TY - JOUR
T1 - A phase 1b study evaluating the effect of elacestrant treatment on estrogen receptor availability and estradiol binding to the estrogen receptor in metastatic breast cancer lesions using 18F-FES PET/CT imaging
AU - Jager, Agnes
AU - de Vries, Elisabeth G. E.
AU - der Houven van Oordt, C. Willemien Menke-Van
AU - Neven, Patrick
AU - Venema, Clasina M.
AU - Glaudemans, Andor W. J. M.
AU - Wang, Yamei
AU - Bagley, Rebecca G.
AU - Conlan, Maureen G.
AU - Aftimos, Philippe
N1 - Funding Information: We thank Geraldine Gebhart, MD, from the Institut Jules Bordet for performing the FES-PET and CT scans and Phillips Gilmore Oncology Communications Inc., for professional assistance with manuscript preparation, which was funded by Radius Health, Inc. Funding Information: This work was supported by Radius Health, Inc. on behalf of its wholly owned subsidiary, Radius Pharmaceuticals, Inc. Funding Information: AJ: No competing interest. EdV: Institutional financial support for advisory role from Daiichi Sankyo, Merck, NSABP, Pfizer, Sanofi, and Synthon and institutional financial support for clinical trials or contracted research from Amgen, AstraZeneca, Bayer, Chugai Pharma, CytomX Therapeutics, G1 Therapeutics, Genentech, Nordic Nanovector, Radius Health, Regeneron, Roche, Servier, and Synthon. CWMdHvO: Institutional financial support for clinical trials or contracted research from BMS, Boeringher Ingelheim, Crystal Therapeutics, CytomX Therapeutics, G1 Therapeutics, Pfizer, Takeda, and Synthon. PN: No competing interest. CMV: No competing interest. AWJMG: No competing interest. PA: Honoraria/advisory fees from Novartis, Roche, Macrogenics, G1 Therapeutics, Servier, Synthon, Amcure, Amgen, and Boehringer Ingleheim and travel grants from MSD, Pfizer, and Roche. YW, RGB, and MGC are employees and stockholders of Radius Health, Inc. Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/9/11
Y1 - 2020/9/11
N2 - Background: Elacestrant is an oral selective estrogen receptor (ER) degrader. This phase 1b open-label, non-randomized study (RAD1901-106) was initiated to determine the effect of elacestrant on the availability of ER in lesions from postmenopausal women with ER+ advanced breast cancer (ABC) using 16α-18F-fluoro-17β-estradiol positron emission tomography with low-dose computed tomography (FES-PET/CT). Methods: Eligible patients were postmenopausal women with ER+, HER2- ABC; tumor progression after ≥ 6 months of 1-3 lines of endocrine treatment for ABC; and measurable or evaluable disease. Two 8-patient cohorts were enrolled: one treated with 400 mg elacestrant once daily (QD) and one treated with 200 mg elacestrant QD with dose escalation to 400 mg QD after 14 days. Elacestrant was dosed continuously until progressive disease, toxicity, or withdrawal. FES-PET/CT was performed pre-dose at baseline and 4 h post-dose on day 14. The primary endpoint was the percentage difference in FES uptake in tumor lesions (maximum 20) after 14 days of treatment compared to baseline. Overall response was investigator-assessed by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1. Results: Patients (n = 16; median age, 53.5 years) had ABC with a median 2.5 prior lines of endocrine therapy. Median reduction in tumor FES uptake from baseline to day 14 was 89.1% (Q1, Q3: 75.1%, 94.1%) and was similar in both cohorts (89.1% [Q1, Q3: 67.4%, 94.2%], 200/400 mg and 88.7% [Q1, Q3: 79.5%, 94.1%], 400 mg). Residual ER availability (> 25% persistence in FES uptake) on day 14 was observed in 3 patients receiving 200/400 mg (3/78, 37.5%) and 1 patient receiving 400 mg (1/8, 12.5%). The overall response rate (ORR) was 11.1% (1 partial response), and clinical benefit rate (CBR) was 30.8%. Median percentage change in FES uptake did not correlate with ORR or CBR. Adverse events occurring in > 20% of the patients were nausea (68.8%), fatigue (50.0%), dyspepsia (43.8%), vomiting (37.5%), and decreased appetite, dysphagia, and hot flush (31.3% each). Most events were grade 2 in severity. Conclusion: Elacestrant 200 mg and 400 mg QD greatly reduced ER availability measured by FES-PET/CT. In a heavily pretreated population, elacestrant was associated with antitumor activity. Trial registration: ClinicalTrials.gov, NCT02650817. Registered on 08 January 2016
AB - Background: Elacestrant is an oral selective estrogen receptor (ER) degrader. This phase 1b open-label, non-randomized study (RAD1901-106) was initiated to determine the effect of elacestrant on the availability of ER in lesions from postmenopausal women with ER+ advanced breast cancer (ABC) using 16α-18F-fluoro-17β-estradiol positron emission tomography with low-dose computed tomography (FES-PET/CT). Methods: Eligible patients were postmenopausal women with ER+, HER2- ABC; tumor progression after ≥ 6 months of 1-3 lines of endocrine treatment for ABC; and measurable or evaluable disease. Two 8-patient cohorts were enrolled: one treated with 400 mg elacestrant once daily (QD) and one treated with 200 mg elacestrant QD with dose escalation to 400 mg QD after 14 days. Elacestrant was dosed continuously until progressive disease, toxicity, or withdrawal. FES-PET/CT was performed pre-dose at baseline and 4 h post-dose on day 14. The primary endpoint was the percentage difference in FES uptake in tumor lesions (maximum 20) after 14 days of treatment compared to baseline. Overall response was investigator-assessed by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1. Results: Patients (n = 16; median age, 53.5 years) had ABC with a median 2.5 prior lines of endocrine therapy. Median reduction in tumor FES uptake from baseline to day 14 was 89.1% (Q1, Q3: 75.1%, 94.1%) and was similar in both cohorts (89.1% [Q1, Q3: 67.4%, 94.2%], 200/400 mg and 88.7% [Q1, Q3: 79.5%, 94.1%], 400 mg). Residual ER availability (> 25% persistence in FES uptake) on day 14 was observed in 3 patients receiving 200/400 mg (3/78, 37.5%) and 1 patient receiving 400 mg (1/8, 12.5%). The overall response rate (ORR) was 11.1% (1 partial response), and clinical benefit rate (CBR) was 30.8%. Median percentage change in FES uptake did not correlate with ORR or CBR. Adverse events occurring in > 20% of the patients were nausea (68.8%), fatigue (50.0%), dyspepsia (43.8%), vomiting (37.5%), and decreased appetite, dysphagia, and hot flush (31.3% each). Most events were grade 2 in severity. Conclusion: Elacestrant 200 mg and 400 mg QD greatly reduced ER availability measured by FES-PET/CT. In a heavily pretreated population, elacestrant was associated with antitumor activity. Trial registration: ClinicalTrials.gov, NCT02650817. Registered on 08 January 2016
KW - 16α-F-fluoro-17β-estradiol (FES)
KW - Advanced breast cancer
KW - Elacestrant
KW - Endocrine therapy
KW - Estrogen receptor
KW - Hormonal therapy
KW - Metastatic breast cancer
KW - Positron emission tomography (PET)
KW - RAD1901
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85090818904&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/32912274
U2 - https://doi.org/10.1186/s13058-020-01333-3
DO - https://doi.org/10.1186/s13058-020-01333-3
M3 - Article
C2 - 32912274
SN - 1465-5411
VL - 22
JO - Breast Cancer Research
JF - Breast Cancer Research
IS - 1
M1 - 97
ER -