Research in context
Evidence before this study
The incidence of intrahepatic cholangiocarcinoma has steadily increased worldwide over the past several decades, as have annual age-adjusted mortality rates. The standard-of-care first-line treatment for locally advanced or metastatic cholangiocarcinoma is gemcitabine plus cisplatin. However, treatment options are limited in the second-line setting. Several potentially actionable oncogenic alterations have been identified in patients with cholangiocarcinoma, including alterations in the fibroblast growth factor receptor (FGFR) gene. We searched PubMed and the American Society of Clinical Oncology and European Society for Medical Oncology abstract databases for manuscripts and abstracts published from database inception to Nov 14, 2019, without language restrictions. The search terms used were (“cholangiocarcinoma” OR “biliary tract cancer”) AND (“fibroblast growth factor receptor” OR “FGFR”). We identified 67 publications supporting a role for FGFR inhibitors in the treatment of intrahepatic cholangiocarcinoma, and for clinical trials in molecularly selected patient populations. Preclinical studies show that pemigatinib is a selective, potent, oral competitive inhibitor of FGFR1, FGFR2, and FGFR3. There are currently no published clinical studies of pemigatinib in this patient population.
Added value of this study
The FIbroblast Growth factor receptor inhibitor in oncology and Hematology Trial (FIGHT-202) is an international, open-label phase 2 trial evaluating the safety and antitumour activity of pemigatinib in 146 previously treated patients with locally advanced or metastatic cholangiocarcinoma. Among 107 patients with FGFR2 fusions or rearrangements, 38 (36%) achieved an objective response. This encouraging antitumour activity was observed across demographic and disease subgroups, including in heavily pretreated patients. The most common all-cause adverse event was hyperphosphataemia. Notable aspects of this study include incorporation of FGFR2 fusion partner-agnostic next-generation sequencing (ability to detect both known and novel FGFR2 fusions), and an independent central review of clinical responses. Moreover, the international design facilitated the enrolment of a large number of patients with cholangiocarcinoma with FGF/FGFR alterations (mostly FGFR2 rearrangements), despite this being a relatively rare cancer and a rare genomic alteration. This achievement provides impetus for future clinical trials in cholangiocarcinoma and in other rare cancers, for which achieving sufficient patient enrolment numbers can be challenging. Taken together, the data from this study add to a growing body of evidence supporting a role for FGFR inhibitors and other targeted agents for the treatment of cholangiocarcinoma by demonstrating that pemigatinib possesses antitumour activity and is associated with a manageable safety profile in patients with FGFR2 fusions or rearrangements.
Implications of all the available evidence
Based on the encouraging findings from this study, an international, phase 3, randomised, active-controlled trial is currently recruiting patients to compare pemigatinib with gemcitabine plus cisplatin chemotherapy as first-line therapy for unresectable or metastatic cholangiocarcinoma with FGFR2 rearrangements (FIGHT-302; ClinicalTrials.gov, NCT03656536). Pemigatinib could add to the range of treatments available to patients with cholangiocarcinoma and FGFR2 fusions or rearrangements, for whom current systemic therapies are not sufficiently effective.