The Pros and Cons of Targeted Therapy as a First-Line Option in Biliary Tract Cancer

Gentry King, MD

Shubham Pant, MD

The 2025 Cholangiocarcinoma (CCA) Summit featured a crossfire debate on the use of targeted therapy in the frontline setting in biliary tract cancer (BTC). The debate explored the scientific rationale, clinical evidence, and practical barriers to integrating targeted therapies early in treatment, and featured Gentry King, MD, advocating for frontline use, and Shubham Pant, MD, cautioning against routine use outside clinical trials.

Dr King opened with a strong case for frontline adoption, citing actionable molecular alterations in BTC such as FGFR2 fusions, HER2 hyperexpression, and IDH1, for which targeted therapies exist or are emerging. These mutations can be detected early through next-generation sequencing or circulating tumor DNA. He highlighted superior outcomes with targeted agents compared with the standard of care (SOC). For example, futibatinib demonstrated an objective response rate (ORR) of 42% and a median overall survival of 21.7 months in the second-line (2L) setting in the FOENIX-CCA2 trial.¹ Similarly, larotrectinib demonstrated an ORR of 60% to 70% across multiple tumor types with NTRK fusions, including BTC, in the SCOUT and NAVIGATE trials. He further stressed that earlier intervention could amplify these benefits, especially given that approximately 50% of patients with metastatic BTC never reach 2L therapy. He noted FGFR inhibitors like infigratinib show greater efficacy when used earlier, with a higher ORR of 34% in patients with CCA in the 2L setting compared with 13.8% in the third-line setting and beyond.¹

Dr King highlighted that practical hurdles, including difficulty enrolling rare subtypes, further complicate frontline adoption. In the PROOF 301 trial, infigratinib showed an ORR of 38% in FGFR2-rearranged CCA, but enrollment was slow, with only 48 patients enrolled over a span of 40 months, due to a low incidence of FGFR2 fusions (6.8%) leading to trial termination.1 Similarly, zanidatamab in the HERIZON-BTC-01 trial achieved an ORR of 41% in HER2-positive BTC, yet applicability is limited to approximately 5%.¹ These examples underscore the difficulty of generating robust evidence in small, molecularly defined BTC subgroups. Dr King emphasized the need to overcome enrollment barriers and produce strong first-line (1L) data. Additionally, mechanistic differences among targeted agents also shape clinical outcomes and trial design. For instance, IDH inhibitors function by promoting cellular differentiation rather than cytotoxicity, resulting in disease stabilization rather than tumor shrinkage.

Countering Dr King’s view, Dr Pant emphasized that chemotherapy plus immune checkpoint inhibitors remain the SOC for BTC regardless of molecular alterations and should not be displaced without robust 1L evidence. Current data for targeted therapies, such as pemigatinib (FIGHT-202) and zanidatamab (HERIZON-BTC-01), are limited to 2L settings, with ORRs of 35.5% and 41.3%, respectively, and carry risks of distinct toxicities like diarrhea, fatigue, and rarely, interstitial lung disease.²

Dr Pant advocated for sequencing strategies, starting with gemcitabine/cisplatin plus durvalumab followed by targeted agents like zanidatamab, to optimize survival without prematurely moving targeted treatments to the front line. He concluded by stressing the need for clinical trials for frontline use and improved enrollment to advance research.

The discussion highlighted key considerations for advancing targeted therapies in BTC. Improved trial designs that reflect real-world practice are needed to address enrollment challenges. It was noted that targeted therapies vary in their effects on tumor biology and immunity, and not all are suitable for frontline use. Biomarker-driven approaches are critical to understanding response variability and identifying patients most likely to benefit. Experts cautioned against cross-trial comparisons and stressed the importance of accounting for geographic factors when interpreting outcomes. Overall, although compelling efficacy data support the use of targeted therapies in select biomarker-defined subgroups, advancing clinical trials and personalized approaches will be essential to improving outcomes in BTC.

Sources

1. Gentry K. Should We Use Targeted Therapy in Front Line? PRO. Presented at: 2025 CCA Summit. October 2-3, 2025; Scottsdale, AZ.
2. Pant S. Should We Use Targeted Therapy in Front Line? CON. Presented at: 2025 CCA Summit. October 2-3, 2025; Scottsdale, AZ.