Fibroblast growth factor receptors (FGFRs) are broadly distributed transmembrane tyrosine kinase receptors. They promote cell development, differentiation, survival, migration, angiogenesis, and carcinogenesis. Specific FGFR aberrations was observed in certain cancers, some are known to be driver for tumor progression, and related to prognosis or sensitivity to cancer treatments. It is consistent to hypothesize that targeting these cancers with FGFR inhibitors would be therapeutically beneficial.
We lead a retrospective, descriptive, monocentric study, involving results of three phase I trials of Institut Gustave Roussy, for patients with refractory various solid tumors, previous selected on FGFR abnormality (amplification, single nucleotid variant (SNV), translocation). Primary endpoint was tumor response. Secondary endpoints were difference in tumor according to the type of mutation, and time to failure (TTF).
55 patients with median age of 55 years and various solid tumors were enrolled between February 16, 2011 and October 26, 2016. All patients had advanced or metastatic cancer with a median of 3.5 metastatic sites. They were heavily pretreated, in median 3 prior regimens of chemotherapy, 0 to 2 lines of targeted therapy, and one patient had immunotherapy. For patients with FGFR fusion proteins, 43% achieved partial response (PR). Median tumor response was - 46%, sustained response until 17 months. Response of SNV group depended on the type of mutation and degree of pathogenicity, in the different tumor locations. 20% had PR. Whereas some pathogenic mutations lead to dramatic response until 18 months; others failed to achieve tumor shrinkage or stabilization. 5% of patient with FGFR amplification had tumor response for 3 months only. Main clinical and biological toxicities were grade ½ and resolved after interruption. Treatment was resumed, at same or lower dose, excepted for 3 patients with permanently discontinuation. There was no death due to toxicity.
We identified genetic alterations in various members of the FGF/FGFR system that represent suitable predictive biomarkers to guide patient selection for treatment with selective pan FGFRs targeting agents.
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Institut Gustave Roussy
A. Hollebecque, R. Bahleda, J-C. Soria: Amgen, Astellas, Astra Zeneca, Bayer, Cellgene, Genentech, Ipsen, Jansen, Lilly, Novartis, Pfizer, Roche, Sanofi Aventis All other authors have declared no conflicts of interest.