Cholangiocarcinoma News

New Treatment Strategy for FGFR2 Fusion–Positive CCA

June 2023, Vol 4, No 2

Michael E. Lidsky, MD

Michael E. Lidsky, MD, presented his research on a novel model to investigate FGFR signaling and how this information may lead to a new treatment strategy for FGFR2 fusion–positive cholangiocarcinoma (CCA). For patients with advanced CCA, surgery is often not an option, and patients are left with systemic therapy as the only treatment option. Targeted therapies have growing potential as a therapeutic area for CCA, with FDA-approved FGFR inhibitors as an option for patients with previously treated, locally advanced or metastatic CCA; however, outcomes remain limited, with modest progression-free survival and overall survival benefits.

Dr Lidsky described a novel investigative model of FGFR2 fusion–positive intrahepatic CCA using patient-derived tissue to establish xenografts that are then inserted into mice. Using this model, the investigators found that FGFR2 signaling persists despite removing serum from the culture, and the FGFR inhibitor pemigatinib impairs FGFR2 signaling. To test the clinical relevance of this model, the cell lines and organoids were treated with pemigatinib. It was found that with increasing dose, increasing loss of viability was seen, and mice treated with pemigatinib had decreased tumor volume and increased survival probability.

Additional research aimed to investigate gemcitabine with pemigatinib in this model, and it was found that the addition of gemcitabine to pemigatinib was simply additive, not synergistic. A high-throughput small-molecule screen was then performed to determine a combination strategy that would augment pemigatinib therapy. Researchers found that quisinostat, a histone deacetylase (HDAC) inhibitor, in combination with pemigatinib is synergistic in cell lines and organoids, which was confirmed using panobinostat in combination with pemigatinib. This synergistic effect was also confirmed in vivo, where mice were randomized to pemigatinib, quisinostat, or a combination of both; mice receiving the combination therapy showed a significant difference in reduction of their tumor volume compared with either monotherapy, and this is beyond additive. Although the mechanism of this combination is not well understood, it was hypothesized that HDAC inhibition shifts the model toward an FGFR-dependent state, which can be effectively blocked with FGFR inhibition. Early-phase trials are needed to understand the clinical relevance of HDAC/FGFR inhibition in patients with CCA.


  1. Lidsky ME. Improving therapeutic efficacy and durability in FGFR2-f CCA. Presented at: Cholangiocarcinoma Foundation meeting, April 12-14, 2023; Salt Lake City, UT.

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