Treatment Of Biliary Tract Cancer Research Articles

64P Phase I/II study of nivolumab plus lenvatinib for advanced biliary tract cancer (JCOG1808/NCCH1817, SNIPE)

Although cisplatin plus gemcitabine and other cytotoxic chemotherapy combinations have improved the survival of advanced biliary tract cancer (BTC) patients (pts), high unmet medical needs remain for the treatment of BTC. Immune checkpoint inhibitors have shown limited efficacy in monotherapy for advanced BTC. Recently, combinations of them with other therapies have shown remarkable efficacy in multiple cancer types. This study aimed to assess the efficacy and safety of nivolumab plus lenvatinib in second-line treatment for advanced BTC.

Real-life analysis of treatment approaches and the role of inflammatory markers on survival in patients with advanced biliary tract cancer

Objectives Advanced stage biliary tract cancers (BTC) are rare malignancies with poor prognosis. There are few prospective trials, but several retrospective studies regarding treatment options. In this study, we aimed to investigate the role of systemic inflammatory parameters (SIP) and other possible independent factors that may affect survival and treatment approaches and to determine the benefit of later-line treatments in these patients. Methods A total of 284 patients, initially diagnosed with advanced stage or progressed after curative treatment of BTC, from different oncology centers in Turkey were included in this retrospective study. The prognostic significance of clinicopathological factors, SIPs and treatment options was analyzed. Results At a median follow-up of 13 months, the median progression-free survival (PFS) was 6.1 months (95% CI:5.51–6.82), and the median overall-survival (OS) time was 16.8 months (95% CI: 13.9–19.6). Treatment choice (p < 0.001 HR:0.70 CI95% 0.55-0.9), performance status (p < 0.001 HR:2.74 CI 95% 2.12-3.54) and neutrophil-to-lymphocyte ratio (NLR) (p = 0.02 HR:1.38 CI 95% 1.03-1.84) were independent prognostic factors for PFS. For OS, the independent prognostic indicators were determined as The Eastern Cooperative Oncology Group Performance Status (ECOG PS) (p < 0.001 HR:1.78 CI 95% 1.5-2.3), Systemic Immune-inflammation Index (SII) (p < 0.001 HR:0.51 CI95% 0.36-0.73) and stage at diagnosis (p = 0.002 HR:1.79 CI 95% 1.24-2.59). Furthermore, second and third line treatments significantly prolonged OS in advanced BTC (p < 0.001 HR:0.55 CI 95% 0.38-0.79; p = 0.007 HR:0.51 CI95% 0.31-0.83, respectively). Conclusion SII and NLR are useful prognostic factors and may be helpful in making treatment decisions. Additionally, second and later-line treatments in advanced BTC have a significant impact on survival under real-life conditions.

Cost-Effectiveness Analysis of Capecitabine Plus Oxaliplatin Versus Gemcitabine Plus Oxaliplatin as First-Line Therapy for Advanced Biliary Tract Cancers.

Background: In the first-line treatment of biliary tract cancers (BTCs), XELOX (capecitabine plus oxaliplatin) showed comparable clinical efficacy and safety to gemcitabine and oxaliplatin (GEMOX), with fewer visits and better treatment management. Our study aims to investigate the cost-effectiveness of XELOX and GEMOX as the first-line therapy for BTCs from the perspective of the Chinese healthcare systems and to provide valuable suggestions for clinical decision-making. Methods: A Markov model was developed using the phase 3 randomized clinical trial (ClinicalTrials.gov number, NCT01470443) to evaluate the cost-effectiveness of XELOX and GEMOX. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were used as the primary outcomes of the model. Uncertainty was assessed using univariate and probabilistic sensitivity analysis. Results: The QALYs for the XELOX and GEMOX groups were 0.66 and 0.54, respectively. In China, the total cost of XELOX treatment is US $12,275.51, which is lower than that of the GEMOX regimen. In addition, XELOX is more effective than GEMOX, making it the preferred regimen. A sensitivity analysis determined that XELOX therapy has a stable economic advantage in China. Conclusion: Compared to GEMOX, XELOX is a more cost-effective treatment as a first-line treatment for advanced BTC from the perspective of the Chinese health service system.

Precision Medicine in Biliary Tract Cancer.

Precision medicine has become a dominant theme in the treatment of biliary tract cancers (BTCs). Although prognosis remains poor, technologies for improved molecular characterization along with the US Food and Drug Administration approval of several targeted therapies have changed the therapeutic landscape of advanced BTC. The hallmark of BTC oncogenesis is chronic inflammation of the liver and biliary tract regardless of the anatomical subtype. Subtypes of BTC correspond to distinct molecular characteristics, making BTC a molecularly heterogenous collection of tumors. Collectively, up to 40% of BTCs harbor a potentially targetable molecular abnormality, and the National Comprehensive Cancer Network guidelines recommend molecular profiling for all patients with advanced BTC. Use of circulating tumor DNA, immunohistochemistry, and next-generation sequencing continues to expand the utility for biomarker-driven management and molecular monitoring of BTC. Improving outcomes using biomarker-agnostic treatment for nontargetable tumors also remains a priority, and combinational treatment strategies such as immune checkpoint inhibition plus chemotherapy hold promise for this subgroup of patients.

Triple therapy in biliary tract cancers: GemOX plus immune checkpoint inhibitor in combination with lenvatinib or NGS-guided targeted therapy.

The combination of gemcitabine-based chemotherapy and immune checkpoint inhibitors has a good efficacy in advanced biliary tract cancer (BTC). The multi-target TKI lenvatinib and NGS-guided targeted therapy are also promising in BTC treatment. This study aimed to explore the performance of GemOX plus sintilimab and TKI (either lenvatinib or by NGS-guided targeted therapy) for local advanced or metastatic BTCs. This prospective single-arm study included patients with local advanced or metastatic BTCs and applied intravenous infusion of standard GemOX plus sintilimab and lenvatinib (no targetable gene alterations) or targeted therapy based on NGS (olaparib for BRCA1/2 mutation, dasatinib for IDH1/2 mutation, afatinib for EGFR amplification, lenvatinib for PDGFR and KIT mutation, and lenvatinib for FGFR/KIT mutation). From November 2020 to December 2021, 22 patients BTCs (6 GBC, 14 iCCA, 1 pCCA and 1 dCCA cases) were enrolled, with an average age of 58.4years. Partial response (PR) was achieved in 10 cases, stable disease (SD) in 9 cases and progression disease (PD) in 3 cases (13.6%). The objective response rate (ORR) was 45.5%, and the disease control rate (DCR) was 86.4%. During the treatment, the incidence of adverse reactions was 81.8%, and the incidence of grade 3/4 adverse events was 9.09%. For 14 patients with NGS, 5 patients were treated by targeted therapy and there were 1 SD and 4 PR cases. For four patients with positive PD-L1 expression, the ORR was 100%. While among the three patients with super-progression markers such as RET, MDM2 and FGF14/STK24, there were two SD and one PD cases. In patients with advanced BTCs, the combination of GemOX plus sintilimab and lenvatinib or NGS-guided targeted therapy showed promising ORR and DCR, especially for the patients with positive PD-L1 expression and targetable gene alterations.

Abstract 5098: Genetic and immunologic characteristics of biliary tract cancer patients with LRP1B mutation

Abstract Background: Although the initial clinical results of immune checkpoint inhibitors (ICI) have been obtained in biliary tract cancer (BTC), and previous researches explored potential biomarkers for predicting response to ICI in BTC, and gene LRP1B was found as one of predictive biomarkers. Here we evaluated the mutation information of LRP1B in Chinese patients with BTC, and analyzed the potential explanation for more benefit from ICI treatment in patients with LRP1B mutation. Methods: The formalin-fixed paraffin-embedded specimens of 1324 cancer patients who have underwent next-generation sequencing (NGS) from 2016 to 2021, were included in this study. NGS was performed to detect gene mutation, and tumor mutational burden (TMB) measured by a 733 gene panel. PD-L1 expression detected by using Dako PD-L1 IHC 22C3 pharmDx. Result: The NGS results revealed that 12.76% (169/1324) patients with BTC have LRP1B mutation. Among these 1324 patients, 931 (patients with or without LRP1B mutations were 129 and 802, respectively) patients were available for analysis of TMB level, 820 ((patients with or without LRP1B mutations were 114 and 706, respectively)) patients for analysis of PD-L1 expression, and 1163 (patients with or without LRP1B mutations were 172 and 991, respectively) patients for analysis of MSI-H. TMB level and PD-L1 expression level were compared between groups with and without LRP1B mutation, and results showed that both these two biomarkers were higher in group with LRP1B mutation than without LRP1B mutation, especially TMB level was significantly higher (p&amp;lt;0.001).Further analysis revealed that the median TMB level, proportion of strong positive PD-L1 expression, and proportion of MSI-H were all higher in group of LRP1B mutation than wild type. Conclusion:These results suggest that LRP1B can be considered as one of effective biomarkers for ICI treatment in BTC, the underly mechanism may be related to the high TMB level. Citation Format: Weiwei Chen, Hushan Zhang, Hongmin Dong, Gang Wang, Xiaokai Li, Wanghua Chen, Guodong Li, Saixi Bai, Juan Chen, Wenling Wang. Genetic and immunologic characteristics of biliary tract cancer patients with LRP1B mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5098.

Evaluation of risk factors for chemotherapy-induced nausea and vomiting in cisplatin and gemcitabine treatment for biliary tract cancer: acid suppressants do not prevent nausea.

Chemotherapy-induced nausea and vomiting (CINV) is one of the most serious adverse effects of cancer therapy. Cancer patients frequently use acid suppressants (AS) for palliation of gastrointestinal symptoms associated with malignancy and/or anticancer therapy. AS are suggested as an additional option for CINV management in several antiemetic guidelines, although their efficacy remains unknown. The aim of this study was to determine whether AS administration affects CINV incidence in cisplatin and gemcitabine treatment for biliary tract cancer. The primary endpoint was to evaluate whether AS administration was associated with the incidence of all-grade nausea in the first administration by logistic analysis. The secondary endpoints were to assess factors associated with anorexia. Prophylactic antiemetics were based on current guidelines. Nausea occurred in 34.2% of patients (grade 1, 31.7%; grade 2, 2.5%). Patients exhibiting vomiting and anorexia represented 4.2% and 39.1%, respectively, without grade 3/4 symptoms. Multivariate analysis suggested that the independent risk factors for nausea as female sex, and no- or less-alcohol drinking habit and regular narcotics administration were associated with anorexia. In contrast, AS administration was not associated with nausea and anorexia incidence (odds ratio, 95% confidence interval: 1.43, 0.64-3.23; P =0.38 for nausea, 1.62, 0.71-3.68; P =0.25 for anorexia). In conclusion, we found that AS administration is not associated with CINV incidence, and female sex is a risk factor for nausea, and non-alcohol drinking habits and regular narcotic use are factors associated with anorexia in cisplatin and gemcitabine treatment for biliary tract cancer. We should correctly administer AS depending on the patient's situation. Successful CINV management needs effective monitoring and administration of prophylactic antiemetics and counter-measure medicines for patients at risk.

Efficacy and safety of anlotinib with PD-1 blockades in the treatment of advanced biliary tract cancer: A real-world study.

e16129 Background: Several clinical trials have demonstrated that antiangiogenic drugs combined with PD-1 blockades are effective for patients with advanced biliary tract cancer (BTC). However, the efficacy of this combination in real-world patients needs to be explored. Anlotinib is a novel oral multi-targeted tyrosine kinase inhibitor for tumor angiogenesis and proliferation, which had been licensed for treatment of considerable malignancies in China. The aim of this study was to investigate the efficacy and safety of anlotinib combined with PD-1 blockades in the treatment of advanced BTC in real world. Methods: This is a multi-center prospective real-world study. Patients with advanced BTC receiving anlotinib combined with PD-1 blockades were recruited. Clinical efficacy was summarized, and adverse events were documented. Tumor response was assessed by investigator according to RECIST version 1.1. The primary endpoint was overall survival (OS), secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and safety. Results: From May 2020 to Sep 2021, a total of 14 eligible pts were recruited. 1 patient was in stage IIIa, 4 pts in stage IIIb, and 9 pts in stage IV. Among them, 10 pts received anlotinib as first-line treatment, 3 pts as second-line treatment and 1 pts as third-line treatment. DCR was 85.71% (57.19%, 98.22%). At the data cut-off date, 7 pts discontinued treatment due to disease progression, the preliminarily prognostic results indicated that the median OS was 8.21 months (95%CI: 5.88, NA) and the median PFS of the 14pts was 6.28 months (95%CI: 3.17-8.21). The safety profile suggested that the most common drug-related adverse events were hypertension (21.43%), decreased white blood cell count (21.43%), decreased platelet count (21.43%), hypoalbuminemia (14.29%), vomit (14.29%), gastrointestinal bleeding (14.29%). The common grade 3 adverse event were gastrointestinal bleeding (7.14%), anemia (7.14%), biliary infection (7.14%). Conclusions: Present study indicated that the combination of anlotinib and PD-1 blockades exhibited potential efficacy and manageable adverse events in the treatment of advanced BTC in the real world. The conclusion should be validated in more patients included subsequently. Clinical trial information: NCT04954521.

Toripalimab combined with gemcitabine and S-1 in the first-line treatment of advanced biliary tract cancer.

4081 Background: Gemcitabine combined with platinum/fluorouracil drugs is the standard first-line treatment for advanced biliary tract cancers (BTCs), but the overall effect needs to be further improved. This study intended to explore the safety and efficacy of toripalimab combined with chemotherapy in the first-line treatment of advanced BTCs. Methods: This single-arm, phase II clinical trial enrolled patients with advanced BTCs who had not received systemic treatment. Toripalimab combined with chemotherapy were applied as first-line treatment: toripalimab (240 mg, iv, d1), gemcitabine (1000 mg/m2, iv, d1&amp;d8), and S-1 (40-60mg bid po, d1-14, Q21d). The primary endpoint was progression-free survival (PFS), and the secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR) and safety. The study explored the association between response with PD-L1 expression, tumor mutational burden (TMB) and genetic variations identified by next-generation sequencing (NGS) of peripheral blood. Results: 50 patients were enrolled from January 2019 to August 2021 with a median follow-up time of 24.0 months (4.3-31.0). The median PFS was 7.0 months (95%CI: 5.0-8.9 months); median OS was 15.0 months (95%CI: 11.6-18.4 months). Of the 49 patients who completed the evaluation for tumor response, the ORR was 30.6% (95%CI: 17.2%-44.0%), and the disease control rate was 87.8% (95%CI: 78.2%-97.3%). The most common treatment-related adverse events (TRAEs) were leukopenia (98.0%), neutropenia (92%), and anemia (86.0%). Grade III/IV TRAEs included leukopenia (38.0%), neutropenia (32%), skin rash (6%), anemia (2.0%), mucositis (2%) and immune-related colitis (2%).Among them, the Grade III/IV immune-related adverse events irAEs) worthy of attention included were skin rash and immune-related colitis. There was no significant difference in PFS and OS among intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma and gallbladder cancer. Exploratory study showed that patients with CPS≥1 had longer PFS. However, there was no significant correlation between TMB and PFS. Conclusions: Toripalimab combined with gemcitabine and S-1 (GS) has shown good safety in the first-line treatment of advanced BTCs. Although the primary endpoint did not reach the preset goal, toripalimab plus GS as first-line treatment has shown encouraging data of PFS and OS in patients with advanced BTC, which is worthy for further verification. Biomarker analysis showed that the expression level of PD-L1 could predict the curative effect. Clinical trial information: NCT03796429.

Systematic literature review and meta-analysis of clinical outcomes for previously-treated patients with advanced biliary tract cancer.

e16143 Background: There is no standard chemotherapy available for previously treated, advanced (unresectable and/or metastatic) biliary tract cancer (BTC). This systematic literature review and meta-analysis were conducted to assess clinical outcomes of chemotherapies in this patient population. Methods: A systematic literature search was conducted through mid-2021 to identify relevant studies using Embase, MEDLINE, and Cochrane Central Register of Controlled trials (January 1, 2000–July 6, 2021) with additional searches of recent ASCO and ESMO conferences. Eligible study designs included randomized controlled trials, controlled clinical trials, and non-randomized clinical trials in patients (≥18 years age, Eastern Cooperative Oncology Group performance score 0 or 1) previously treated for advanced BTC and who had progressed on prior treatment (i.e., ≥2L). The outcomes of interest were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). A meta-analysis among chemotherapies was performed to obtain a pooled estimate of the efficacy of standard treatments in BTC. The ORR meta-analysis was performed using the Freeman-Tukey double arcsine transformation. For time-to-event outcomes, published Kaplan-Meier curves for OS and PFS were digitized to create pseudo- individual patient data. A meta-analysis of the resulting pooled survival curves for OS and PFS were conducted following the methodology of Combescure et al. (2014). Results: In total, 39 unique studies were identified. Seventeen studies representing 22 unique therapy arms evaluating chemotherapies among 903 patients were included in the meta-analysis for ORR. The random effects pooled estimate for ORR was 6.6% (95% confidence interval [CI]: 4.1-9.7%). Median PFS (12 studies; 16 survival curves) was 3.1 months (95% CI: 2.5-3.8) with PFS rates at 6 and 12 months of 26.7% (95% CI: 19.8-36%) and 6.9% (95% CI: 4.1-11.7%), respectively. Median OS (15 studies; 19 survival curves) was 6.8 months (95% CI: 5.9-7.5) with OS rates at 6, 12, and 24 months of 55.3% (95% CI: 49.9-61.3%), 24.6% (95% CI: 20.0-30.2%), and 2.0% (95% CI: 1.1-3.8%), respectively. Conclusions: The limited efficacy of clinical outcomes for chemotherapies used in the treatment of advanced BTC suggest an opportunity to explore the potential clinical benefits of newer treatments (e.g., immunotherapies).

Trastuzumab plus FOLFOX for gemcitabine/cisplatin refractory HER2-positive biliary tract cancer: A multi-institutional phase II trial of the Korean Cancer Study Group (KCSG-HB19-14).

4096 Background: HER2 over-expression/amplification, which accounts for roughly 15% of total biliary tract cancer (BTC) patients, has been identified as a druggable molecular target by recent genomic profilings, Trastuzumab is a humanized monoclonal antibody against HER2 that has been shown to be effective in patients with HER2-positive breast and gastric cancer, but it has not been studied prospectively in HER2-positive BTC. In the phase III ABC-06 trial, the FOLFOX regimen showed survival benefit as a second-line therapy of BTC. We report the result of a multi-institutional phase II trial of Trastuzumab plus modified-FOLFOX as a second- or third-line treatment for HER2-positive BTC (KCSG-HB19-14; NCT04722133). Methods: HER2-positive (defined as IHC3+ or IHC2+/ISH+ or ERBB2 gene copy number ≥6.0 by NGS) BTC (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer and ampulla of vater cancer) patients who progressed on gemcitabine/cisplatin containing chemotherapy (1 or 2 previous chemotherapy lines permitted) were enrolled. Pts received trastuzumab 4mg/kg (after 6mg/kg load) D1, oxaliplatin 85mg/m2 D1, Leucovorin 200mg/m2 D1, 5-FU 400mg/m2 bolus D1, and 5-FU 2400mg/m2 infusion D1-2 every 2 weeks until unacceptable toxicities or disease progression. The primary endpoint was ORR per RECIST v1.1. Secondary endpoints included PFS, DCR, OS, safety, QOL and correlative biomarker exploration. Results: Total of 34 pts were treated with median follow up of 9.9 months, and 6 pts remained on treatment (treatment duration range: 1.0 to 14.7 months). The primary endpoint was met, with 29.4% (95%CI 15.1-47.5) ORR (PR n = 10), and 79.4% DCR. Median PFS was 5.1 months (95%CI 3.6-6.7) and median OS was not reached (95%CI 7.1-NR; 12-months OS rate 50.6%, 95%CI 29.3-63.6). Pts with HER2 IHC3+ (n = 23, 67.6%) showed tendency for better PFS compared to pts with HER2 IHC 2+/ISH+ (median 5.5 vs 4.9 months, HR 0.52, 95%CI 0.23-1.16). Pts with HER2 3+ tumor cell proportion ≥30% (n = 10) by an artificial intelligence-powered automated HER2 IHC analyzer (Lunit SCOPE HER2) showed significantly better PFS compared to pts without (median 6.67 vs 4.87 months, HR 0.33 95%CI 0.13-0.88). Targeted-panel sequencings were done with tumor tissues from 32 pts and tissue HER2-amplification by NGS did not confer better survival. Treatment-related AE (≥G3) occurred in 29 pts (85.3%) including 19 pts (55.9%) with neutropenia G3-4 and 4 pts (11.8%) with peripheral neuropathy G3-4. No pt showed cardiac AE nor treatment-related study discontinuation. Conclusions: For HER2-positive BTC, 2nd- or 3rd-line trastuzumab plus FOLFOX exhibited a promising efficacy with acceptable toxicity, warranting further investigations. Targeted NGS analyses with ctDNAs from pre-treatment and post-progression liquid biopsies are ongoing. Clinical trial information: NCT04722133.

Cell-Free Tumor DNA Dominant Clone Allele Frequency Is Associated With Poor Outcomes in Advanced Biliary Cancers Treated With Platinum-Based Chemotherapy.

This investigation sought to evaluate the prognostic value of pretreatment of circulating tumor DNA (ctDNA) in metastatic biliary tract cancers (BTCs) treated with platinum-based first-line chemotherapy treatment. We performed a retrospective analysis of 67 patients who underwent ctDNA testing before platinum-based chemotherapy for first-line treatment for metastatic BTC. For analysis, we considered the detected gene with highest variant allele frequency as the dominant clone allele frequency (DCAF). Results of ctDNA analysis were correlated with patients' demographics, progression-free survival (PFS), and overall survival (OS). The median age of patients was 67 (27-90) years. Fifty-four (80.6%) of 67 patients evaluated had intrahepatic cholangiocarcinoma; seven had extrahepatic cholangiocarcinoma, and six gallbladder cancers. Forty-six (68.6%) of the patients were treated with cisplatin plus gemcitabine, and 16.4% of patients received gemcitabine and other platinum (carboplatin or oxaliplatin) combinations, whereas 15% of patients were treated on a clinical trial with gemcitabine and cisplatin plus additional agents (CX4945, PEGPH20, or nab-paclitaxel). TP53, KRAS, FGFR2, ARID1A, STK11, and IDH1 were the genes with highest frequency as DCAF. The median DCAF was 3% (0%-97%). DCAF > 3% was associated with worse OS (median OS: 10.8 v 18.8 months, P = .032). Stratifying DCAF in quartiles, DCAF > 10% was significantly related to worse PFS (median PFS: 3 months, P = .014) and worse OS (median OS: 7.0 months, P = .001). Each 1% increase in ctDNA was associated with a hazard ratio of 13.1 in OS when adjusting for subtypes, metastatic sites, size of largest tumor, age, sex, and CA19-9. DCAF at diagnosis of advanced BTC can stratify patients who have worse outcomes when treated with upfront platinum-based chemotherapy. Each increase in %ctDNA decreases survival probabilities.

The potential use of blood-based tumor fibrosis markers as diagnostic and prognostic biomarkers in patients with biliary tract cancer.

4082 Background: Patients with biliary tract cancer (BTC) have a very poor prognosis. A better understanding of the disease and potential novel biomarkers are needed. BTC is characterized by a collagen-rich desmoplastic extracellular matrix (ECM), and tumor fibrosis is linked to cancer progression and treatment resistance. We tested the diagnostic and prognostic use of seven circulating biomarkers associated with ECM remodeling. We evaluated both pro-peptides (pro-peptide of collagen type III (Pro-C3), VI (PRO-C6), XI (PRO-C11)) and degradation fragments (matrix metalloproteinase (MMP) degraded collagen type III (C3M) and IV (C4M), granzyme B degraded collagen type IV (C4G), citrullinated and MMP degraded vimentin fragment (VICM)). Methods: The study included 269 patients with all stages of BTC (intrahepatic cholangiocarcinoma (CC) (n=124), extrahepatic CC (n=89), and gall bladder cancer (n=56)), and 49 patients with benign biliary tract disease. Serum samples were collected from the patients with BTC before surgery (n=36), 1st line (n=199), and 2nd line (n=56) treatment. A total of 22 patients had samples collected at two timepoints. The seven ECM markers and carbohydrate antigen 19-9 (CA19-9) were analyzed using enzyme-linked immunosorbent assay (ELISA) and electrochemiluminescence immunoassay. Results: The levels of C3M, C4M, PRO-C3, PRO-C6, PRO-C11, and VICM were significantly elevated in patients with BTC compared to patients with benign disease (Wilcoxon test, adjusted p-value &lt; 0.05). Area under receiver operating characteristics curve (AUC) identified PRO-C3 (AUC=0.87) as the ECM marker that best discriminated between patients with BTC and controls. A model combining PRO-C3 and CA19-9 further improved the diagnostic accuracy (AUC=0.97). Elevated levels of four markers (C3M, C4M, PRO-C3 and PRO-C6) before 1st line treatment for BTC were associated with short overall survival (OS) in separate multivariate cox regression analyses adjusting for CA19-9, performance status, and stage. Similarly, elevated levels of PRO-C3 and PRO-C6 before 2nd line treatment were associated with short OS (Table). Conclusions: We identified specific blood-based collagen fragments as potential novel biomarkers for BTC. Our results indicate that patients with BTC have an elevated collagen remodeling, and that increased collagen turnover is associated with a poor prognosis for these patients. [Table: see text]

P-72 Real-world treatments and outcomes for biliary tract cancer patients using administrative databases in Ontario, Canada

There is a paucity of literature on treatment patterns and outcomes in biliary tract cancer (BTC) patients in Canada. The aim of this study was to better understand treatment patterns and survival outcomes of BTC patients in Ontario. We conducted a retrospective population-level study in Ontario using ICES datasets on patients diagnosed with de novo or recurrent, advanced BTC (including: gallbladder cancer, intrahepatic and extrahepatic cholangiocarcinoma [IHC and EHC, respectively], Ampulla of Vater [AoV]) between January 1, 2010 and December 31, 2019. Follow-up data were available until December 31, 2020. Patients were categorized as de novo if they had stage IV disease at the time of first diagnosis, and as recurrent if they had a prior diagnosis of early stage (I-III) or unknown/missing (UNK/M) disease and received a BTC treatment (proxy for progression). Patients were excluded if they died before BTC diagnosis or had a prior cancer diagnosis. To determine the longitudinal trajectory of care for BTC patients, linkages were made between 8 national/provincial data sets. A total of 2,666 advanced BTC patients were identified, of which 471 (17.7%) were gallbladder, 785 (29.4%) were IHC, 864 (32.4%) were EHC, 304 (11.4%) were AoV and 242 (9.1%) had an unspecified BTC diagnosis. Out of 2,666, 828 (31.1%) were diagnosed with de novo and 1,838 (68.9%) were diagnosed with recurrent disease. The median age at diagnosis was 67 (interquartile range [IQR] 59-74) that significantly (p<0.001) varied between de novo and recurrent patients, and a majority (50.5%) of the patients were male. A total of 2,307 (86.5%) patients received first-line (1L) treatment. The most common 1L treatments were a platinum and gemcitabine combination – cisplatin and gemcitabine ( gem/cis ) (50.1%) and carboplatin and gemcitabine ( gem/carbo) (4.9%), followed by gemcitabine monotherapy ( gemmono ) (17.5%), and capecitabine- or fluorouracil-based treatments (fluoropyrimidine [ FP ]) (16.5%). For AoV patients, the most common 1L treatment was gemmono (47.6%). Of those treated with 1L treatments, 38.7% received subsequent treatment(s). The most common treatment in second line (2L) was FP (32.1%). Among the 2,307 treated patients, 1,132 (49.1%) of patients received a stenting procedure. The mean (standard error [SE]) and median (IQR) overall survival (OS) for all advanced BTC patients from diagnosis was 28.8 months (0.83) and 13.1 months (5.7-32.0), respectively. Mean and median OS from diagnosis was longer for patients who received a 1L treatment (32.3 months [0.93] and 16.4 months [IQR 7.8-37.0], respectively) versus untreated patients (6.2 months [0.71] and 2.8 months [1.7-5.6], respectively). Mean and median OS from initiation of treatment was 16.7 months [0.71] and 9.2 months (IQR 4.0-18.9), respectively for non-AoV patients who received gem/cis. This is the first comprehensive, Canadian-specific, real-world evidence study of advanced BTC patients. This study showed that 1L treatment options vary between AoV and non-AoV BTC patients, and patients who receive 1L treatment have greater survival than those who do not. The short OS in advanced BTC patients highlight the need for novel and more effective first-line therapies.

Lymphadenectomy and margin-negative resection for biliary tract cancer surgery in the United States-Differential technical performance by approach.

As minimally invasive surgery (MIS) approaches to biliary tract cancers become more commonplace, understanding the adequacy of their oncologic performance is key. The National Cancer Database 2010-2016 was queried for patients who underwent hepatectomy for intrahepatic cholangiocarcinoma (IHC) and T1b or more advanced gallbladder cancer (GBC). Patients were grouped by approach: open (OA), laparoscopic (LA), and robotic (RA). Margin status, rate of lymph node (LN) dissection, and yield of LN dissection were evaluated. This cohort of 8612 patients, including 4034 patients with IHC (OA: 3281, LA: 675, RA: 78) and 4578 patients with GBC (OA: 1893, LA: 2588, RA: 97), MIS was used 40% of the time. R0 resection was achieved in 82% OA, 84% LA, and 91% RA, p = 0.004. Rate of LN dissection was 53% (OA: 60%, LA: 42%, RA: 51%, p < 0.001). Among patients who underwent lymphadenectomy, 6 + LN were retrieved less commonly with a LA (OA: 27%, LA: 20%, and RA: 30%, p < 0.001). High-volume MIS hepatectomy centers were more likely to perform a lymphadenectomy (odds ratio [OR]: 1.41) and a sampling of 6 + LN (OR: 1.18). Regardless of approach, lymphadenectomy is underperformed nationwide for biliary tract tumors, particularly with LA. As the use of MIS grows for the treatment of biliary tract cancers, scrutiny of oncologic outcomes is required.

Toripalimab in advanced biliary tract cancer

Gemcitabine combined with platinum/fluorouracil drugs is the standard first-line treatment for advanced biliary tract cancers (BTCs). We explored the safety and efficacy of toripalimab plus gemcitabine and S-1 (GS) as the first-line treatment for advanced BTCs. At a one-sided significance level of 0.025, a total of 50 patients could provide 80% power to show the efficacy at targeted progression-free survival (PFS) rate at 6 months of 70% versus 40% for the combined treatment. This single-arm, phase II study enrolled 50 patients with advanced BTCs who previously received no systemic treatment. The regimen was as follows: toripalimab (240 mg, i.v., d1), gemcitabine (1,000 mg/m2, i.v., d1 and d8), and S-1 (40–60 mg bid p.o., d1–14, Q21d). The primary endpoint was progression-free survival. The secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR), and safety. The associations between response with PD-L1 expression, tumor mutational burden (TMB), and genetic variations were explored. Patients were enrolled from January 2019 to August 2020, with a median follow-up time of 24.0 months (IQR: 4.3–31.0 months). The 6-month PFS rate was 62%. The median PFS was 7.0 months (95% CI: 5.0–8.9 months), and median OS was 15.0 months (95% CI: 11.6–18.4 months). Forty-nine patients completed the evaluation for tumor response. The ORR was 30.6% (95% CI: 17.2%–44.0%), and the disease control rate was 87.8% (95% CI: 78.2%–97.3%). The most common treatment-related adverse events (TRAEs) were leukopenia (98.0%), neutropenia (92%), and anemia (86.0%). Grade III/IV TRAEs included leukopenia (38.0%), neutropenia (32%), skin rash (6%), anemia (2.0%), mucositis (2%), and immune-related colitis (2%). Among them, the grade III/IV immune-related adverse events (irAEs) were skin rash and colitis. In addition, biomarker analysis showed that negative PD-L1 expression and SMARCA4 mutation were significantly associated with worse survival outcomes, while no significant associations were observed for TP53, KRAS, or CDKN2A mutation as well as TMB. In conclusion, our data suggest that a regimen of toripalimab plus GS could improve PFS and OS with a good safety profile as a first-line treatment option for advanced BTC and warrants further verification.

Immunotherapy in the Treatment of Biliary Tract Cancer: The Future?

Biliary tract cancer is known for its dismal prognosis, both due to late diagnosis as well as to the short width span of therapeutic options available. Although much more common in Asian countries, the number of patients with these tumours has been rising in European and American countries, mainly due to the increased rates of chronic hepatic diseases. Currently the only curative treatment revolves around surgical resection, although only possible in roughly 10-15% of patients. First line systemic therapies include chemotherapy with gemcitabine and cisplatin, unfortunately with also poor results with a 5-year survival rate of only 10-20%. With this in mind, the need for other therapeutic options has been proved, with the rising popularity of immunotherapy leading to several studies analysing the use of immune checkpoint inhibitors in the treatment of patients with biliary tract cancer.

Individual patient data meta-analysis of adjuvant gemcitabine-based chemotherapy for biliary tract cancer: combined analysis of the BCAT and PRODIGE-12 studies

BackgroundAlthough gemcitabine-based chemotherapy is the standard of care for advanced biliary tract cancers (BTCs), adjuvant phase III studies (BCAT in Japan, PRODIGE 12 in France) failed to show benefit, possibly owing to fewer patients (n = 225 and n = 194) compared with the adjuvant capecitabine BILCAP trial (n = 447). We performed a combined analysis of both gemcitabine-based chemotherapy adjuvant studies. MethodsWe performed individual patient data meta-analysis of all patients included in BCAT and PRODIGE 12. BCAT study randomised patients with extrahepatic cholangiocarcinoma to single-agent gemcitabine or observation. PRODIGE 12 randomised patients with all BTC subtypes to gemcitabine-oxaliplatin combination or observation. Combined analysis was performed using Kaplan–Meier curves and a Cox regression model stratified on the trial. ResultsTwo hundred and twelve versus 207 patients were randomised in the gemcitabine-based chemotherapy versus observation arms. Baseline characteristics were balanced between arms. The median follow-up was 5.5 years. After 258 relapse-free survival (RFS) events, there was no difference in RFS (log-rank p = 0.45; hazard ratio [HR] = 0.91 [95% confidence interval [CI] 0.71–1.16]; p = 0.46). RFS rates at five years were 40.8% (95%CI: 33.9%–47.5%) for gemcitabine-based chemotherapy versus 36.6% (95%CI: 29.8%–43.4%) for observation. After 201 deaths, there was no difference in overall survival (OS) (log-rank p = 0.83; HR = 1.03 [95%CI: 0.78–1.35]; p = 0.85). OS rates at five years were 50.5% (95%CI: 43.1%–57.4%) for gemcitabine-based chemotherapy versus 49.3% (95%CI: 41.6%–56.5%) for observation. ConclusionWith 419 patients included, this analysis did not show significant improvement in RFS and no trend in improvement in OS. Gemcitabine-based chemotherapy should not be used as an adjuvant treatment for BTC.

Systemic Treatment for Metastatic Biliary Tract Cancer: State of the Art and a Glimpse to the Future.

Recent years have seen some breakthroughs in the therapeutic landscape of advanced biliary tract cancer (BTC). Firstly, a better understanding of the molecular background of BTC has led to important improvements in the management of these hepatobiliary malignancies, with the advent of targeted agents representing an unprecedented paradigm shift, as witnessed by the FDA approval of pemigatinib and infigratinib for FGFR2-rearranged and ivosidenib in IDH1-mutant cholangiocarcinoma. In addition, several novel treatments are under assessment, including immune checkpoint inhibitors and combination chemotherapies. In the current review, we provide an overview of systemic treatment for metastatic BTC, summarizing recent clinical data on chemotherapy as well as the main results of targeted therapies and immunotherapy.

Emerging treatment evolutions and integrated molecular characteristics of biliary tract cancers.

Biliary tract cancers (BTCs) consist of a group of highly heterogeneous malignancies that are characterized by genomic differences among tumors from different anatomic sites. The current treatment for BTC includes surgery, chemotherapy, target therapy, and immunotherapy. Although surgery remains the primary option for localized disease, representing the only potential curative treatment, a high risk of recurrence cannot be neglected. Chemotherapy has been considered the standard of care for both advanced and metastatic disease and in adjuvant settings. However, drug resistance is a major obstacle associated with chemotherapy. The development of genetic testing technologies, including next‐generation sequencing, has opened the door for the identification of drug targets and candidate molecules. A series of preclinical studies has demonstrated the role of gene mutations, abnormal signaling pathways, and immunosuppression in the pathogenesis of BTC, laying the foundation for the application of targeted therapy and immunotherapy. A variety of molecularly targeted agents, including pemigatinib, have shown promising survival benefits in patients with advanced disease. The rapidly evolving role of multimodal therapy represents the subject of this review.