LUGANO-COPENHAGEN – The first-in-human dose escalation study of the pan-FGFR (fibroblast growth factor receptor) inhibitor BAY 1163877 in patients with treatment-refractory locally advanced or metastatic solid tumours were reported today at the ESMO 2016 Congress in Copenhagen.1 The novel compound uses messenger RNA (mRNA) in tumours to identify patients who will respond.
“Most studies of FGFR inhibitors have looked at FGFR abnormalities in tumours with limited success,” said lead author Dr Markus Joerger, attending medical oncologist, St Gallen Cancer Centre, Switzerland. “This study used an innovative biomarker approach of tumour FGFR mRNA expression.”
This multicentre phase I study was conducted in six countries. The dose-escalation study was followed by expansion cohorts in patients with high tumour FGFR mRNA levels. A total of 80 patients were enrolled and treated, including 23 patients in the dose-escalation phase and 57 patients in the expansion cohorts in bladder cancer, head and neck cancer, lung cancer, and all comers.
The dose escalation study tested five doses ranging from 50–800 mg BID (twice daily). BAY 1163877 has a half-life of about 12 hours and revealed less than dose-proportional increase in exposure at doses above 200 mg. A maximum tolerated dose was not defined because there were no dose-limiting toxicities. Based on the results of preclinical studies, the effect on serum phosphate levels and clinical analyses, 800 mg BID was recommended for future study.
Regarding toxicities, most patients developed low-grade hyperphosphatemia, which occurs with all FGFR inhibitors. These patients were given a phosphate binder and the dose of BAY 1163877 could be reduced to avoid further increases of phosphate levels in the blood.
In the expansion cohorts, the highest activity of BAY 1163877 was seen in bladder cancer, with three partial remissions out of eight patients. Partial remissions were also seen in individual patients with squamous cell lung cancer, squamous cell carcinoma of the head and neck and adenoid cystic carcinoma, the latter response lasting more than one year.
Joerger said: “BAY 1163877 is a well-tolerated compound with an innovative biomarker approach that effectively identifies patients who have a good chance to benefit. Further studies should be conducted, particularly in bladder cancer where about 35% of patients are FGFR mRNA positive.”
Commenting on the results, Prof Giuseppe Curigliano, Chair of the Division of Early Drug Development Therapeutics, European Institute of Oncology in Milan, Italy said: “FGFR inhibitors may provide a therapeutic opportunity to patients with rare tumours. In this patient population there were some patients with adenoid cystic carcinoma with long term control of the disease. In the context of molecular screening programmes we may offer a chance to patients with FGFR mRNA expression.”
“The toxicity profile of BAY 1163877 is better than other FGFR inhibitors under development,” he continued. “More studies are needed to identify which patients will benefit from FGFR inhibitors – in this study, tumour FGFR mRNA expression was the best predictor of response. The next step will be to validate these results in future clinical trials.”
Notes to Editors
- Abstract 360O_PR - ‘Phase I study of the pan-fibroblast growth factor receptor (FGFR) inhibitor BAY 1163877 with expansion cohorts for subjects based on tumor FGFR mRNA expression levels‘ will be presented by Dr Markus Joerger during the Proffered Paper session, Developmental Therapeutics on Saturday, 8 October, 11:00 to 12:30 (CEST) in room Rome.
- FGFR: fibroblast growth factor receptor
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Abstract for 360O_PR
Phase I study of the pan-fibroblast growth factor receptor (FGFR) inhibitor BAY 1163877 with expansion cohorts for subjects based on tumor FGFR mRNA expression levels
M. Joerger1, R. Soo2, B.C. Cho3, A. Navarro Mendivil4, C. Sayehli5, H. Richly6, D. Tai7, D.-W. Kim8, J. Wolf9, P. Cassier10, P. Ellinghaus11, S. Hildebrandt12, S. Behre13, C. Helmbrecht13, S. Kerpen13, D. Zielinski14, S. Ince15, P. Rajagopalan16, M. Ocker17, M. Schuler18
1Dept. of Oncology, Cantonal Hospital, St. Gallen, Switzerland, 2Cancer Institute, National University Cancer Institute, Singapore, 3Internal Medicine, Yonsei Cancer Center, Seoul, Republic of Korea, 4Medical Oncology, Vall d`Hebron University Hospital Institut d'Oncologia, Barcelona, Spain, 5Medical Oncology, University Hospital Wuerzburg, Würzburg, Germany, 6West German Cancer Center, University Hospital Essen, Essen, Germany, 7Dept. Medical Oncology, National Cancer Center, Singapore, 8Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea, 9Internal Medicine, University Hospital of Cologne, Cologne, Germany, 10Medical Oncology, Léon Bérard Cancer Center, Lyon, France, 11Biomarker Research, Bayer AG, Berlin, Germany, 12Clinical Development, Bayer AG, Berlin, Germany, 13Clinical Development, Linical Europe GmbH, Frankfurt Am Main, Germany, 14Molecular Pathology, Targos GmbH, Kassel, Germany, 15Clinical Development, Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA, 16Clinical Pharmacology, Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA, 17Clinical Sciences, Bayer AG, Berlin, Germany, 18Medical Oncology, University Hospital Essen, Essen, Germany
Background: 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).
Methods: 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.
Results: 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.
Conclusions: 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: NCT01976741
Legal entity responsible for the study: Bayer AG
Funding: Bayer AG
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.
Keywords: RNA expression, FGFR inhibitor, dose escalation, safety