The 2025 Cholangiocarcinoma (CCA) Summit featured a session on medical advancements in CCA, focusing on the exploration of novel combination treatment strategies. The session featured presentations by Sangeeta Goswami, MD, PhD, Marina Baretti, MD, and James Harding, MD, focusing on immuno-oncology–based strategies, novel combinations and sequencing, and antibody–drug conjugates (ADCs) to address the unmet needs in oncology, particularly in biliary tract cancers (BTCs).
Dr Goswami discussed the transformative potential of immune checkpoint therapy (ICT) in cancer treatment and its integration with surgery. She noted that ICT can induce durable responses in 50% to 60% of patients, and emphasized the value of neoadjuvant ICT, which may enhance postsurgical immune activity by leveraging the intact tumor microenvironment (TME). An investigator-initiated trial in metastatic clear cell renal carcinoma demonstrated the safety and efficacy of combining surgery with ICT. Among 104 patients, those receiving cytoreductive surgery plus nivolumab-based ICI therapy achieved a median overall survival of 54.7 months versus 23.5 months with ICI therapy alone.1 Cellular analysis showed reduced immunosuppressive myeloid cells and increased effector CD8 T cells post-surgery, suggesting that surgery modulates the immune microenvironment and enhances the ICI therapy response.1 Pretreatment data showed that higher interferon-gamma and tertiary lymphoid structure gene expression correlated with an improved response. Spatial analysis revealed that responders exhibited proximity between dendritic cells and CD8-positive T cells, whereas nonresponders exhibited proximity between CD8 and regulatory T cells.1 Dr Goswami also highlighted emerging strategies targeting tumor plasticity, such as targeting EZH2 with anti–CTLA-4 agents as BTC treatments.
Next, Dr Baretti focused on novel combinations and sequencing strategies in BTCs. She discussed a phase 2 study of CTX-009, a bispecific antibody targeting DLL4 and VEGF-A, which showed promising results when combined with paclitaxel in previously treated patients with BTC. The study reported an objective response rate (ORR) of 37.5%, a disease control rate of 91.5%, and median progression-free survival of 9.4 months.2 However, safety remains a concern, with 83.3% of patients experiencing grade ≥3 neutropenia. Dr Baretti also discussed strategies for IDH1 mutation–positive BTCs. Preliminary data combining LY3410738, a covalent inhibitor of DH1 and IDH2, with gemcitabine/cisplatin demonstrated an ORR of 46% and stable disease in 46% of patients. She noted the immunosuppressive TME in IDH1 mutation–positive intrahepatic CCA, characterized by an enrichment of myeloid cells, underscoring the potential of immunomodulatory approaches, such as targeting CCL2 to reprogram the TME and enhance therapy effectiveness.
Dr Baretti addressed key resistance mechanisms in FGFR2-positive CCA, often driven by FGFR2 mutations and off-target pathways involving MEK/ERK and PI3K/AKT/mTOR. She noted that preclinical studies support combining FGFR inhibitors with MEK/ERK or PI3K/mTOR inhibitors, although overlapping toxicities demand careful dose optimization.
Shifting to immunotherapy, Dr Baretti introduced T-cell immunoreceptor with Ig and ITIM domains (TIGIT) as a promising target, citing early GEMINI-HPB study results where the anti-TIGIT/anti–programmed death-ligand 1 (PD-L1) bispecific antibody rilvegostomig combined with chemotherapy achieved a 31% ORR in 29 patients with BTC. She also highlighted opportunities in targeting MTAP loss with PRMT inhibitors and KRAS mutations with agents like adagrasib to reprogram the TME and enhance ICT.
Expanding on molecularly targeted therapies, Dr Harding reviewed the emerging role of ADCs in BTCs. ADCs deliver cytotoxic payloads directly to cancer cells via monoclonal antibodies, thereby enhancing their therapeutic efficacy. Dr Harding explained that the effectiveness of ADCs in BTC depends on accurate target selection, efficient internalization, and payload delivery through stable linkers.3 Highlighting clinical progress, he cited DESTINY-Pan Tumor02, a phase 2 trial of trastuzumab deruxtecan in HER2-expressing solid tumors, which demonstrated the feasibility of using ADCs across ER2-positive cancers. This laid the foundation for DESTINY-BTC-01, a phase 3 trial that compares trastuzumab deruxtecan plus rilvegostomig with trastuzumab deruxtecan alone and the standard of care in advanced HER2-expressing BTC, with patient stratification by HER2 status, PD-L1 expression, and tumor site. These findings underscore ADCs as promising targeted options for patients with BTC with HER2 expression. Dr Harding highlighted preclinical and clinical data, noting promising activity with targets such as HER2, MET, TROP2, and CLDN18.2 in BTCs. While basket trials have demonstrated ADC activity, he advocated for larger, disease-specific studies to refine patient, target, and payload selection.
The session concluded with a discussion on practical challenges and future directions, including optimizing therapy selection post-surgery. Dr Harding addressed a question on expression-level eligibility criteria cutoffs in BTC, emphasizing the need to refine thresholds based on biologic subsets, target heterogeneity, and tumor saturation. Experts agreed that prioritizing target saturation over the maximum tolerated dose could improve efficacy and reduce toxicity. Dr Goswami highlighted the value of leveraging the intact TME before surgery to prime the immune response. The discussion emphasized the need for predictive biomarkers and correlative studies to understand response and resistance biology. Although ADCs offer exciting opportunities, concerns about off-target toxicities such as pneumonitis and neurotoxicity or skin toxicity remain. Overall, the session highlighted the potential of innovative combination strategies to address the unique challenges of BTCs, offering hope for improved outcomes through precision oncology and immunotherapy.
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