FGFRs are potential targets for anticancer therapy. Because FGFR expression can be de-regulated by genetic and epigenetic mechanisms, tumor FGFR mRNA levels may identify patients likely to benefit from FGFR-targeted approaches. BAY 1163877 (BAY) is an oral, potent small molecule inhibitor of FGFRs 1-3. We conducted a first-in-human dose-escalation (DE) study of BAY in subjects with advanced solid tumors, followed by expansion cohorts (ECs) in selected subjects with high tumor FGFR1-3 mRNA levels (NCT01976741).
Subjects with treatment-refractory advanced or metastatic solid tumors were enrolled in 6 dose cohorts ranging from 50-800 mg BID on a continuous 21-day cycle. Pharmacokinetics (PK) were evaluated on days 1 and 15 of cycle 1. Subjects were enrolled to 3 ECs (non-small cell lung cancer [NSCLC], bladder cancer and head and neck squamous cell carcinoma [HNSCC], and all-comers) based on high FGFR expression levels by RNAscope™ and Nanostring™ analysis of fresh or archival tumor specimens. Objective responses were assessed by RECIST 1.1 after cycle 2.
Seventy-six patients with advanced solid tumors were enrolled and treated, including 23 patients in the DE phase and 53 patients in the ECs. BAY was absorbed rapidly and exhibited an average plasma half-life of 12.7 hours. The most common adverse events were hyperphosphatemia, diarrhea and alopecia (grade 1 and 2). We observed a less than dose-proportional increase in exposure at doses > 200 mg BID, and based on effective target inhibition and a lack of dose-limiting toxicities 800 mg BID was declared as the recommended phase-2 dose. From 44 evaluable patients, 5 partial responses (PR) were seen from patients in the ECs, including HNSCC, sqNSCLC, adenoidcystic carcinoma of the tongue, and 2 with bladder cancer. An additional 18 EC patients had stable disease (SD) >12 weeks, of whom 8 had SD >24 weeks. The majority of patients, including 4 of 5 with PR, did not have FGFR genetic alterations.
BAY 1163877 at doses up to 800 mg BID was safe and well tolerated. The response profile supports selection of patients for treatment with a FGFR inhibitor based on tumor FGFR mRNA levels.
Clinical trial identification
Legal entity responsible for the study
R. Soo: Honoraria: Astra-Zeneca, Boehringer Ingelheim, Lilly, Merck, Novartis, Pfizer, Roche, Taiho Consulting/advisory: Astra-Zeneca, Boehringer Ingelheim, Merck, Novartis, Pfizer, Roche, Taiho. P. Ellinghaus, S. Hildebrandt, M. Ocker: Employee of Bayer AG. S. Behre, C. Helmbrecht, S. Kerpen: Employee of Linical Europe GmbH. D. Zielinski: Employee of Targos GmbH. S. Ince, P. Rajagopalan: Employee of Bayer HealthCare Pharmaceuticals. M. Schuler: Research: Boehringer-Ingelheim, BMS, Novartis Honoraria/consultancies: Alexion, AZ, BI, BMS, Celgene, IQWig, GSK, Lilly, Novartis, Pfizer. All other authors have declared no conflicts of interest.