BGJ398, a first-in class pan–fibroblast growth factor receptor (pan-FGFR) kinase inhibitor, had modest clinical activity and a manageable toxicity profile, according to results of a phase 2 study of 61 patients with chemotherapy-refractory, advanced or metastatic cholangiocarcinoma with alterations in genes encoding FGFR.

FGFR-2 fusion mutations are found in 13% to 17% of patients with intrahepatic cholangiocarcinoma, a rare and highly aggressive cancer. Cholangiocarcinomas have a poor prognosis and are often diagnosed at an advanced unresectable stage with limited options after disease progression on gemcitabine-based therapy.

In the multicenter, open-label, single-arm study, single agent BGJ398 was associated with an overall response rate of 14.8% in 61 patients with predominant FGFR-2 fusions. The disease control rate (complete response plus partial response plus stable disease rate) was 75.4% with a median progression-free survival of 5.8 months, Milind Javle, MD, and his colleagues at the University of Texas MD Anderson Cancer Center, Houston, wrote in the Journal of Clinical Oncology (2017. doi: 10.1200/JCO.2017.75.5009 ).

BGJ398 was given orally once daily at a dose of 125 mg for 21 days followed by 7 days off the drug as part of a 28 day cycle that was based on findings from a phase 1 study. However, primarily because of treatment-related adverse events, 77% of patients required dose interruptions, and 62.3% required a median of two dose reductions to achieve a median drug exposure of about 4.7 months.

The most common all-grade treatment-related adverse event reported was hyperphosphatemia (72.1%), followed by fatigue (36.1%), stomatitis (29.5%), and alopecia (26.2%). Other toxicities, such as dry eyes (21.3%), blurred vision (14.8%), and onychomadesis (18%) were also reported. Serious adverse events (grade 3 or 4) were reported in 41% of patients, and 8.2% of patients discontinued treatment due to adverse events.

The toxicity profile was predictable, however, and was alleviated by intermittent (3-weeks-on/1-week-off) dosing, prophylaxis using phosphate-lowering agents, and dose reductions.

Although 100% of patients enrolled eventually acquired resistance to BGJ398 and experienced disease progression, a median progression-free survival of 5.8 months is encouraging, and this targeted therapy warrants further clinical evaluation, the authors concluded.

The study was funded by Novartis Pharmaceuticals. Dr. Javle and two other authors reported having no disclosures. Four of the study authors are Novartis employees, and several other authors reported conflicts of interest involving the sponsor or other pharmaceutical companies.


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