Biliary Tract Cancer



Biliary Tract Cancer


Sunyoung S. Lee

Milind Javle




Molecular Targeted Therapy



  • The molecular analyses of molecular profiling show that up to 35% of patients with cholangiocarcinoma have potentially targetable genomic alterations (1).


  • Gene mutations commonly found in cholangiocarcinoma are categorized into five subgroups: receptor tyrosine kinases (FGFR), cell cycle-related genes (TP53, CDKN2A mutation/deletion, and CCND1 amplification), IDH1/2 alterations, MAPK pathway (KRAS, NRAS, and BRAF), and chromatin modifying (ARID1A/B, BAP1, and PBRM1) (2,3,4).


  • Patients with FGFR2 alterations show better prognosis, and those with KRAS and TP53 mutations have worse prognosis. IDH1/2 alterations are neutral in prognosis. BAP1 is related to a more aggressive subtype and associated with poor prognosis.


IDH1 MUTATION



  • Isocitrate dehydrogenase (IDH) mutations (IDH1 and 2) are found in 20% to 25% of patients with intrahepatic cholangiocarcinoma.


  • An IDH1 inhibitor, ivosidenib (ClarIDHy trial) showed a modest survival benefit (5). Patients who progressed on placebo crossed over to ivosidenib: ORR, 2%; DCR, 53%; mPFS, 2.7 months. In an earlier analysis, 32% and 22% of patients on ivosidenib did not progress at 6 and 12 months (6).


  • Ivosidenib was recently approved by the FDA in the second-line setting.


FGFR2 GENE ALTERATIONS



  • Fibroblast growth factor receptor 2 (FGFR2) alterations are commonly found in 14% to 20% of patients with intrahepatic cholangiocarcinoma (7,8).


  • Pemigatinib, an FDA-approved inhibitor of FGFR1, 2, and 3, showed ORR, DCR, and median duration of response (mDOR) of 35.5%, 80.0%, and 7.5 months in FGFR2 fusions/rearrangements. Patients with other FGFR alterations or no FGF/FGFR alterations showed stable disease in 40% and 22% patients with no overall response.



  • Infigratinib, another FDA-approved inhibitor of FGFR1, 2, and 3, showed ORR of 23.1% (35% in the second-line setting and 13.8% in the third- and later-line settings) in FGFR2 fusions or rearrangements; mPFS, 7.3 months (9).


  • Futibatinib, an inhibitor of FGFR1, 2, 3, and 4 (10,11), showed mDOR of 6.2 months, ORR of 34.3%, and DCR of 76.1%.


  • Common adverse events from FGFR inhibitors include hyperphosphatemia, arthralgias, and ophthalmologic side effects including serous retinal detachment and dry eyes.


ERBB2 (HER2) AMPLIFICATION

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Nov 2, 2025 | Posted by in ONCOLOGY | Comments Off on Biliary Tract Cancer

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