Abstract 4881: Molecular screening of patients with FGFR alterations for phase 1 (ph1) study with the selective FGFR inhibitor Debio 1347
Authors: Anthony J. Iafrate, Darrell R. Borger, Ana Vivancos, Martin Voss, James Cleary, Funda Meric-Bernstam, Josep Tabernero, Keith Flaherty, Nobuya Ishii, Franck Brichory, Hiroaki Tanaka, Anna Pokorska-Bocci, Jose Baselga, Paolo Nuciforo
Journal: Cancer Research (2019)

Abstract Background: Oncogenic alterations in fibroblast growth factor receptors (FGFR) are seen across multiple solid tumors. Debio 1347 is an orally available, highly selective FGFR1,2,3 inhibitor that is undergoing phase I clinical trial evaluation in patients harboring an FGFR genetic abnormality. The availability of tumor tissue for retrospective genotyping, diversity of genetic alterations identified, and concordance with central laboratory testing were evaluated. Methods: Patients harboring an FGFR1/2/3 gene amplification, mutation, or fusion were identified by local laboratories using different technologies. Patients received escalating doses of Debio 1347 from 10mg up to 150mg daily. Diagnostic tumor tissue was secured for post-hoc analysis at a central laboratory (CL) to confirm the alterations reported on enrollment. Whenever possible, fresh biopsies were collected prior to starting treatment for comparison. Results: Archived diagnostic samples were available for most patients but material adequacy allowed for post-hoc genotyping to be performed in only 43 of 58 patients. For 23 of these patients, both a diagnostic sample and an on-study screening biopsy were secured and suitable for comparative analysis. Availability of screening material varied across tumor types. Overall, post hoc genetic testing on diagnostic tissue did not confirm the main FGFR alteration in 9 cases (23%): 4 FGFR amplifications, 2 fusions and 3 mutations. Four of FGFR amplifications could not be confirmed: two discordant calls were attributed to the difference in identifying polysomy over focal gene amplification. Two of 11 fusion cases were not centrally confirmed. For one of these cases, the low number of fusion reads for an FGFR3:TACC3 fusion was below the cutoff for CL reporting. When comparing genotypes between diagnostic and screening samples, concordance was 76% between the 2 CL sites. Efforts are ongoing to address all examples of discordance. Conclusions: The clinical diagnostic landscape proves to be complex. The use of different technologies with different sensitivities and analysis pipelines constitute one of many diagnostic hurdles. Biopsy availability across different cancer types and tumor heterogeneity add to its complexity, as well as tumor evolution over time from initial diagnosis to treatment. Citation Format: Anthony J. Iafrate, Darrell R. Borger, Ana Vivancos, Martin Voss, James Cleary, Funda Meric-Bernstam, Josep Tabernero, Keith Flaherty, Nobuya Ishii, Franck Brichory, Hiroaki Tanaka, Anna Pokorska-Bocci, Jose Baselga, Paolo Nuciforo. Molecular screening of patients with FGFR alterations for phase 1 (ph1) study with the selective FGFR inhibitor Debio 1347 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4881.