A 74-year-old male was diagnosed with an advanced iCC of both liver lobes and pulmonary metastases (Figures 5 and 6). First-line chemotherapy with gemcitabine 800 mg/m2, cisplatin 25 mg/m2, and nab-paclitaxel 100 mg/m2 days 1 and 8 qd22 was initiated. After the fifth treatment cycle, progressive disease was observed. Biopsies of the liver lesions as well as a liquid biopsy were taken and a hybrid capture-based next-generation sequencing (NGS; FoundationOne CDx, Penzberg, Germany) was performed for the tissue biopsies and FoundationOne Liquide CDx for the blood samples.   The test is based on the examination of 324 genes as well as introns of 34 genes known to be involved in rearrangements. In addition, tumor mutation burden and microsatellite instability were evaluated. Sequencing revealed a p.C382R mutation located in the transmembrane receptor domain. The p.C382R was detected in both specimens with a variant allele frequency of 76.48% in the tissue biopsy and 8.1% in the blood sample. Regarding downstream signaling pathways, we detected a PTEN alteration (loss of exons 7-9 in tissue samples and loss of exons 3-8 in the liquid biopsy). The sequencing results are shown in Table 1. The results of the histologic examination are shown in Figure 4.
Furthermore, we performed an in silico study to understand the potential mode of p.C382R action. To modulate and visualize the protein structure results from p.C382R, we used AlphaFold2 (https://alphafold.ebi.ac.uk/entry/P21802). The evaluation revealed that the p.C382R mutation is located in the transmembrane domain at a position that is crucial for the oncogenic tyrosine kinase activation but does not interfere with the binding ability and inhibition of autophosphorylation of FGFR by pemigatinib.
Following the promising in vitro data for pemigatinib-targeted treatment and the reported results of three patients carrying FGFR2 p.C382R mutations who were treated with pemigatinib in the FIGHT 202 trial, we decided to initiate therapy after a discussion of the clinical case in the molecular tumor board (MTB).  
Pemigatinib of 13.5 mg was administered once daily for 14 days, followed by 7 days of therapy-free interval. The treatment outcome was evaluated by magnetic resonance imaging (MRI) and fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) before pemigatinib administration and after 3 months (Figures 5 and 6). In the pre- and post-MRI image data, an interactive tumor delineation method previously applied to liver CT data was used to determine the change in tumor size.   The images show a significant decrease in the tumor lesion volume from 453.9 to 133.7 ml after 3 months of treatment (Figure 5).
The FDG-PET/CT revealed a complete functional remission of the iCC and lung metastases after 3 months of treatment (Figure 6). The therapy is well tolerated without any side effects. The patient continues to be treated with 13.5 mg as described above. Over the course of the treatment, tumor markers that were elevated at baseline measurement decreased to a plateau (Figure 7).