Use Of Tumor Mrna Expression For Patient Selection In A Phase I Study Of The Pan-Fibroblast Growth Factor Receptor Inhibitor Bay 1163877

BAY 1163877 is a potent and selective, oral, small molecule pan-FGFR inhibitor with anti-tumor activity in a wide range of cancer types. In vivo profiling in xenograft models identified tumor FGFR mRNA levels as a predictor of drug efficacy. Anti-tumor efficacy was largely independent of the tumor type surveyed or the FGFR isoform being overexpressed. Preclinical models included a patient-derived squamous head and neck cancer (HNSCC) xenograft (PDx) model overexpressing FGFR3 mRNA, a bladder cancer PDx model overexpressing FGFR2 mRNA, and a squamous esophageal cancer PDx model overexpressing FGFR1 mRNA. Against this background, clinical proof-of-concept was assessed by enrolling patients into the stratified expansion cohort of a Phase 1 study of BAY 1163877 (NCT01976741) based on tumor FGFR1-3 mRNA levels. FGFR1-3 mRNA was quantified in archival or newly obtained FFPE tumor biopsies by RNA in situ hybridization (RNAscope, ACD) and digital transcript counting (NanoString). In total, biopsies from u003e 500 patients were studied for FGFR1-3 mRNA expression levels. Based on preclinical xenograft experiments showing that low to moderate FGFR1-3 mRNA overexpression was not sufficient for a robust drug response, only patients with an RNAscope score of 3 or 4 (range 0-4) or a normalized Nanostring signal of 800 counts were eligible for enrollment. By applying these stringent criteria, FGFR1-3 mRNA positivity was on average observed with a 2- to 3-fold higher prevalence than published data for genetic aberrations of FGFRs in the respective tumor types (including amplifications, translocations, mutations). We further identified FGFR mRNA(+) tumor types in which genetic FGFR aberrations have not been previously reported. FGFR1-3 mRNA positivity ranged from 10% in lung adenocarcinoma to 45% in squamous non-small cell lung cancer (sqNSCLC) and 54% in HNSCC. As of August 2016, 57 FGFR mRNA(+) patients were enrolled and treated with BAY 1163877. Six patients experienced a partial remission (PR) by RECIST v1.1 criteria; including an FGFR3 mRNA(+) HNSCC patient without FGFR3 amplification or translocation, an FGFR1 mRNA(+) adenoid cystic carcinoma patient, and an FGFR1 mRNA(+) sqNSCLC patient (both without FGFR1 gene amplification), as well as an FGFR3 mRNA(+) bladder cancer patient without FGFR3 amplification, mutation or translocation. These results suggest that high FGFR1-3 mRNA expression identifies patients sensitive to FGFR inhibition. This population includes patients with and without genetic aberrations of FGFR1-3 encoding genes. In summary, an mRNA expression-based selection approach may identify a broader patient population with potential benefit from BAY 1163877, including tumor types not previously associated with altered FGFR signaling. Citation Format: Peter Ellinghaus, Matthias Ocker, Sebastian Bender, Christoph Kneip, Stuart Ince, Markus Joerger, Martin Schuler. Use of tumor mRNA expression for patient selection in a phase I study of the pan-fibroblast growth factor receptor inhibitor BAY 1163877 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3738. doi:10.1158/1538-7445.AM2017-3738