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.
Bibliographical noteFunding Information:
Rogaratinib treatment in patients selected by FGFR overexpressing cancers resulted in a manageable safety profile and encouraging antitumour activity, even in patients refractory to immune checkpoint inhibitors. Our data suggest that FGFR mRNA positivity could be a clinically useful biomarker in addition to genetic alterations, identifying more patients who are likely to be susceptible to FGFR inhibition. Considering their pleiotropic effects in cancer development and progression, FGFRs are promising drug targets for a broad range of cancers. The therapeutic window of currently available FGFR inhibitors is restricted by effects in non-malignant tissues. Accordingly, strategies have been devised to identify malignancies that are more susceptible to FGFR inhibition. So far, oncogenic FGFR gene fusions or activating FGFR3 mutations have been validated as predictors for clinical activity of FGFR inhibitors. 4 However, these genetic aberrations have only been identified in a small number of patients with specific cancer types. 12 We have coordinated clinical development of rogaratinib, a novel, highly selective, and potent oral pan-FGFR inhibitor, 23 with an innovative biomarker strategy to broaden the spectrum of patients who might benefit from treatment. Preclinical studies identified tumour FGFR1–3 mRNA expression as a robust predictor of rogaratinib response, including in models devoid of FGFR gene aberrations. 14 This first-in-human phase 1 study established safety and tolerability of rogaratinib, and explored its clinical activity in patients selected by FGFR mRNA expression levels in tumour biopsies. Rogaratinib was well tolerated, and no dose-limiting toxicities were observed up to a dose of 800 mg twice daily in continuous 21-day treatment cycles. As expected for FGFR inhibitors because of their mode of action, rogaratinib induced dose-dependent hyperphosphataemia ( figure 1B , appendix pp 16–17 ) in patients treated with doses higher than 400 mg twice daily, due to on-target inhibition of the FGF23–FGFR1–Klotho pathway involved in renal phosphate homeostasis. 22 The observed hyperphosphataemia is consistent with results from other recently developed FGFR inhibitors. 4,5 In the overall study population, 15% of evaluable patients achieved an objective response, which compares favourably with the proportion of responses observed with other selective pan-FGFR inhibitors in early clinical trials, such as AZD4547 (8%), 3 infigratinib (8–15%), 4,7 and erdafitinib (21·7%). 5 By contrast with our study, patients with urothelial carcinoma in other trials were selected based on FGFR3 -activating mutations or FGFR2 / 3 gene fusions. The proportion of patients with urothelial cancer selected by FGFR mRNA overexpression who achieved an objective response with rogaratinib (24%) was similar to the proportion of patients selected by FGFR genetic alterations responding to other FGFR inhibitors (21% with pemigatinib, 24 25·4% with infigratinib 25 ), whereas the most potent FGFR inhibitor, erdafitinib, has been associated with a higher proportion of patients achieving an objective response (40%). 26 Our FGFR mRNA-based screening identified a broader proportion (up to 50%) of FGFR mRNA-positive patients in the overall urothelial carcinoma patient population, including patients with and without apparent FGFR genetic alterations. In preclinical models, antitumour activity of rogaratinib strongly correlated with high tumour FGFR1–3 mRNA expression and was independent of tumour type or FGFR subtype. 14 Therefore, we analysed all tumour biopsies obtained during the prescreening phase for FGFR1–3 mRNA expression. The FGFR4 subtype was excluded from analysis because few FGFR4 mRNA-positive tumours were identified during the assay validation phase. Tumour-agnostic FGFR1–3 mRNA expression-based screening identified around 2–3 times more patients as FGFR -positive, and eligible for rogaratinib treatment, in all cancers evaluated (50% in urothelial carcinoma), than that reported for the prevalence of FGFR genetic alterations (21% in urothelial carcinoma 19,26 ). The higher proportion of FGFR -positive patients identified by our screening approach can be explained by the overexpression of FGFRs independent of apparent genetic alterations—eg, epigenetic dysregulation, transcriptional dysregulation, or non-coding alterations. 27,28 The importance of these non-genetic mechanisms is corroborated by preclinical data showing that nearly half of the tested infigratinib-sensitive cell lines have no apparent FGFR genetic alterations. 29 We observed high FGFR3 mRNA expression in patients with urothelial carcinoma harbouring FGFR3 gene mutations or fusions in our population and in a dataset obtained from The Cancer Genome Atlas. Screening for FGFR RNA expression in addition to multiplex profiling of genomic biomarkers, which is now broadly done across many cancer entities, might increase the likelihood of a given patient benefiting from FGFR-directed targeted therapy. The potential of our tumour-agnostic biomarker approach is highlighted by responses observed for the first time, to our knowledge, in tumours without apparent FGFR genetic alterations, including tumours positive for FGFR subtypes that have not yet been reported to be drug-sensitive by FGFR DNA-based screening: FGFR1 mRNA-positive urothelial carcinoma, FGFR3 mRNA-positive HNSCC, and FGFR1 mRNA-positive adenoid cystic carcinoma. No differences were observed in the proportion and extent of best tumour response between patients with FGFR mRNA-positive and DNA-positive urothelial carcinoma compared with patients with only FGFR mRNA-overexpressing urothelial carcinoma. The prevalence of FGFR3 mRNA-positive tumours in advanced, muscle-invasive urothelial carcinoma was substantially higher in our study (50%) than that of FGFR DNA alterations (around 20%) reported previously. 4,26,30,31 This difference is particularly important, since treatment options for patients with urothelial carcinoma remain scarce. FGFR positivity was confirmed as a molecular hallmark of the luminal-papillary subtype of urothelial carcinoma that is characterised by a low level of T-cell infiltration and low PD-L1 expression, thus deriving the smallest benefit of immune checkpoint inhibitor treatment. 32 Our finding that rogaratinib induced objective responses and shrinkage of target lesions in patients with urothelial carcinoma in whom previous treatment with immune checkpoint inhibitors had no benefit supports the use of FGFR inhibitor treatment over checkpoint inhibition for FGFR-positive patients with urothelial carcinoma who have progressed on prior platinum-based therapies, which is consistent with other studies. 4,26 Several mechanisms of resistance to FGFR-directed therapy have been postulated on the basis of preclinical findings, including PIK3CA and RAS hotspot activating mutations 21 or MET overexpression. 14 Retrospective analysis of tumour genomic DNA obtained before rogaratinib treatment identified PIK3CA or RAS mutations in four of 14 patients with urothelial carcinoma who had progressive disease, however, no such mutations were detected in patients who had an objective response. Excluding patients with PIK3CA or RAS mutations from the urothelial carcinoma cohort increased the proportion of patients who achieved an objective response in our study from 24% to 27%. A fully automated companion diagnostics assay to detect FGFR1 and FGFR3 mRNA expression is currently in development ( NCT03410693 ). Limitations of this study include the small sample size for some of the tumour types evaluated, and the lack of genomic data for all patients. Additionally, the cutoff values used to determine FGFR mRNA overexpression have not yet been clinically validated. Overall, the clinical application of FGFR mRNA overexpression as a novel biomarker enables the identification of more patients who could benefit from FGFR inhibition. Rogaratinib is currently being investigated in several ongoing clinical trials as a monotherapy ( NCT03762122 , NCT03410693 ) and in combination with immune checkpoint inhibitors ( NCT03473756 ) or targeted therapies ( NCT03517956 , NCT03088059 ). In summary, rogaratinib treatment in patients selected by overexpression of FGFR1–3 mRNA is a promising new option in precision oncology for the treatment of advanced cancers. Contributors MSchu, PR, OB, MO, and PE designed the study. All authors generated the data. MSchu, JG, SB, HN, MO, PE, and MJ reviewed the data and wrote the report. Declaration of interests PR, SB, OB, HN, MO, and PE are employees of Bayer AG. HN, MO, and PE are shareholders of Bayer AG. JG is employed by BAST, which received funding from Bayer AG. PE has a patent pending (20180333418). MSchu is a consultant (compensated) for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb (BMS), Novartis, and Roche; has received honoraria for continuing medical education presentations from AbbVie, Alexion, Boehringer Ingelheim, BMS, Celgene, Lilly, Merck Sharp & Dohme (MSD), Novartis, and Pierre Fabre; and has received research funding (to his institution) from AstraZeneca, Boehringer Ingelheim, BMS, and Novartis. BCC reports research funding from AstraZeneca, Bayer, Champions Oncology, Dizal Pharma, Dong-A ST, Janssen, MOGAM Institute, MSD, Novartis, Ono, and Yuhan; has acted as a consultant for AstraZeneca, BMS, Boehringer Ingelheim, Janssen, Lilly, MSD, Novartis, Ono, Pfizer, Roche, Takeda, and Yuhan; has stock ownership in TheraCanVac Inc; and has received royalties from Champions Oncology. CMS has received personal fees from BMS and Celgene, outside the submitted work. AN reports personal fees from BMS, Oryzon Genomics, and Roche, and personal fees and non-financial support from Boehringer Ingelheim and Pfizer, outside the submitted work. RAS reports grants from AstraZeneca, and personal fees from AstraZeneca, BMS, Boehringer Ingelheim, Celgene, MSD, Novartis, Pfizer, Roche, Taiho, Takeda, and Yuhan, outside the submitted work. PAC reports personal fees and non-financial support from AstraZeneca; personal fees from Amgen and Roche; and grants, personal fees, and non-financial support from MSD and Novartis, outside the submitted work. LN reports grants from Bayer, during the conduct of the study; grants and personal fees from BMS and Janssen; grants, personal fees, and non-financial support from Novartis and Pfizer; grants from MSD; personal fees from Roche and Takeda; and personal fees and non-financial support from Boehringer Ingelheim and Celgene, outside the submitted work. MScho reports grants from Bayer, during the conduct of the study; grants from AstraZeneca, Bayer, BMS, MSD, Novartis, and Sanofi, outside the submitted work; and has received honoraria from AstraZeneca, Bayer, BMS, EDAP-TMS, MSD, Novartis, Sanofi, and Takeda, outside the submitted work. RC reports personal fees from Astellas, AstraZeneca, Bayer, BMS, MSD, and Roche, outside the submitted work. HR, DT, NP, SHP, PG, and MJ declare no competing interests.
Availability of study data will be determined according to Bayer's commitment to the EFPIA/PhRMA Principles for Responsible Clinical Trial Data Sharing. This pertains to scope, time point, and process of data access. Bayer commits to sharing upon request from qualified scientific and medical researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the USA and European Union (EU) as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after Jan 1, 2014. Interested researchers can make a request via www.clinicalstudydatarequest.com to access anonymised patient-level data and supporting documents. Data will be available no later than within 1 year of study completion. Data access will be granted for anonymised patient-level data, protocols, and clinical study reports after approval by an independent scientific review panel. Bayer is not involved in the decisions made by the independent review panel. Bayer will take all necessary measures to ensure that patient privacy is safeguarded. Acknowledgments This study was funded by Bayer AG. We thank all patients and their families for supporting this study. We thank Sandra Hildebrandt, Frieder Wolff, Simone Behre, Dubravka Pavic-Sladoljev, Corinna Helmbrecht, and Stephanie Kerpen for their operational support. We also thank Jack Adams (Complete HealthVizion, Manchester, UK), who provided medical writing assistance on the basis of detailed discussion and feedback from all the authors, which was funded by Bayer AG.
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