Alterations in fibroblast growth factor receptor (FGFR) genes have been 
identified as potential driver oncogenes. Pharmacological targeting of FGFRs may 
therefore provide therapeutic benefit to selected cancer patients, and 
proof-of-concept has been established in early clinical trials of FGFR 
inhibitors. Here, we present the molecular structure and preclinical 
characterization of INCB054828 (pemigatinib), a novel, selective inhibitor of 
FGFR 1, 2, and 3, currently in phase 2 clinical trials. INCB054828 
pharmacokinetics and pharmacodynamics were investigated using cell lines and 
tumor models, and the antitumor effect of oral INCB054828 was investigated using 
xenograft tumor models with genetic alterations in FGFR1, 2, or 3. Enzymatic 
assays with recombinant human FGFR kinases showed potent inhibition of FGFR1, 2, 
and 3 by INCB054828 (half maximal inhibitory concentration [IC50] 0.4, 0.5, and 
1.0 nM, respectively) with weaker activity against FGFR4 (IC50 30 nM). 
INCB054828 selectively inhibited growth of tumor cell lines with activation of 
FGFR signaling compared with cell lines lacking FGFR aberrations. The 
preclinical pharmacokinetic profile suggests target inhibition is achievable by 
INCB054828 in vivo with low oral doses. INCB054828 suppressed the growth of 
xenografted tumor models with FGFR1, 2, or 3 alterations as monotherapy, and the 
combination of INCB054828 with cisplatin provided significant benefit over 
either single agent, with an acceptable tolerability. The preclinical data 
presented for INCB054828, together with preliminary clinical observations, 
support continued investigation in patients with FGFR alterations, such as 
fusions and activating mutations.