Sequencing of Fibroblast Growth Factor Receptor Inhibitors in Cholangiocarcinoma: A Review of Published Cases.

Abstract

Cholangiocarcinomas (CCAs) are aggressive biliary tumors that can develop within the intrahepatic (iCCA) or perihilar and distal bile ducts. The prognosis of patients with iCCA is poor due to its relative resistance to chemotherapy. Comprehensive genomic profiling of CCA biopsies by next-generation sequencing has revealed a rich landscape of genomic alterations, including fibroblast growth factor receptor (FGFR) gene fusions and rearrangements that are constitutively active and oncogenic. Several FGFR inhibitors (FGFRis) targeting these FGFR genomic alterations have been developed as potential treatments for iCCA, each of which are highly potent but differ in structure, mechanism of inhibition (ie, adenosine triphosphate-competitive reversible v covalent/irreversible v allosteric), pharmacologic/pharmacodynamic profiles, and selectivity for the four FGFR isoforms. Because of these differences, and due to resistance mutations acquired during FGFRi treatment, determining the optimal sequencing of FGFRis for the treatment of CCA remains contentious and is the subject of ongoing debate. To address this question, this review conducted an analysis of the literature on the FGFRi currently approved or in development, focusing on their distinct mechanisms of action and FGFR selectivity. Publicly available data from case reports on FGFRi sequencing in second and later lines of treatment were compiled from a PubMed search of published congress abstracts and articles. The results support a hypothesis that strategic sequencing of reversible followed by irreversible FGFRi may potentially prolong the duration of treatment benefit from FGFR inhibition compared with nonsequenced treatments. A hypothetical treatment-sequencing algorithm for reversible and irreversible FGFRi is discussed.