Results of the phase IIa RADICAL trial of the FGFR inhibitor AZD4547 in endocrine resistant breast cancer

Coombes, R.C. et al. (2022) Results of the phase IIa RADICAL trial of the FGFR inhibitor AZD4547 in endocrine resistant breast cancer. Nature Communications, 13, 3246. (doi: 10.1038/s41467-022-30666-0) (PMID:35688802) (PMCID:PMC9187670)

Abstract

We conducted a phase IIa, multi-centre, open label, single arm study (RADICAL; NCT01791985) of AZD4547 (a potent and selective inhibitor of Fibroblast Growth Factor Receptor (FGFR)-1, 2 and 3 receptor tyrosine kinases) administered with anastrozole or letrozole in estrogen receptor positive metastatic breast cancer patients who had become resistant to aromatase inhibitors. After a safety run-in study to assess safety and tolerability, we recruited 52 patients. The primary endpoint was change in tumour size at 12 weeks, and secondary endpoints were to assess response at 6 weeks, 20 weeks and every 8 weeks thereafter and tolerability of the combined treatment. Two partial responses (PR) and 19 stable disease (SD) patients were observed at the 12-week time point. At 28 weeks, according to centrally reviewed Response Evaluation Criteria in Solid Tumours (RECIST) criteria, five PR and 8 SD patients were observed in 50 assessable cases. Overall, objective response rate (5 PR) was of 10%, meeting the pre-specified endpoint. Fourteen patients discontinued due to adverse events. Eleven patients had retinal pigment epithelial detachments which was asymptomatic and reversible in all but one patient. Exploratory ribonucleic acid sequencing (RNA-Seq) analysis was done on patients’ samples: 6 differentially-expressed-genes could distinguish those who benefited from the addition of AZD4547.

• Item Type: Articles
• Additional Information: This work was supported by Cancer Research UK (C1312/A12956) and AstraZeneca (D9010C00011) as part of the Experimental Cancer Medicines Centre (ECMC), DoH and CRUK Combinations Alliance initiative
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: MacPherson, Professor Iain
• Authors: Coombes, R.C., Badman, P.D., Lozano-Kuehne, J.P., Liu, X., MacPherson, I. R., Zubairi, I., Baird, R.D., Rosenfeld, N., Garcia-Corbacho, J., Cresti, N., Plummer, R., Armstrong, A., Allerton, R., Landers, D., Nicholas, H., McLellan, L., Lim, A., Mouliere, F., Pardo, O.E., and Seckl, M.J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Nature Communications 13(1):3246
• Publisher Policy: Reproduced under a Creative Commons License