Background: Fibroblast growth factor receptor (FGFR)-mediated pathways are considered to be promising anticancer therapy targets. There are several types of genetic evidence that support an oncogenic function of FGFRs: identification of gene amplifications, activating mutations, chromosomal translocations, and aberrant splicing at the post-transcriptional level. Since FGFR expression is regulated not only by genetic but also by epigenetic mechanisms, examination of tumor FGFR mRNA levels may identify cancer patients likely to benefit from rogaratinib (BAY 1163877), an oral, potent small-molecule pan-FGFR inhibitor. We conducted a phase I study of rogaratinib in Japanese subjects with refractory, locally advanced or metastatic solid tumors selected by elevated tumor FGFR1-3 mRNA expression to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy (NCT02592785). Methods: Japanese subjects were enrolled at 600 mg BID (Cohort1) or 800 mg BID as the recommended phase 2 dose (Cohort 2) on a continuous 21-day cycle based on high FGFR1-3 mRNA expression. Archival or newly obtained formalin-fixed, paraffin-embedded (FFPE) tumor tissue samples were analyzed for elevated FGFR1-3 mRNA levels by RNA in situ hybridization (RNAscope®; Advanced Cell Diagnostics, Inc., Newark, CA) and Nanostring® assay (NanoString Technologies, Inc., Seattle, WA). Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results: In the prescreening phase of this study, 62 FFPE samples from cancer patients with several tumor types were assessed for FGFR1-3 tumor mRNA expression levels and the valid prescreening results were obtained from 48 samples. Among them, 16 samples (16/48, 33%) were found to overexpress FGFR mRNA. Overall, 9 FGFR mRNA-positive patients were enrolled and treated with rogaratinib, 3 in Cohort 1 and 6 in Cohort 2. All subjects had experienced more than one adverse event (AE). Most of them were Grade 1 or 2. No DLT, no SAE, no Grade 4 or 5 AEs were reported. Two G3 drug-related AEs were hyponatremia and increased ALT. The most common treatment related AE was hyperphosphatemia with Grade 1 or 2 and all cases were controllable with anti-hyperphosphatemia treatment. PK exposure in Japanese subjects was comparable to Western subjects. Eight patients could be advanced to at least one tumor response assessment by CT imaging. As a result, 1 patient with epipharynx cancer achieved a partial response (PR) while 5 patients had stable disease (SD) as best response in target lesions, including three SD patients with tumor shrinkage compared to baseline CT imaging. Conclusions: Rogaratinib showed a good tolerability with a confirmed PR and a disease control rate (DCR) of 56% (5/9). We concluded that 800 mg BID is safe and well tolerable to Japanese patients confirming the global recommended dose. The high prevalence of FGFR mRNA overexpression in tumors as well as the clinical response of FGFR-positive tumors support an mRNA-based patient selection for FGFR inhibitor treatment of cancer.

Citation Format: Makoto Tahara, Shunji Takahashi, Matthias Ocker, Stuart Ince, Hendrik Nogai, Changliang Zhang, Fumiyoshi Sei, Peter Ellinghaus. Safety, tolerability, pharmacokinetics, and efficacy of pan-fibroblast growth factor receptor inhibitor rogaratinib in Japanese patients with refractory, locally advanced metastatic solid tumors selected with a novel, mRNA-based patient selection strategy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A099.