Lirafugratinib (Lyrfigtu)

Cholangiocarcinoma is a malignancy of the biliary epithelium, usually an adenocarcinoma, classified by anatomic site as intrahepatic, perihilar, or distal. In the United States, perihilar disease accounts for approximately 50% to 60% of cholangiocarcinomas, distal disease for 20% to 30%, and intrahepatic disease for 10% to 20%, and cholangiocarcinoma comprises approximately 15% of primary liver tumours. Together with gallbladder and ampullary cancer, it forms biliary tract cancer, which accounts for less than 1% of all cancers worldwide.

The indication is defined by a genomic alteration. FGFR2 fusions or rearrangements occur almost exclusively in intrahepatic cholangiocarcinoma. The fusions most commonly join FGFR2 exons 1 to 17, which carry the extracellular and kinase domains, to one of many partner genes, and loss of the C-terminal negative regulatory domain encoded by exon 18 leads to constitutive kinase activity. The previously treated population is the population in which lirafugratinib was approved: adults with unresectable, locally advanced or metastatic disease after prior systemic therapy, which in REFOCUS meant prior chemotherapy or chemoimmunotherapy without a prior FGFR inhibitor.

Most established risk factors for cholangiocarcinoma share chronic inflammation of the biliary epithelium and bile stasis, including choledochal cyst, Caroli disease, primary sclerosing cholangitis, choledocholithiasis, cirrhosis, chronic hepatitis B and C, and, in endemic regions, liver fluke infection; cirrhosis, non-alcoholic fatty liver disease, and hepatitis B are more strongly associated with intrahepatic disease. In most locations the majority of cases have no identifiable risk factor. No risk factor specific to FGFR2 fusion-positive disease was identified in the cited sources; in one institutional series FGFR alterations were more frequent in participants aged 40 years or younger (20%) than in older participants (6.7%).