At the 2025 Annual Cholangiocarcinoma (CCA) Summit, Juan Valle, MD, discussed the future of clinical trials in biliary tract cancer (BTC). He outlined the evolving therapeutic and clinical research landscape of CCA, and emphasized the need for continued innovation and collaboration. He prefaced his presentation by stating that although the exact destination of clinical trials in BTC is unknown, the road being traveled is moving toward more precise, biomarker-guided, and globally cooperative research strategies.
Dr Valle stated that 2 decades ago, clinical evidence in CCA was largely confined to small institutional series and anecdotal reports. Furthermore, biliary tract, gallbladder, and ampullary cancers were grouped together out of necessity despite biological differences. The introduction of gemcitabine represented a turning point in BTC treatment, as it enabled the first randomized clinical trials and established the foundation for today’s standard of care (SOC). This progress was driven by the expansion of national and international collaboration, which continues to accelerate patient recruitment. As the space has evolved, the differences in biliary tract, gallbladder, and ampullary cancer types have been recognized, thus shifting clinical trial design from being heterogeneous out of necessity to homogenous by design. As the treatment of those cancers has evolved to the point of individualized treatment strategies, the treatment of CCA has benefited primarily from tissue-agnostic approvals. Most tissue-agnostic approvals rest on phase 2 data, although the phase 3 ClarIDHy study remains a notable exception focused specifically on patients with CCA.
Dr Valle cautioned that although there has been incremental progress in advancing the care of patients with CCA, almost all patients with CCA present with advanced disease, and approximately half receive no treatment. Subsequently, current survival outcomes should be viewed not as achievements, but as baselines for future improvements. Building upon those baselines, comprehensive molecular profiling has transformed the therapeutic landscape, with targeted agents now available for several key alterations such as FGFR2 fusions, IDH1 mutations, and HER2 amplification.
With the advent of molecular subgroups, ongoing translational research now seeks to optimize therapy sequencing and combination strategies. Ongoing studies are investigating IDH1 inhibitors with immunotherapy, mechanisms of resistance to FGFR blockade treatment, and integration of HER2-targeted therapy into first-line treatment. These studies highlight the necessity of biologically driven trials as opposed to one-size-fits-all.
Dr Valle spotlighted platform trial designs as a pragmatic solution to the rarity and biological diversity of CCA. The SAFIR-ABC10 study screens patients for molecular alterations and randomizes patients without disease progression after induction chemotherapy to receive either targeted therapy or continued chemotherapy. This approach evaluates a treatment strategy rather than a single drug and allows efficient allocation to multiple biomarker-defined arms. Furthermore, the efficient trial design of SAFIR-ABC10 allows for multiple clinical questions to be answered simultaneously, a feature that is critical in disease states where trial recruitment is difficult. A similar platform study called ARBOR-BTC is now in development in the United States to guide second-line therapy selection.
He further emphasized the promise of decentralized trial models, noting that digital tools such as e-consent, telemedicine, and local lab partnerships can expand access and diversity in rare cancer trials. These designs, although not currently applicable to current studies that are being run, may be useful in trials or phases of trials focusing on maintenance of CCA.
Dr Valle also addressed the limited evidence supporting locoregional therapies and called for more phase 3 data to guide their use. He highlighted emerging randomized studies in hepatic artery infusion and stereotactic body radiotherapy as encouraging developments.
He concluded by urging clinicians to prioritize comprehensive biomarker testing, not only for facilitating the SOC, but also to further research efforts in CCA. Dr Valle also urged clinicians to integrate circulating tumor DNA analysis into regular practice and to refer patients to platform protocols. He called on industry partners to design confirmatory studies early, invest in decentralized infrastructure, and to put some thought into what will change practice when designing clinical trials. Through these collaborative efforts from both healthcare providers and industry partners, clinical trials in BTC and CCA can evolve to become more efficient and can generate data that are the most impactful toward optimizing patient outcomes.
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