Clinical trials and molecular therapies in iCCA

Abstract

Cisplatin and gemcitabine (CisGem) has been the stadard of care for patients presenting with advanced iCCA for over a decade. Intensified (triplet) chemotherapy remains investigational except in Japan, where the CisGem and S1 is an option. Robust data has shown that 5FU-based, second-line, combination chemotherapy has modest activity in a molecularly-unselected population. An improved understanding of the biology underpinning iCCA has led to the identification of molecular alterations linked to targeted therapies. The most prominent alterations are mutations in IDH1 and FGFR2 fusions; both of these are addressed later in the session. This presentation will highlight other selected subgroups, including patients whose tumours are harbouring BRAF-V600E mutations, HER2 amplification/over-expression, and NTRK fusions as examples, although additional groups continue to emerge. Cholangiocarcinoma is recognised to have an underlying immune predisposition, in selected cases. Harnessing the immune response has previously provided limited signals of efficacy. However, the TOPAZ-1 study, a randomised phase III study has recently shown an incremental survival benefit in patients with biliary tract cancer with the addition of durvalumab to CisGem chemotherapy, including intrahepatic cholangiocarcinoma. No predictive factors are known to enrich for patients most likely to benefit from immunotherapy to date. Additional analysis of patient subgroups in TOPAZ-1 as well as the results of the KEYNOTE-966 phase III study (CisGem +/- pembrolizumab) are eagerly awaited.