Cholangiocarcinoma - Emerging treatments

Selective internal radiation therapy

Selective internal radiation therapy (SIRT) or radioembolisation, targets high doses of radiation directly to unresectable liver metastases. The National Institute for Health and Care Excellence (NICE) in the UK has published guidance for the use of SIRT for unresectable primary intrahepatic cholangiocarcinoma. NICE recommends that the procedure should be carried out in specialist centres and only in the context of research, due to safety concerns and the lack of good quality evidence for its efficacy.[83]

Devimistat

Devimistat, an experimental antimitochondrial drug that targets the mitochondrial tricarboxylic acid cycle, has been granted orphan drug status by the Food and Drug Administration (FDA) for the treatment of biliary cancer. A phase 1B/2 trial of devimistat in combination with gemcitabine and cisplatin for patients with biliary cancer is ongoing.[84]

Etoposide toniribate

The FDA and European Medicines Agency (EMA) have granted orphan drug designation to the novel topoisomerase II inhibitor, etoposide toniribate, for the treatment of relapsed refractory cholangiocarcinoma. One randomised phase 2 trial of patients with relapsed refractory, metastatic, unresectable biliary tract cancer (n=22) reported a 1-year overall survival of 44% with etoposide toniribate versus 11% with best supportive care.[85]

Infigratinib

Infigratinib, an oral, small molecule kinase inhibitor of fibroblast growth factor receptor (FGFR), has been granted accelerated approval by the FDA for adults with previously treated, unresectable locally, advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptors 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test. The approval was premised on the results of one multi-centre, open-label, single-arm, phase 2 study.[86] In October 2022, the application to the EMA for marketing authorisation for infigratinib was withdrawn. This followed the initial EMA evaluation that there was insufficient evidence of efficacy, as well as a number of severe side effects and questions over metabolism and excretion, that suggested the benefits of infigratinib did not outweigh its risks.

Futibatinib

Futibatinib, an oral, highly selective and irreversible small molecule inhibitor of FGFR types 1 to 4, has received approval from the FDA for patients with previously treated locally advanced or metastatic cholangiocarcinoma harbouring FGFR2 gene rearrangements, including gene fusions. Futibatinib is also approved by the EMA for patients with locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or rearrangement that have progressed after at least one prior line of systemic therapy. One phase 2 trial reported a measurable clinical benefit with futibatinib in patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors).[87] One phase 3 trial (FOENIX-CCA3) is in progress.[88]

Gunagratinib

Gunagratinib, a pan-FGFR inhibitor, has been granted orphan drug status by the FDA for the treatment of cholangiocarcinoma. Anti-tumour activity was demonstrated in patients with FGF/FGFR gene aberrations in multiple tumour types, including cholangiocarcinoma.[89] One phase 2A dose expansion study is ongoing.[90][91]

Ivosidenib

Ivosidenib, an oral, small molecule inhibitor of isocitrate dehydrogenase-1 (IDH1), has been approved by the FDA and EMA for the treatment of adults with previously treated, locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation as detected by an approved test. In patients with previously treated IDH1-mutant cholangiocarcinoma, progression-free survival was significantly improved with ivosidenib compared with placebo (median 2.7 months vs 1.4 months).[92] Median overall survival, a secondary end point, was 10.3 months with ivosidenib versus 7.5 months with placebo.[93] When adjusted for crossover from placebo to ivosidenib (permitted if patients had disease progression), median overall survival with placebo was 5.1 months. The NCCN recommends ivosidenib as a subsequent line treatment which is useful in some circumstances for patients with unresectable or metastatic cholangiocarcinoma with IDH1 mutations following disease progression.[34][53] NICE recommends ivosidenib as an option for treating locally advanced or metastatic cholangiocarcinoma with an IDH1 R132 mutation in adults after one or more systemic treatments.[94]

Pemigatinib

Pemigatinib, a selective oral inhibitor of FGFR types 1, 2, and 3, has been approved by the FDA and EMA to treat adult patients with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma with a fusion or other rearrangement of the FGFR2 gene. The approval is based on the results of one phase 2 clinical trial in this patient population.[95] The NCCN recommends pemigatinib as a subsequent line treatment which is useful in some circumstances for unresectable or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements following disease progression.[34][53] NICE recommends pemigatinib as an option for relapsed or refractory advance cholangiocarcinoma with FGFR2 fusion or rearrangement that has progressed after systemic therapy.[96]

Zanidatamab

Zanidatamab, a bispecific antibody that simultaneously binds two nonoverlapping epitopes of HER2, has received breakthrough therapy designation from the FDA for patients with previously treated HER2 gene-amplified biliary tract cancer. Zanidatamab has demonstrated meaningful clinical benefit with a manageable safety profile in patients with treatment-refractory, HER2-positive biliary tract cancer in one phase 2B single-arm clinical trial (HERIZON-BTC-01).[97]

Silmitasertib

Silmitasertib, a small molecule casein kinase 2 (CK2) inhibitor, has received orphan drug designation by the FDA for biliary tract cancers. One phase 1B/2 study showed preliminary evidence for the efficacy of silmitasertib when combined with gemcitabine and cisplatin in patients with locally advanced or metastatic cholangiocarcinoma, and a phase 3 trial is planned.[98]

ZB131

ZB131 is a monoclonal antibody with a high affinity and specificity for cancer-specific plectin (a cell surface protein associated with many aggressive cancers). The FDA has granted ZB131 orphan drug status for the treatment of cholangiocarcinoma. Interim data from one phase 1/2 trial showed that ZB131 had good tolerability with encouraging signs of activity and target engagement in heavily pre-treated patients.[99] Further trials are warranted.