Key Advances in the Treatment of Patients with BTC in 2023: New Targeted Therapies, Potential Biomarkers, and Combination Strategies


In 2023, much research has been conducted on the treatment of biliary tract cancer (BTC), with an emphasis on novel targeted therapies and combination strategies. Important advances in treatment for patients with BTC were presented at society conferences such as the American Society of Clinical Oncology (ASCO), ASCO GI, and European Society for Medical Oncology. This edition of the Cholangiocarcinoma Year in Review seeks to disseminate this information in a concise and timely manner;below is a quick review of some of the topics discussed in this issue, with a focus on new targeted therapies, potential predictive biomarkers, and therapeutic combinations for the treatment of patients with BTC.

Recent research has focused on the development of promising new targeted therapies for the treatment of cholangiocarcinoma (CCA), with several emerging in recent years. A new potential therapeutic target, KLF5, was investigated in CCA tumor models, and we will continue to watch its development in this space. Advances in newer FGFR inhibitors include the use of the novel FGFR inhibitor tinengotinib in patients with refractory or relapsed CCA, including efficacy in patients who progressed on a prior FGFR inhibitor.

Pooled data from 3 small trials was used to summarize safety and clinical benefit of this novel FGFR inhibitor. Additionally, the FGFR inhibitor gunagratinib was evaluated in a phase 2a expansion study, which demonstrated promising activity. The interaction of MDM2-p53 is another target of interest for the treatment of patients with advanced BTC. Blocking the interaction between MDM2 and p53 has been found to have antitumor activity in multiple tumor types. BI 907828, an MDM2-p53 antagonist, is currently being studied in 2 phase 1a/1b dose-escalation/expansion trials in patients with advanced solid tumors, including patients with BTC as monotherapy and in combination with the anti–PD-1 monoclonal antibody ezabenlimab in TP53 wild-type cancers, and preliminary results in patients with BTC warrant further investigation. Zanidatamab, a bispecific antibody, was another exciting targeted therapy of interest and was evaluated in the HERIZON-BTC-01 study in patients with previously treated HER2-amplified BTC. This agent is well tolerated and led to approximately 40% responses in pretreated patients.

Circulating tumor DNA (ctDNA) is emerging as a promising biomarker for patients with BTC. Results of the STAMP adjuvant chemotherapy trial showed that ctDNA can be used as a predictive molecular biomarker of recurrence in patients after surgery that could then be evaluated further to direct appropriate therapy. Other data show that liquid biopsy measuring ctDNA can detect FGFR2 and other actionable rearrangements, which can be used as potential therapeutic targets, and may be useful in patients for whom tissue biopsies are not available.

In this issue of Cholangiocarcinoma Year in Review, we see immunotherapies moving into new settings, such as the curative space and maintenance in the advanced setting; however, results show that these are not practice-changing data. Adjuvant durvalumab plus tremelimumab with or without capecitabine for resectable BTC (the ADJUBIL study) is reviewed as a trial in progress. The DEBATE trial also investigated durvalumab but in combination with gemcitabine/cisplatin (GemCis) in the neoadjuvant setting. In the BilT-02 study, rucaparib (a poly ADP ribose polymerase inhibitor) and nivolumab were used as maintenance therapy following chemotherapy response in patients with advanced BTC. KEYNOTE-966, a large phase 3 trial evaluating the benefits of pembrolizumab and GemCis for first-line treatment of advanced BTC, demonstrated a survival advantage over GemCis alone, adding to the body of data that started with the TOPAZ-1 trial.

Dose intensification of chemotherapy in BTC has been disappointing, with 2 negative phase 3 trials this year. First, SWOG 1815 compared the safety and efficacy of albumin-bound paclitaxel combined with GemCis with GemCis alone in patients with advanced BTC but failed to show an improvement in survival. In the NuTide:121 trial evaluating NUC-1031, a phosphoramidate transformation of gemcitabine added to cisplatin, NUC-1031 was clearly inferior to the standard combination of GemCis. Both of these trials built on promising phase 1/2 data that did not hold up in the larger phase 3 trials. In addition, a post-hoc analysis of the early ABC-01, -02, and -03 clinical trials further analyzed the survival data of patients treated with first-line GemCis chemotherapy with a focus on the extrahepatic sites. Finally, in the JCOG1202 adjuvant trial of S1 therapy versus observation, clinical risk factors for early relapse were analyzed in patients with BTC undergoing surgical resection.

We are pleased to present the highlights of these topics and many more!


Jennifer Knox, MD, MSc, FRCPC(C)
Medical Oncologist, Princess Margaret Cancer Centre
Co-Director, McCain Centre for Pancreatic Cancer
Professor of Medicine and Wilfred G. Lewitt Chair in Pancreatic Cancer Research, University of Toronto
Toronto, Ontario, Canada

Subscribe Today!

To sign up for our newsletter or print publications, please enter your contact information below.

I'd like to receive: