TY - JOUR
T1 - Results of the phase IIa RADICAL trial of the FGFR inhibitor AZD4547 in endocrine resistant breast cancer
AU - Coombes, R. C.
AU - Badman, P. D.
AU - Lozano-Kuehne, J. P.
AU - Liu, X.
AU - Macpherson, I. R.
AU - Zubairi, I.
AU - Baird, R. D.
AU - Rosenfeld, N.
AU - Garcia-Corbacho, J.
AU - Cresti, N.
AU - Plummer, R.
AU - Armstrong, A.
AU - Allerton, R.
AU - Landers, D.
AU - Nicholas, H.
AU - McLellan, L.
AU - Lim, A.
AU - Mouliere, F.
AU - Pardo, O. E.
AU - Seckl, M. J.
N1 - Funding Information:
We thank all the RADICAL trial participants and the women who participated in this study, the research teams at participating hospitals (Russells Hall Hospital and Queen’s Hospital Burton), the ECMCs (Imperial College London, Glasgow, Cambridge, Newcastle and Manchester) and the ECMC Combinations Alliance for their support. We also acknowledge the NIHR Manchester Clinical Research Facility at The Christie NHS Foundation Trust. 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. IMP (AZD4547) was provided free of charge by AZ and distributed by Fisher Clinical Services. The study was Sponsored by Imperial College London and coordinated by the Imperial Clinical Trials Unit – Cancer, Imperial College London (ICTU-Ca) on behalf of the Sponsor. ICTU-Ca were involved in study design, data collection, analysis and manuscript writing. The authors thank ICTU Clinical Data Systems team for designing the eCRFs and database capture system. ICTU–Ca receives infrastructure support from Imperial Experimental Cancer Medicine Centre, Cancer Research UK Imperial Centre, National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC) and Imperial College Healthcare NHS Trust Tissue Bank. The study was also supported by the CRUK Cambridge Centre, the Cambridge ECMC and NIHR BRC and Cambridge Clinical Research Centre. We also thank the independent members of the trial steering committee (Prof Robert Coleman (Chair); Prof. Chris Twelves and Dr Janine Mansi) and the independent data monitoring committee (Prof. Daniel Rea (Chair); Dr Shah-Jalal Sarker and Dr Larry Hayward). We are also extremely grateful to the Independent Cancer Patients’ Voice, particularly Adrienne Morgan for her input, guidance and help with the patient information sheet and to April Ann Matthews for her participation in the study steering committee meetings. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
Funding Information:
We thank all the RADICAL trial participants and the women who participated in this study, the research teams at participating hospitals (Russells Hall Hospital and Queen’s Hospital Burton), the ECMCs (Imperial College London, Glasgow, Cambridge, Newcastle and Manchester) and the ECMC Combinations Alliance for their support. We also acknowledge the NIHR Manchester Clinical Research Facility at The Christie NHS Foundation Trust. 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. IMP (AZD4547) was provided free of charge by AZ and distributed by Fisher Clinical Services. The study was Sponsored by Imperial College London and coordinated by the Imperial Clinical Trials Unit – Cancer, Imperial College London (ICTU-Ca) on behalf of the Sponsor. ICTU-Ca were involved in study design, data collection, analysis and manuscript writing. The authors thank ICTU Clinical Data Systems team for designing the eCRFs and database capture system. ICTU–Ca receives infrastructure support from Imperial Experimental Cancer Medicine Centre, Cancer Research UK Imperial Centre, National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC) and Imperial College Healthcare NHS Trust Tissue Bank. The study was also supported by the CRUK Cambridge Centre, the Cambridge ECMC and NIHR BRC and Cambridge Clinical Research Centre. We also thank the independent members of the trial steering committee (Prof Robert Coleman (Chair); Prof. Chris Twelves and Dr Janine Mansi) and the independent data monitoring committee (Prof. Daniel Rea (Chair); Dr Shah-Jalal Sarker and Dr Larry Hayward). We are also extremely grateful to the Independent Cancer Patients’ Voice, particularly Adrienne Morgan for her input, guidance and help with the patient information sheet and to April Ann Matthews for her participation in the study steering committee meetings. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12/1
Y1 - 2022/12/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85131820221
UR - https://www.ncbi.nlm.nih.gov/pubmed/35688802
U2 - 10.1038/s41467-022-30666-0
DO - 10.1038/s41467-022-30666-0
M3 - Article
C2 - 35688802
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3246
ER -
SDG 3 Good Health and Well-being