Pemigatinib Is Active in Some FGFR2-Altered Cholangiocarcinomas

FGFR2 fusions or rearrangements occur in 10% to 16% of intrahepatic cholangiocarcinomas (bile duct cancers) and are thought to promote tumorigenesis via altered FGFR signaling, resulting in increased cell proliferation, migration, survival, and invasion. In a multicenter, open-label, single-arm phase II clinical trial, Abou-Alfa and colleagues evaluated the efficacy of the selective FGFR1/2/3 competitive inhibitor pemigatinib in 146 patients with previously treated locally advanced or metastatic cholangiocarcinoma with or without FGF or FGFR alterations. Patients were divided into three cohorts: one including those with FGFR2 fusions or rearrangements (107 patients), another including those with other FGF or FGFR alterations (20 patients), and a third including those with no FGF or FGFR alterations (18 patients). One patient was of undetermined FGF/FGFR alteration status and was included in the safety but not efficacy analysis. Pemigatinib was generally tolerable in this patient population, with the most common side effect being hypophosphatemia, a common side effect of FGFR inhibitors likely arising from FGFR1's involvement in phosphate homeostasis. The best responses were observed in patients with FGFR2 fusions or rearrangements, among whom the median duration of response was 7.5 months and the overall response rate was 35.5%, including 2.8% with complete responses and 32.7% with partial responses. Further, 82.0% of patients in this cohort had disease control. In contrast, 40.0% of patients with other FGF or FGFR alterations and 22.2% of patients without FGF or FGFR alterations experienced stable disease, and no patient in either cohort exhibited a response. Limitations of this study include the lack of an active comparator group and the inability to determine the potential influence of FGFR alterations on survival. In summary, this trial indicates that pemigatinib is a promising treatment for cholangiocarcinomas with FGFR2 fusions or rearrangements. As a result of these findings, a phase III trial comparing pemigatinib to standard-of-care gemcitabine plus cisplatin chemotherapy as first-line treatment in metastatic or unresectable FGFR2-rearranged cholangiocarcinoma is now under way.

Abou-Alfa GK, Sahai V, Hollebecque A, Vaccaro G, Melisi D, Al-Rajabi R, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol 2020 Mar 20 [Epub ahead of print].

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