BACKGROUND: The clinical activity of fibroblast growth factor receptor (FGFR) 
inhibitors seems restricted to cancers harbouring rare FGFR genetic aberrations. 
In preclinical studies, high tumour FGFR mRNA expression predicted response to 
rogaratinib, an oral pan-FGFR inhibitor. We aimed to assess the safety, maximum 
tolerated dose, recommended phase 2 dose, pharmacokinetics, and preliminary 
clinical activity of rogaratinib.
METHODS: We did a phase 1 dose-escalation and dose-expansion study of 
rogaratinib in adults with advanced cancers at 22 sites in Germany, Switzerland, 
South Korea, Singapore, Spain, and France. Eligible patients were aged 18 years 
or older, and were ineligible for standard therapy, with an Eastern Cooperative 
Oncology Group performance status of 0-2, a life expectancy of at least 3 
months, and at least one measurable or evaluable lesion according to Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1. During dose 
escalation, rogaratinib was administered orally twice daily at 50-800 mg in 
continuous 21-day cycles using a model-based dose-response analysis (continuous 
reassessment method). In the dose-expansion phase, all patients provided an 
archival formalin-fixed paraffin-embedded (FFPE) tumour biopsy or consented to a 
new biopsy at screening for the analysis of FGFR1-3 mRNA expression. In the 
dose-expansion phase, rogaratinib was given at the recommended dose for 
expansion to patients in four cohorts: urothelial carcinoma, head and neck 
squamous-cell cancer (HNSCC), non-small-cell lung cancer (NSCLC), and other 
solid tumour types. Primary endpoints were safety and tolerability, 
determination of maximum tolerated dose including dose-limiting toxicities and 
determination of recommended phase 2 dose, and pharmacokinetics of rogaratinib. 
Safety analyses were reported in all patients who received at least one dose of 
rogaratinib. Patients who completed cycle 1 or discontinued during cycle 1 due 
to an adverse event or dose-limiting toxicity were included in the evaluation of 
recommended phase 2 dose. Efficacy analyses were reported for all patients who 
received at least one dose of study drug and who had available post-baseline 
efficacy data. This ongoing study is registered with ClinicalTrials.gov, number 
NCT01976741, and is fully recruited.
FINDINGS: Between Dec 30, 2013, and July 5, 2017, 866 patients were screened for 
FGFR mRNA expression, of whom 126 patients were treated (23 FGFR mRNA-unselected 
patients in the dose-escalation phase and 103 patients with FGFR 
mRNA-overexpressing tumours [52 patients with urothelial carcinoma, eight 
patients with HNSCC, 20 patients with NSCLC, and 23 patients with other tumour 
types] in the dose-expansion phase). No dose-limiting toxicities were reported 
and the maximum tolerated dose was not reached; 800 mg twice daily was 
established as the recommended phase 2 dose and was selected for the 
dose-expansion phase. The most common adverse events of any grade were 
hyperphosphataemia (in 77 [61%] of 126 patients), diarrhoea (in 65 [52%]), and 
decreased appetite (in 48 [38%]); and the most common grade 3-4 adverse events 
were fatigue (in 11 [9%] of 126 patients) and asymptomatic increased lipase (in 
10 [8%]). Serious treatment-related adverse events were reported in five 
patients (decreased appetite and diarrhoea in one patient with urothelial 
carcinoma, and acute kidney injury [NSCLC], hypoglycaemia [other solid tumours], 
retinopathy [urothelial carcinoma], and vomiting [urothelial carcinoma] in one 
patient each); no treatment-related deaths occurred. Median follow-up after 
cessation of treatment was 32 days (IQR 25-36 days). In the expansion cohorts, 
15 (15%; 95% CI 8·6-23·5) out of 100 evaluable patients achieved an objective 
response, with responses recorded in all four expansion cohorts (12 in the 
urothelial carcinoma cohort and one in each of the other three cohorts), and in 
ten (67%) of 15 FGFR mRNA-overexpressing tumours without apparent FGFR genetic 
aberration.
INTERPRETATION: Rogaratinib was well tolerated and clinically active against 
several types of cancer. Selection by FGFR mRNA expression could be a useful 
additional biomarker to identify a broader patient population who could be 
eligible for FGFR inhibitor treatment.
FUNDING: Bayer AG.