Biliary Tract Cancer

For decades, the combination of gemcitabine with cisplatin (GemCis) has been the standard of care for palliative treatment. Due to the high frequency of targetable genetic alterations in BTC patients, there is a growing emphasis on obtaining tissue or liquid biopsy samples to identify markers like microsatellite instability and other actionable oncogenic driver genes. Early initiation of systemic therapies in combination with multimodal approaches is essential for maximizing survival outcomes in patients with BTC.

Collaboration between nephrologists and oncologists is crucial for optimizing treatment benefits and managing side effects. Further research is warranted to refine management strategies and to understand the clinical implications of hyperphosphatemia.

In the expert opinion, we discuss the problem of the scarcity of patients eligible for target therapies and how can clinical trials be designed to overcome this challenge. We also summarize the most promising trials that have the potential to change clinical practice both for immunotherapies and target drugs.

The data presented in this study are consistent with the results of TOPAZ1 trial. However about a third of patients do not respond to CHT or have a short response duration. In our experience both NLR and basal elevated AST/ALT seem to be associated with an improved mPFS and a better outcome but further studies are needed.

Among pts with EMP available, 64.2% had intrahepatic cholangiocarcinoma and 69.8% received CT1 (36.1% cisplatinum-gemcitabine). Despite a broader availability of EMP in advanced BTC in recent years, access to TT remains suboptimal even in referral Institutions. Our results demonstrate TT administration as a pivotal positive prognostic factor in a real-world setting, whilst FGFR2 or IDH1 alterations did not act as prognostic determinants per-se. Therefore, strategies aiming at improving the rate of patients receiving TT are warranted.

This report supports the clinical benefit of anti-EGFR antibodies for EGFR-amplified biliary tract cancers and the importance of genomic analysis in personalized therapy and drug resistance research.

Here, we developed a catalog of BTC PDXs which underwent comprehensive molecular profiling and therapeutic modeling. To date, this is one of the largest collections of BTC PDX models and will facilitate the development of personalized treatments for patients with these aggressive malignancies.

P1/2, N=368, Recruiting, Innovent Biologics (Suzhou) Co. Ltd. | Not yet recruiting --> Recruiting | Trial completion date: Jul 2025 --> Oct 2025 | Trial primary completion date: Oct 2024 --> Apr 2025

P3, N=68, Completed, Krankenhaus Nordwest | Recruiting --> Completed | N=300 --> 68

P2, N=54, Not yet recruiting, The second hospital of Lanzhou University; The second hospital of Lanzhou University

P2, N=38, Not yet recruiting, Shanghai Eastern Hepatobiliary Surgery Hospital; Shanghai Eastern Hepatobiliary Surgery Hospital

P2, N=27, Not yet recruiting, West China Hospital of Sichuan University; West China Hospital of Sichuan University

The most frequent grade 3 or 4 treatment-related adverse event was neutropenia (n = 4, 29%). The combination of camrelizumab, gemcitabine, and apatinib showed promising efficacy and acceptable safety in patients with advanced PD-L1-positive biliary tract cancer.

P=N/A, N=360, Recruiting, Cedars-Sinai Medical Center | Trial primary completion date: Jun 2025 --> Jan 2026

P2/3, N=206, Not yet recruiting, Sun Yat-sen University

Ferroptosis inhibitor Fer-1 administration could reverse the beneficial effects caused by Rg3 treatment while ferroptosis inducer Erastin treatment enhanced the effects...Rg3 inactivated the circFOXP1-miR-4477a-PD-L1 signaling axis to activate the immune function of CD8+ T cells, thereby inducing ferroptosis and apoptosis in GBC cells. This research recognizes the mechanism of Rg3-mediated anti-cancer effect and offers evidence for the potentiality of Rg3 in clinical application for GBC therapy.

P=N/A, N=60, Recruiting, Jiangsu Healthy Life Innovation Medical Technology Co., Ltd | Not yet recruiting --> Recruiting

P2, N=30, Not yet recruiting, Tianjin Medical University Cancer Institute and Hospital

Among patients with advanced BTC, ctDNA-based genotyping showed acceptable concordance with tissue genomic profiling. Liquid biopsy using ctDNA could be a valuable complement to tissue-based genomic analysis in BTC.

P2, N=23, Not yet recruiting, Fujian Cancer Hospital

P3, N=452, Active, not recruiting, SWOG Cancer Research Network | Trial completion date: Jul 2024 --> Oct 2024

P=N/A, N=50, Not yet recruiting, Tongji Hospital

P1/2, N=320, Recruiting, Suzhou Transcenta Therapeutics Co., Ltd. | Trial completion date: Nov 2024 --> May 2025 | Trial primary completion date: Aug 2024 --> Feb 2025

P1, N=90, Active, not recruiting, Fujifilm Pharmaceuticals U.S.A., Inc. | Recruiting --> Active, not recruiting | Trial completion date: Jun 2025 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Jun 2025

P2, N=74, Active, not recruiting, Jazz Pharmaceuticals | Trial primary completion date: Aug 2024 --> Jul 2025

P=N/A, N=100, Recruiting, CHA University

Malignant cell states co-varied with distinct immune cell states, revealing diverse mechanisms of myeloid and T-cell mediated immune suppression, including M2 myeloid and terminally exhausted T cell programs that were induced by DKN-01/nivolumab. Here, we provide the first systematic classification of functionally annotated cell states in biliary tract cancer and provide new insight into resistance mechanisms to an immunotherapy combination that can inform the next generation of trials.

These results underline the potential use of SLC7A5/LAT1 as a prognostic marker in BTC. Furthermore, the higher frequency of SLC7A5/LAT1 positive immune cells in PSC-BTC compared to sBTC may hint at the potential role of SLC7A5/LAT1 in inflammation-driven carcinogenesis.

Genetic and pharmacological MRP3 inhibition enhances the anti-CCA effect of several drugs, which constitutes a promising strategy to improve the response to chemotherapy in CCA patients.

P=N/A, N=600, Active, not recruiting, Peking University | Recruiting --> Active, not recruiting | Trial completion date: Feb 2024 --> Mar 2025 | Trial primary completion date: Feb 2024 --> Nov 2024

P2, N=34, Suspended, Zhejiang Cancer Hospital | Recruiting --> Suspended

In second-line treatment, no difference between an Irinotecan-based regimen and re-exposure to platinum-based agents (12.36 vs 10.13 months; HR 0.92; P=0.85) could be observed (HR 1.45; P=0.35). HRRm BTC patients showed a potential advantage in OS following platinum-based first-line chemotherapy, presumably attributed to enhanced opportunities for targetable co-alterations. Further investigation is needed to delineate HRD in the context of personalizing systemic therapies of BTC.

The prevalence of lithiasis seems to be higher in Chilean versus US patients with GBC. A similar prevalence of ERBB2 alterations of overall 14% and better OS suggests that a proportion of them could benefit from human epidermal growth factor receptor type 2-targeted therapies. The smaller cohort of Chile, where the disease prevalence is higher, is a reminder and invitation for the need of more robust next-generation sequencing analyses globally.

Although some typical FGFR inhibitor-related side effects were observed, they were manageable and futibatinib had a good safety profile. Futibatinib is an important drug for biliary tract cancer, which has limited treatment options; its development is underway for other types of cancer, and it is expected to benefit more patients.

Of the biliary tract cancer cases examined with this method, 13 (54%) and 4 (17%) resulted in positive cancer driver mutation detection in the bile and plasma cfDNAs, respectively. These results suggest that bile is a more reliable source for LB than plasma for multigene panel analyses of biliary tract cancers.

We herein report uncommon instances of strong and diffuse expression of these markers in two examples of adenocarcinomas arising from the bile duct and gallbladder. A review of the literature and a summary of similar studies relating to aberrant TTF-1 and Napsin-A expression in biliary tract adenocarcinomas are presented.

In addition to the most common alterations such as isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations, fibroblast growth factor receptor 2 (FGFR2) fusions, and alterations, we will also discuss less frequently encountered alterations such as BRAF V600E mutation and neurotrophic tyrosine kinase receptor gene (NTRK) fusion. We highlight the importance of molecular profiling in guiding therapeutic decisions and emphasize the need for continued research to optimize and expand targeted treatment strategies for this aggressive malignancy.

This study confirms the phase 3 trial results of durvalumab with platinum and gemcitabine, providing a substantial real-world dataset with detailed molecular characterization. No specific patient subgroup showed a markedly better response to durvalumab based on conventional NGS panels. Further research is needed to explore the link between immunotherapy responses and molecular subgroups.

Tepotinib showed remarkable efficacy in treating MET-amplified intrahepatic cholangiocarcinoma, underscoring the importance of molecular profiling in BTCs and suggesting a potential new therapeutic approach for this rare cancer subtype.

This study revealed the causal relationships between complement components and certain cancers, with five immune cells as potential mediators.

P3, N=195, Not yet recruiting, InnoPharmax Inc.

P2, N=49, Not yet recruiting, Shanghai Zhongshan Hospital