Sequential Fibroblast Growth Factor Receptor Inhibition in Intrahepatic Cholangiocarcinoma: Navigating an Evolving Landscape of Resistance and Opportunity-A Case Report and Current Opinion.

Fibroblast growth factor receptor (FGFR)2 rearrangements define a distinct molecular subset of intrahepatic cholangiocarcinoma (iCCA) with therapeutic potential using FGFR inhibitors. However, acquired resistance invariably limits long-term efficacy, posing a significant clinical challenge. Sequential targeting with different FGFR inhibitors is an emerging strategy, yet robust evidence, particularly for third-line and beyond, is scarce, and a consensus on optimal sequencing and patient selection remains unreached. Here, we report a case of FGFR2-rearranged iCCA where the patient achieved a radiographic partial response (PR) to tasurgratinib (a third-line FGFR inhibitor) following prior progression on pemigatinib and futibatinib. This case underscores the sustained dependency on the FGFR pathway and highlights the potential clinical utility of rationally sequenced FGFR-targeted therapy even after multiple lines of treatment. More broadly, this report serves as a basis for a current opinion on the evolving landscape of sequential FGFR inhibition in iCCA. We delve into the complexities of acquired resistance, dissect the arguments for and against prolonged FGFR pathway blockade, explore the impact of co-occurring genomic alterations, discuss the controversies, research priorities, and the urgent need for a balanced perspective to guide future clinical practice and trial design in this rapidly advancing but still uncertain field.