLA-4, a bi-specific antibody) plus gemcitabine and cisplatin for patients with advanced BTC in first -line treatment. Methods: In this phase II, single-arm trial, we will enroll 65 patients with previously untreated, unresectable, locally advanced or metastatic BTC, including intrahepatic or extrahepatic cholangiocarcinoma (ICC/ECC) and gallbladder carcinoma (GBC). Participants received Cadonilimab (10 mg/kg, days 1, every three weeks) plus gemcitabine (1000 mg/m2, days 1, 8, Q3W), and cisplatin (25 mg/m2, days 1, 8, Q3W) for up to eight cycles, followed by Cadonilimab (10 mg/kg, days 1, Q3W) until disease progression or unacceptable toxicity. Treatment response was evaluated with image-based assessment according to response evaluation criteria insolid tumors (RECIST) version 1.1. by two experienced experts and further explored multiple methods, such as 3D visualisation and Spectral computed tomography Scan. The primary endpoint was the objective response rate (ORR); the secondary endpoints are disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Exploratory endpoints included associations between response, molecular characteristics, and the immune microenvironment. Results: Between June 30, and January 31, 2024, a total of 30 patients have undergone at least one imaging evaluation. 66.7% of these patients were diagnosed with ICC, 23.3% with GBC, and 10% with ECC. The mean age was 58.4 years, and 60% of the patients were male. 24 (80%) patients had metastasis. Among them, 1 (3.3%) patient acheived complete response (CR), 15 (50%) patients had partial response (PR) and 8 (26.7%) patients presented with stable disease (SD). The ORR was 53.3% and the DCR was 80%. The most common treatment-related adverse events (TRAEs) of any grade were rash (80%) and anaemia (76.7%). Grade 3 TRAEs were observed in 66.7% of the patients. The most frequent grade 3 TRAEs were anaemia (33.3%), and leukocytopenia (33.3%). No grade 4 or 5 events were observed. All patients were microsatellite stable (MSS), and the median TMB was 2.88 (0-109.44) Muts/Mb. Conclusions: Cadonilimab plus gemcitabine and cisplatin shown a promising efficacy and acceptable safety profile as first-line treatment for advanced BTC patients. Clinical trial information: NCT05978609 .

Developing behavioral intervention to support molecular testing of patients with biliary tract cancer.

TPS1641 Background: Biliary tract cancer (BTC) represents 7% of gastrointestinal malignancies in the United States, with an incidence of 0.5 to 2.0 cases per 100,000 individuals. Standard care involves systemic chemotherapy, predominantly gemcitabine and cisplatin. Recent advancements in immunotherapy, as evidenced by the TOPAZ-1 trial and KN966, support the use of durvalumab, and pembrolizumab as treatment options. Genetic tumor testing identifies up to 40% of BTC patients with targetable mutations, leading to recent FDA approvals for FGFR2 inhibitors - pemigatinib, infigratinib, futibatinib, and IDH1 inhibitor ivosidenib. The emerging data on inhibitors targeting the BRAF mutation, together with HER2 amplification, underscore the importance of understanding the tumor's molecular profile. Navigating this evolving treatment landscape emphasizes an unmet need for patients to comprehend the pivotal significance of tumor molecular profiling in formulating effective and personalized treatment plans. Identifying knowledge gaps among BTC patients concerning tumor genetic testing and precision medicine, along with strategies to address these gaps, holds promise for improving the management and the outcome of patients with BTC. Methods: This is a behavioral intervention study where participants will undergo two in-person survey interviews before and after an educational intervention. The initial survey aims to establish baseline knowledge about the BTC diagnosis and treatment and ascertain preferences for various educational interventions. Patients’ knowledge gap will be determined by comparing their responses to the initial survey and medical history documented by their treating physicians. They will then be provided with a 10-minute educational video. Participants will have the flexibility to access the video multiple times. Within 6 weeks from enrollment, they will have a post-education survey to determine the effectiveness of the education intervention. Following completion of baseline surveys, collaboration with key stakeholders including medical oncology and community perspectives will be initiated to identify knowledge gaps and inform the design of an educational intervention. The study enrollment will be targeted at BTC patients receiving systemic therapy at Georgetown University Hospital, Fox Chase Cancer Center, and Hackensack Meridian Health. Ten participants are enrolled and have completed the first survey and intervention. This study is currently enrolling participants: GUIRB: STUDY00007119.

Durvalumab plus gemcitabine/cisplatin/nab-paclitaxel in resectable biliary tract cancer: A phase II, single-arm, open-label study (DurGAP).

e16260 Background: Biliary tract cancer (BTC) presents a formidable challenge, marked by its aggressive nature and dismal prognosis. While surgical resection remains the lone potentially curative option, 5-year survival rates have plateaued below 50%, largely due to high rates of recurrences and metastases. Given these sobering statistics, the imperative for neoadjuvant therapy to enhance outcomes is evident. Building upon the success of the TOPAZ-1 trial, which established durvalumab in combination with gemcitabine and cisplatin as a standard regimen for advanced BTC, this study seeks to assess the safety and efficacy of incorporating neoadjuvant durvalumab alongside gemcitabine, cisplatin, and Nab-paclitaxel for resectable BTC. Methods: Resectable, treatment-naïve BTC patients (pts) were enrolled and administered 3 cycles of neoadjuvant durvalumab (1000mg, iv, d1, q3w) + GAP (gemcitabine 1000mg/m2, cisplatin 25mg/m2, Nab-paclitaxel 100mg/m2, d1, d8, 21d cycle). Primary endpoints included assessing Adverse Events (AEs) and Objective Response Rate (ORR). Secondary endpoints comprised R0 resection rate, Recurrence-Free Survival (RFS), Overall Survival (OS). Results: Between Feb, 2023 to Jan, 2024, a total of 24 patients were enrolled, 12 (50.0%) were male, all with ECOG 0 and 18 (75.0%) presenting with N1 status. Median age: 65 years. Primary sites: intrahepatic (50.0%), extrahepatic (33.3%), gallbladder (16.7%). Median follow-up: 8.75 months; all pts received ≥2 neoadjuvant cycles. The ORR was 62.5%, with all 15 pts demonstrating partial responses (PR). The DCR was 87.5% with 15 PR and 6 stable disease (SD) responses. The most common treatment-related adverse events (TRAEs) were increased ALT/AST (28.6%), anemia (21.8%), hypoalbuminemia (16.0%). Grade ≥3 TRAEs occurred in 2 (8.3%) pts. 13 pts underwent resection, achieving R0 resection in 12 (92.3%) of cases, comprising 10 PR, 2 SD, and 1 pt deemed eligible for surgery post-assessment despite a PD response. 11 pts did not undergo resection, with reasons including patient refusal (4 PR, 1 SD), not meeting resection criteria (2 PD), lost to follow-up (1 PR, 1 SD), and still under active follow-up (2 SD). Conclusions: Neoadjuvant durvalumab combined with gemcitabine/cisplatin/Nab-paclitaxel demonstrated a promising ORR and DCR, with a tolerable safety profile, warranting further investigations in a larger cohort. Clinical trial information: NCT05640791 .

Effect of immune checkpoint inhibitor administration timing on survival outcomes in advanced biliary tract cancers: A single-center propensity score matching analysis.

e16186 Background: Circadian rhythms in the immune system and anti-tumor immune responses have not received adequate attention in terms of their impact on cancer immunotherapy. Recent advances in immune checkpoint inhibitors (ICIs) have marked a significant breakthrough in the treatment of advanced biliary tract cancer (BTC), but not all patients benefit from this therapy. Our study aimed to investigate whether the timing of ICI administration affects the treatment outcomes in BTC patients. Methods: We included patients with advanced BTC patients at West China Hospital of Sichuan University who received at least two ICI treatments from October 2019 to May 2023, with follow-up until December 2023. The primary outcome was overall survival (OS), with secondary outcomes including progression-free survival (PFS), objective response rate (ORR), and adverse event incidence. Propensity score matching (1:2 ratio, nearest-neighbor caliper width of 0.1) and COX regression were used to analyze the relationship between the proportion of ICI administrations after 16:30 and both OS and PFS, while the Chi-square test was used to compare the ORR and adverse event rates between groups. Results: A total of 207 patients were eligible for analysis. Before matching, 37 patients had more than 20% of their ICI administrations after 16:30, and 170 had less than 20%. After matching, 34 patients receiving more than 20% of ICIs after 16:30 were compared with 65 who did not. The former group showed significantly shorter OS (median 10 months [95%CI: 8-14 months] vs. 17 months [95%CI: 12-20 months], HR = 2.067 [95%CI: 1.226-3.485, P = 0.00645]) and PFS (median 5 months [95%CI: 4-7 months] vs. 9 months [95%CI: 8-12 months], HR = 2.093 [95%CI: 1.315-3.331, P = 0.00183]), with these results remaining robust after multivariate Cox regression analysis. No significant difference in ORR (χ^2 = 2.287, p = 0.131) was observed. Safety analysis showed no difference in the incidence of adverse events, including Grade 3/4 adverse events, immune-related adverse events, and medication discontinuation due to adverse events (all p &gt; 0.050). Sensitivity analyses in patients receiving at least three ICI treatments revealed similar results. Conclusions: The timing of ICI administration influences the efficacy of immunotherapy in advanced biliary cancer, with administrations before 16:30 associated with better survival outcomes. Further research with larger sample sizes and prospective studies is needed to validate these findings.

Two stage, multi-center trial of cadonilimab and LM-302 for patients with CLDN18.2+ biliary tract cancer (BTC) that failed chemotherapy and PD-(L)1 antibody (ZSAB-Calm).

e16152 Background: BTC is a lethal disease with limited effective treatments, especially for those who have failed immune checkpoint inhibitors (ICIs) plus chemotherapy. Cadonilimab, a tetrameric bispecific antibody targeting PD-1 and CTLA-4, showed promising safety profile and efficacy in several malignant tumors. LM-302 is a novel antibody-drug conjugate targeting CLDN18.2, a tight junction protein expressed on the cell surface of many solid tumors, including BTC. Here, we present preliminary data on the safety and efficacy of cadonilimab plus LM-302 in CLDN18.2+ BTC patients (pts) with prior treatment of ICI and chemotherapy. Methods: This ongoing study is a multicenter, two-stage, randomized phase Ib/II clinical trial. In the dose-escalation phase, 6 pts (no requirement for CLDN18.2) are enrolled, using "3+3" design to determine the RP2D. Pts will receive LM302 (1.6mg/kg or 1.8mg/kg Q2W) and cadonilimab (6mg/kg Q2W). The expansion stage is expected to enroll 90 pts (CLDN18.2 + staining in ≥40% of tumor cells), randomized into 3 arms with 30 patients each. Arm 1: cadonilimab (6mg/kg Q2W), Arm 2: LM-302 (1.8mg/kg, Q2W), Arm 3: cadonilimab (6mg/kg Q2W) and LM-302 (RP2D). The primary endpoints are the safety (CTCAE 5.0) in phase 1b and ORR (RECIST1.1) in phase 2. The secondary endpoints include DCR, PFS, OS and safety. Results: A total of 18 pts were enrolled from Aug 4, 2023 to Jan 15, 2024. Median age was 62 (range: 42-79), 44% were male. 61% have intrahepatic cholangiocarcinoma. 78% pts with distant metastasis were diagnosed as stage IV. In the dose-escalation phase, 7 pts were enrolled. The first pt was discontinued after only one dose due to percutaneous transhepatic cholangiography and drainage catheter infection and gastrointestinal bleeding (unrelated to treatment). No DLTs were observed. 7 (100%) pts experienced TRAEs. The most common TRAEs were bilirubin increase (71.4%) thrombocytopenia (57.1%), neutropenia (57.1%), infusion reactions (rash) (42.9%), leukopenia (42.9%), anemia (28.6%). Only 2 pts had grade 3 TRAEs including anemia(1pt), neutropenia, leukopenia and rash (1pt). There was no grade≥4 TRAE. Of the 6 efficacy-evaluable pts, 3 pts(CLDN18.2 expression in 30%, 40%, 80%)achieved PR resulting in a BOR of 50% in Phase Ib. The RP2D for LM-302 was 1.8mg/kg. In expansion phase, 11 pts with CLDN18.2+ BTC were randomly enrolled. The median number of treatment cycles was 2 (range 1-8), with 4 pts each in Arm 1 and Arm 2, and 3 pts in Arm 3. Among the 11 pts, 5 (45.5%) occurred TRAEs, with 3 pts in Arm 3 and 2 pts in Arm 1. The most common TRAEs were neutropenia (18.2%), neutropenia (18.2%). Only 1 pt in Arm 3 experienced grade 3 neutropenia. One pt had a SAE of myocardial infarction (unrelated to treatment). Conclusions: Cadonilimab combined with LM-302 has manageable safety and promising antitumor activity in CLDN18.2+ BTC. Clinical trial information: NCT05994001 .