Pt selection is critical for the future development of FGFRinh. Our institution aimed to implement a translational platform to obtain samples of FGFRalt pt included in phase 1 trials.
Prospective generation of a collection of pt samples with molecularly-selected FGFRalt tumors [amplified(amp)/mRNA high expression(mRNAh)/mutated(mut)/translocated(trans)]. We developed a protocol to obtain serial biopsies (bx) during therapy with an FGFRinh, including warm autopsies, for patient-derived xenografts (PDXs) generation. We collected plasma for analysis of circulating tumor DNA (ctDNA). Clinical benefit (ClinBen) was defined as any tumor shrinkage or disease control for 4 months.
From 2014 to 2017, 40 FGFRalt pt were included [FGFRamp (20)/mRNAh (7)/mut(17)/trans (3)]. 30 cases received an FGFRinh [multi-tyrosin kinase (7), selective reversible-(8) or irreversible-FGFR1-4inh (14) or FGFR4inh (1)]. 8 cases achieved ClinBen (5 breast - 2 FGFR1amp, 2 FGFR1mut, 1 11q+FGFR2amp-/1 biliary tract FGFR2trans/1 head&neck FGFR1mRNAh/1 mullerian carcinosarcoma FGFR2mut). PDXs/bx after progression to FGFRinh (10) and warm autopsies of responding pt (2) will serve to study tumor heterogeneity and resistance mechanisms using novel high-throughput technologies. All PDXs (16 growing/14 in observation) will help in identifying potential predictive biomarkers and further characterizing the mechanism of action of FGFRinh in vivo. In vitro functional profiling of oncogenic activity of FGFRmut (17) will be performed. Blood samples will serve for developing in-house cfDNA analysis to monitor genomic evolution of these 40 pt.
We have succesfully developed a powerful precision medicine framework for linking the molecular biology with the best tumor models in parallel with early clinical research. By integrating the knowledge obtained from the analysis of relevant samples, we aim to validate future hypothesis-driven therapies for selected FGFRalt pt and guide the successful development of FGFRinh. Co-funded by ISCIII-FEDER (PI15/00360).
Clinical trial identification
Legal entity responsible for the study
Vall d'Hebron Institute of Oncology
C. Hierro: Research fundings from Bayer A. Vivancos: Member of advisory boards for AztraZeneca, Sysmex, Merck. J. Tabernero: Member of advisory boards for Amgen, Bayer, Boehringer, Celgene, Chugai, Lilly, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Symphogen, Taiho and Takeda V. Serra: Research fundings from Bayer HealthCare J. Rodon: Member of advisory boards for Novartis, Lilly, Orion and has received research fundings from Principia and Bayer All other authors have declared no conflicts of interest.