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Despite improvements in multidisciplinary management, patients with biliary tract cancer have a poor outcome. Only 20% of patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. To our knowledge, no studies have described a benefit of adjuvant therapy. We aimed to determine whether adjuvant capecitabine improved overall survival compared with observation following surgery for biliary tract cancer. This randomised, controlled, multicentre, phase 3 study was done across 44 specialist hepatopancreatobiliary centres in the UK. Eligible patients were aged 18 years or older and had histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer who had undergone a macroscopically complete resection (which includes liver resection, pancreatic resection, or, less commonly, both) with curative intent, and an Eastern Cooperative Oncology Group performance status of less than 2. Patients who had not completely recovered from previous surgery or who had previous chemotherapy or radiotherapy for biliary tract cancer were also excluded. Patients were randomly assigned 1:1 to receive oral capecitabine (1250 mg/m2 twice daily on days 1–14 of a 21-day cycle, for eight cycles) or observation commencing within 16 weeks of surgery. Treatment was not masked, and allocation concealment was achieved with a computerised minimisation algorithm that stratified patients by surgical centre, site of disease, resection status, and performance status. The primary outcome was overall survival. As prespecified, analyses were done by intention to treat and per protocol. This study is registered with EudraCT, number 2005-003318-13. Between March 15, 2006, and Dec 4, 2014, 447 patients were enrolled; 223 patients with biliary tract cancer resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. The data cutoff for this analysis was March 6, 2017. The median follow-up for all patients was 60 months (IQR 37–60). In the intention-to-treat analysis, median overall survival was 51·1 months (95% CI 34·6–59·1) in the capecitabine group compared with 36·4 months (29·7–44·5) in the observation group (adjusted hazard ratio [HR] 0·81, 95% CI 0·63–1·04; p=0·097). In a protocol-specified sensitivity analysis, adjusting for minimisation factors and nodal status, grade, and gender, the overall survival HR was 0·71 (95% CI 0·55–0·92; p=0·010). In the prespecified per-protocol analysis (210 patients in the capecitabine group and 220 in the observation group), median overall survival was 53 months (95% CI 40 to not reached) in the capecitabine group and 36 months (30–44) in the observation group (adjusted HR 0·75, 95% CI 0·58–0·97; p=0·028). In the intention-to-treat analysis, median recurrence-free survival was 24·4 months (95% CI 18·6–35·9) in the capecitabine group and 17·5 months (12·0–23·8) in the observation group. In the per-protocol analysis, median recurrence-free survival was 25·9 months (95% CI 19·8–46·3) in the capecitabine group and 17·4 months (12·0–23·7) in the observation group. Adverse events were measured in the capecitabine group only, and of the 213 patients who received at least one cycle, 94 (44%) had at least one grade 3 toxicity, the most frequent of which were hand-foot syndrome in 43 (20%) patients, diarrhoea in 16 (8%) patients, and fatigue in 16 (8%) patients. One (<1%) patient had grade 4 cardiac ischaemia or infarction. Serious adverse events were observed in 47 (21%) of 223 patients in the capecitabine group and 22 (10%) of 224 patients in the observation group. No deaths were deemed to be treatment related. Although this study did not meet its primary endpoint of improving overall survival in the intention-to-treat population, the prespecified sensitivity and per-protocol analyses suggest that capecitabine can improve overall survival in patients with resected biliary tract cancer when used as adjuvant chemotherapy following surgery and could be considered as standard of care. Furthermore, the safety profile is manageable, supporting the use of capecitabine in this setting. Cancer Research UK and Roche.

Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636. Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7–30·4). Median overall survival was 12·7 months (95% CI 11·5–13·6) in the pembrolizumab group versus 10·9 months (9·9–11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72–0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events. Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer. Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Purpose To assess the incidence, clinical characteristics, and post-progression management strategy of resistance to immunotherapy–chemotherapy combination in unresectable biliary tract carcinoma (uBTC). Experimental Design Patients with uBTC from multiple centers who received immunotherapy–chemotherapy combination were retrospectively included. Baseline characteristics, treatments, pattern of progression, and posttreatment managements were recorded. The primary endpoint was post-progression survival (PPS). Results Out of 194 patients, 130 (67.0%) developed resistance, including 78 (40.2%) with acquired resistance (AR) and 52 (26.8%) with primary resistance (PR). Normal CA19-9 level and combining target therapy were more common in patients with AR. Patients with both AR and PR commonly experience deterioration in general condition and systemic progression. Patients with AR and PR showed no difference in patterns of progression or current post-progression management strategies. A total of 103 (79.2%) patients receiving post-resistance antitumor treatments showed improved prognosis than those receiving best supportive care, while patients with AR received additional survival benefit than those with PR. Changing immunotherapy regimen after resistance brings significant survival benefit in patients with AR (mPPS: 15.1 vs. 9.50 months, HR = 0.41), but not those with PR. Adding/switching target therapy regimens (HR = 0.39) and local regional therapies (LRT) (HR = 0.36) after resistance brings potential benefit in patients with PR. Conclusions Changing immunotherapy regimen is a promising strategy for overcoming AR to first-line immunotherapy–chemotherapy combination in uBTC, while adjusting targeted therapy and adding LRT may help overcome PR.

In the ongoing, randomised, double-blind phase 3 TOPAZ-1 study, durvalumab, a PD-L1 inhibitor, plus gemcitabine and cisplatin was associated with significant improvements in overall survival compared with placebo, gemcitabine, and cisplatin in people with advanced biliary tract cancer at the pre-planned intermin analysis. In this paper, we present patient-reported outcomes from TOPAZ-1. In TOPAZ-1 (NCT03875235), participants aged 18 years or older with previously untreated, unresectable, locally advanced, or metastatic biliary tract cancer with an Eastern Cooperative Oncology Group performance status of 0 or 1 and one or more measurable lesions per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) were randomly assigned (1:1) to the durvalumab group or the placebo group using a computer-generated randomisation scheme. Participants received 1500 mg durvalumab or matched placebo intravenously every 3 weeks (on day 1 of the cycle) for up to eight cycles in combination with 1000 mg/m2 gemcitabine and 25 mg/m2 cisplatin intravenously on days 1 and 8 every 3 weeks for up to eight cycles. Thereafter, participants received either durvalumab (1500 mg) or placebo monotherapy intravenously every 4 weeks until disease progression or other discontinuation criteria were met. Randomisation was stratified by disease status (initially unresectable vs recurrent) and primary tumour location (intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma vs gallbladder cancer). Patient-reported outcomes were assessed as a secondary outcome in all participants who completed the European Organisation for Research and Treatment of Cancer's 30-item Quality of Life of Cancer Patients questionnaire (QLQ-C30) and the 21-item Cholangiocarcinoma and Gallbladder Cancer Quality of Life Module (QLQ-BIL21). We calculated time to deterioration—ie, time from randomisation to an absolute decrease of at least 10 points in a patient-reported outcome that was confirmed at a subsequent visit or the date of death (by any cause) in the absence of deterioration—and adjusted mean change from baseline in patient-reported outcomes. Between April 16, 2019, and Dec 11, 2020, 685 participants were enrolled and randomly assigned, 341 to the durvalumab group and 344 to the placebo group. Overall, 345 (50%) of participants were male and 340 (50%) were female. Data for the QLQ-C30 were available for 318 participants in the durvalumab group and 328 in the placebo group (median follow-up 9·9 months [IQR 6·7 to 14·1]). Data for the QLQ-BIL21 were available for 305 participants in the durvalumab group and 322 in the placebo group (median follow-up 10·2 months [IQR 6·7 to 14·3]). The proportions of participants in both groups who completed questionnaires were high and baseline scores were mostly similar across treatment groups. For global health status or quality of life, functioning, and symptoms, we noted no difference in time to deterioration or adjusted mean changes from baseline were observed between groups. Median time to deterioration of global health status or quality of life was 7·4 months (95% CI 5·6 to 8·9) in the durvalumab group and 6·7 months (5·6 to 7·9) in the placebo group (hazard ratio 0·87 [95% CI 0·69 to 1·12]). The adjusted mean change from baseline was 1·23 (95% CI –0·71 to 3·16) in the durvalumab group and 0·35 (–1·63 to 2·32) in the placebo group. The addition of durvalumab to gemcitabine and cisplatin did not have a detrimental effect on patient-reported outcomes. These results suggest that durvalumab, gemcitabine, and cisplatin is a tolerable treatment regimen in patients with advanced biliary tract cancer. AstraZeneca.

HER2 mutations are infrequent genomic events in biliary tract cancers (BTCs). Neratinib, an irreversible, pan-HER, oral tyrosine kinase inhibitor, interferes with constitutive receptor kinase activation and has activity in HER2 -mutant tumours. SUMMIT is an open-label, single-arm, multi-cohort, phase 2, ‘basket’ trial of neratinib in patients with solid tumours harbouring oncogenic HER2 somatic mutations (ClinicalTrials.gov: NCT01953926). The primary objective of the BTC cohort, which is now complete, is first objective response rate (ORR) to neratinib 240 mg orally daily. Secondary objectives include confirmed ORR, clinical benefit rate, progression-free survival, duration of response, overall survival, safety and tolerability. Genomic analyses were exploratory. Among 25 treatment-refractory patients (11 cholangiocarcinoma, 10 gallbladder, 4 ampullary cancers), the ORR is 16% (95% CI 4.5–36.1%). The most common HER2 mutations are S310F (n = 11; 48%) and V777L (n = 4; 17%). Outcomes appear worse for ampullary tumours or those with co-occurring oncogenic TP53 and CDKN2A alterations. Loss of amplified HER2 S310F and acquisition of multiple previously undetected oncogenic co-mutations are identified at progression in one responder. Diarrhoea is the most common adverse event, with any-grade diarrhoea in 14 patients (56%). Although neratinib demonstrates antitumour activity in patients with refractory BTC harbouring HER2 mutations, the primary endpoint was not met and combinations may be explored. In biliary tract cancer HER2 alterations correlate with poor prognosis. Here, the authors present the results of a phase II clinical trial reporting the efficacy and safety of the tyrosine kinase inhibitor neratinib in patients with HER2-mutation positive advanced biliary tract cancers.

HER2 is overexpressed or amplified in a subset of biliary tract cancer. Zanidatamab, a bispecific antibody targeting two distinct HER2 epitopes, exhibited tolerability and preliminary anti-tumour activity in HER2-expressing or HER2 (also known as ERBB2)-amplified treatment-refractory biliary tract cancer. HERIZON-BTC-01 is a global, multicentre, single-arm, phase 2b trial of zanidatamab in patients with HER2-amplified, unresectable, locally advanced, or metastatic biliary tract cancer with disease progression on previous gemcitabine-based therapy, recruited at 32 clinical trial sites in nine countries in North America, South America, Asia, and Europe. Eligible patients were aged 18 years or older with HER2-amplified biliary tract cancer confirmed by in-situ hybridisation per central testing, at least one measurable target lesion per Response Evaluation Criteria in Solid Tumours (version 1.1), and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were assigned into cohorts based on HER2 immunohistochemistry (IHC) score: cohort 1 (IHC 2+ or 3+; HER2-positive) and cohort 2 (IHC 0 or 1+). Patients received zanidatamab 20 mg/kg intravenously every 2 weeks. The primary endpoint was confirmed objective response rate in cohort 1 as assessed by independent central review. Anti-tumour activity and safety were assessed in all participants who received any dose of zanidatamab. This trial is registered with ClinicalTrials.gov, NCT04466891, is ongoing, and is closed to recruitment. Between Sept 15, 2020, and March 16, 2022, 87 patients were enrolled in HERIZON-BTC-01: 80 in cohort 1 (45 [56%] were female and 35 [44%] were male; 52 [65%] were Asian; median age was 64 years [IQR 58–70]) and seven in cohort 2 (five [71%] were male and two [29%] were female; five [71%] were Asian; median age was 62 years [IQR 58–77]). At the time of the data cutoff (Oct 10, 2022), 18 (21%) patients (17 in cohort 1 and one in cohort 2) were continuing to receive zanidatamab; 69 (79%) discontinued treatment (radiographic progression in 64 [74%] patients). The median duration of follow-up was 12·4 months (IQR 9·4–17·2). Confirmed objective responses by independent central review were observed in 33 patients in cohort 1 (41·3% [95% CI 30·4–52·8]). 16 (18%) patients had grade 3 treatment-related adverse events; the most common were diarrhoea (four [5%] patients) and decreased ejection fraction (three [3%] patients). There were no grade 4 treatment-related adverse events and no treatment-related deaths. Zanidatamab demonstrated meaningful clinical benefit with a manageable safety profile in patients with treatment-refractory, HER2-positive biliary tract cancer. These results support the potential of zanidatamab as a future treatment option in HER2-positive biliary tract cancer. Zymeworks, Jazz, and BeiGene.

S-1 has shown promising efficacy with a mild toxicity profile in patients with advanced biliary tract cancer. The aim of this study was to evaluate whether adjuvant S-1 improved overall survival compared with observation for resected biliary tract cancer. This open-label, multicentre, randomised phase 3 trial was conducted in 38 Japanese hospitals. Patients aged 20–80 years who had histologically confirmed extrahepatic cholangiocarcinoma, gallbladder carcinoma, ampullary carcinoma, or intrahepatic cholangiocarcinoma in a resected specimen and had undergone no local residual tumour resection or microscopic residual tumour resection were randomly assigned (1:1) to undergo observation or to receive S-1 (ie, 40 mg, 50 mg, or 60 mg according to body surface area, orally administered twice daily for 4 weeks, followed by 2 weeks of rest for four cycles). Randomisation was performed by the minimisation method, using institution, primary tumour site, and lymph node metastasis as adjustment factors. The primary endpoint was overall survival and was assessed for all randomly assigned patients on an intention-to-treat basis. Safety was assessed in all eligible patients. For the S-1 group, all patients who began the protocol treatment were eligible for a safety assessment. This trial is registered with the University hospital Medical Information Network Clinical Trials Registry (UMIN000011688). Between Sept 9, 2013, and June 22, 2018, 440 patients were enrolled (observation group n=222 and S-1 group n=218). The data cutoff date was June 23, 2021. Median duration of follow-up was 45·4 months. In the primary analysis, the 3-year overall survival was 67·6% (95% CI 61·0–73·3%) in the observation group compared with 77·1% (70·9–82·1%) in the S-1 group (adjusted hazard ratio [HR] 0·69, 95% CI 0·51–0·94; one-sided p=0·0080). The 3-year relapse-free survival was 50·9% (95% CI 44·1–57·2%) in the observation group compared with 62·4% (55·6–68·4%) in the S-1 group (HR 0·80, 95% CI 0·61–1·04; two-sided p=0·088). The main grade 3–4 adverse events in the S-1 group were decreased neutrophil count (29 [14%]) and biliary tract infection (15 [7%]). Although long-term clinical benefit would be needed for a definitive conclusion, a significant improvement in survival suggested adjuvant S-1 could be considered a standard of care for resected biliary tract cancer in Asian patients. The National Cancer Center Research and the Ministry of Health, Labour, and Welfare of Japan.

Repair of defects in the common bile duct is hampered by a lack of healthy donor tissue. Developing human extrahepatic cholangiocyte organoids and testing them in mouse models may provide a way to overcome this limitation. The treatment of common bile duct (CBD) disorders, such as biliary atresia or ischemic strictures, is restricted by the lack of biliary tissue from healthy donors suitable for surgical reconstruction. Here we report a new method for the isolation and propagation of human cholangiocytes from the extrahepatic biliary tree in the form of extrahepatic cholangiocyte organoids (ECOs) for regenerative medicine applications. The resulting ECOs closely resemble primary cholangiocytes in terms of their transcriptomic profile and functional properties. We explore the regenerative potential of these organoids in vivo and demonstrate that ECOs self-organize into bile duct–like tubes expressing biliary markers following transplantation under the kidney capsule of immunocompromised mice. In addition, when seeded on biodegradable scaffolds, ECOs form tissue-like structures retaining biliary characteristics. The resulting bioengineered tissue can reconstruct the gallbladder wall and repair the biliary epithelium following transplantation into a mouse model of injury. Furthermore, bioengineered artificial ducts can replace the native CBD, with no evidence of cholestasis or occlusion of the lumen. In conclusion, ECOs can successfully reconstruct the biliary tree, providing proof of principle for organ regeneration using human primary cholangiocytes expanded in vitro .

ABSTRACT The global incidence of biliary tract cancer (BTC) is on the rise, presenting a substantial healthcare challenge. The integration of immune checkpoint inhibitors (ICIs) with molecularly targeted therapies is emerging as a strategy to enhance immune responses. However, the efficacy and underlying mechanisms of these treatments in BTC are still largely unexplored. In this study, tissue samples from 19 BTC patients treated with camrelizumab and apatinib were analysed using the NanoString 289‐panel to identify key molecular biomarkers. Comparative analyses and subsequent experimental validations, including cell‐based assays and histopathological examinations, identified adrenomedullin (ADM) as a critical molecular marker associated with treatment efficacy and poor prognosis. ADM has been shown to promote BTC cell proliferation, migration and angiogenesis, primarily by interacting with vascular endothelial growth factor (VEGF) and increasing AKT phosphorylation. Furthermore, ADM disrupts endothelial cell barrier function via the calcitonin receptor‐like receptor (CRLR) and vascular endothelial (VE)‐cadherin signalling pathway. Preclinical inhibition of ADM or CRLR resulted in suppressed tumour growth. Additionally, elevated ADM expression was correlated with increased tumour‐infiltrating immune cells and higher immune checkpoint expression. These findings suggest that ADM plays a pivotal role in resistance to immunotherapy and anti‐angiogenic treatment in BTC, and thus, targeting ADM may offer a promising therapeutic approach to enhance treatment efficacy.