erdafitinib and Bile-Duct-Neoplasms

Comprehensive genomic profiling has an emerging role in cancer therapeutics. As treatment options remain needed for advanced cancers, patients are relying increasingly more on tumor genomic alterations as possible targets for cancer treatment. Frequent tumor fibroblast growth factor receptor (FGFR) alterations are seen in many cancers, and include genetic amplifications, mutations, rearrangements and fusions. FGFR inhibitors target these receptor alterations and show promise as a drug class. Currently 2 medications are currently FDA approved: erdafitinib and pemigatinib. Through the FDA accelerated approval process, erdafitinib is indicated to treat metastatic urothelial carcinoma with FGFR2 and FGFR3 alterations, whereas pemigatinib is indicated to treat unresectable cholangiocarcinoma with FGFR2 alterations. Despite growing knowledge about such advanced cancers, treatment is usually palliative. With multiple FGFR inhibitors in the pipeline, further FDA approvals are possible, and it is likely their role in therapy will extend to other cancer types. This review outlines erdafitinib, pemigatinib, their role in cancer, as well as outlining the possible future use of other FGFR inhibitors in urothelial carcinoma, cholangiocarcinoma, and other malignancies.

Topics: Bile Duct Neoplasms; Carcinoma, Transitional Cell; Cholangiocarcinoma; Clinical Trials as Topic; Humans; Morpholines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Pyrroles; Quinoxalines; Receptor, Fibroblast Growth Factor, Type 2; Receptor, Fibroblast Growth Factor, Type 3

Cholangiocarcinoma is an aggressive cancer with a poor prognosis and limited treatment. Gene sequencing studies have identified genetic alterations in fibroblast growth factor receptor (FGFR) in a significant proportion of cholangiocarcinoma (CCA) patients. This review will discuss the FGFR signaling pathway's role in CCA and highlight the development of therapeutic strategies targeting this pathway.. The development of highly potent and selective FGFR inhibitors has led to the approval of pemigatinib for FGFR2 fusion or rearranged CCA. Other selective FGFR inhibitors are currently under clinical investigation and show promising activity. Despite encouraging results, the emergence of resistance is inevitable. Studies using circulating tumor DNA and on-treatment tissue biopsies have elucidated underlying mechanisms of intrinsic and acquired resistance. There is a critical need to not only develop more effective compounds, but also innovative sequencing strategies and combinations to overcome resistance to selective FGFR inhibition. Therapeutic development of precision medicine for FGFR-altered CCA is a dynamic process of involving a comprehensive understanding of tumor biology, rational clinical trial design, and therapeutic optimization. Alterations in FGFR represent a valid therapeutic target in CCA and selective FGFR inhibitors are treatment options for this patient population.

Topics: Aniline Compounds; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cholangiocarcinoma; Clinical Trials as Topic; Humans; Morpholines; Mutation; Phenylurea Compounds; Precision Medicine; Pyrazoles; Pyrimidines; Pyrroles; Quinazolines; Quinoxalines; Receptors, Fibroblast Growth Factor; Signal Transduction

Topics: Aged; Bile Duct Neoplasms; Biopsy; Calciphylaxis; Cholangiocarcinoma; Female; Humans; Pyrazoles; Quinoxalines; Receptor, Fibroblast Growth Factor, Type 2; Skin; Thigh