TY - JOUR
T1 - Inhibition of EGFR, HER2, and HER3 signaling with AZD8931 in combination with anastrozole as an anticancer approach
T2 - Phase II randomized study in women with endocrine-therapy-naïve advanced breast cancer
AU - Johnston, Stephen
AU - Basik, Mark
AU - Hegg, Roberto
AU - Lausoontornsiri, Wirote
AU - Grzeda, Lukasz
AU - Clemons, Mark
AU - Dreosti, Lydia
AU - Mann, Helen
AU - Stuart, Mary
AU - Cristofanilli, Massimo
N1 - Funding Information:
SJ acknowledges research funding support to the NIHR Biomedical Research Centre at The Royal Marsden NHS Foundation Trust. This study was sponsored by AstraZeneca. Claire Routley, PhD from Mudskipper Business Ltd provided medical writing support, funded by AstraZeneca.
Funding Information:
SJ has received honoraria from or attended advisory boards for AstraZeneca, Novartis, Puma, and Roche and received research funding from Pfizer. MB has received research funding from AstraZeneca. LD has received honoraria from and attended advisory boards for AstraZeneca. HM and MS are employees of AstraZeneca and hold stock in AstraZeneca. M Cristofanilli has received honoraria from or attended advisory boards for Dompé and Pfizer. RH, WL, LG, and M Clemons have no conflicts of interest to declare.
Publisher Copyright:
© 2016, Springer Science+Business Media New York.
PY - 2016/11/1
Y1 - 2016/11/1
N2 - Purpose: AZD8931 is an orally bioavailable, reversible tyrosine kinase inhibitor of EGFR, HER2, and HER3 signaling. The Phase II MINT study (ClinicalTrials.gov NCT01151215) investigated whether adding AZD8931 to endocrine therapy would delay development of endocrine resistance in patients with hormone-sensitive advanced breast cancer. Methods: Patients were randomized 1:1:1 to receive daily anastrozole (1 mg) in combination with AZD8931 20 mg twice daily (bid), AZD8931 40 mg bid, or placebo. The primary objective was evaluation of progression-free survival (PFS) in patients treated with combination AZD8931 and anastrozole versus anastrozole alone. Secondary objectives included assessment of safety and tolerability, objective response rate, and overall survival. Results: At the interim analysis, 359 patients were randomized and received anastrozole in combination with AZD8931 20 mg (n = 118), 40 mg (n = 120), or placebo (n = 121); 39 % of patients (n = 141) had a progression event. Median PFS (HR; 95 % CI vs placebo) in the AZD8931 20, 40 mg, and placebo arms was 10.9 (1.37; 0.91–2.06, P = 0.135), 13.8 (1.16; 0.77–1.75, P = 0.485), and 14.0 months, respectively. No indication of clinical benefit was observed following treatment with AZD8931 for the secondary endpoints. Safety findings showed a greater incidence of diarrhea (40, 51, and 12 % for AZD8931 20, 40 mg, and placebo, respectively), rash (32, 48, and 12 %), dry skin (19, 25, and 2 %), and acneiform dermatitis (16, 28, and 2 %) in patients treated with AZD8931 versus placebo. Conclusions: AZD8931, in combination with endocrine therapy, does not appear to enhance endocrine responsiveness and is associated with greater skin and gastrointestinal toxicity.
AB - Purpose: AZD8931 is an orally bioavailable, reversible tyrosine kinase inhibitor of EGFR, HER2, and HER3 signaling. The Phase II MINT study (ClinicalTrials.gov NCT01151215) investigated whether adding AZD8931 to endocrine therapy would delay development of endocrine resistance in patients with hormone-sensitive advanced breast cancer. Methods: Patients were randomized 1:1:1 to receive daily anastrozole (1 mg) in combination with AZD8931 20 mg twice daily (bid), AZD8931 40 mg bid, or placebo. The primary objective was evaluation of progression-free survival (PFS) in patients treated with combination AZD8931 and anastrozole versus anastrozole alone. Secondary objectives included assessment of safety and tolerability, objective response rate, and overall survival. Results: At the interim analysis, 359 patients were randomized and received anastrozole in combination with AZD8931 20 mg (n = 118), 40 mg (n = 120), or placebo (n = 121); 39 % of patients (n = 141) had a progression event. Median PFS (HR; 95 % CI vs placebo) in the AZD8931 20, 40 mg, and placebo arms was 10.9 (1.37; 0.91–2.06, P = 0.135), 13.8 (1.16; 0.77–1.75, P = 0.485), and 14.0 months, respectively. No indication of clinical benefit was observed following treatment with AZD8931 for the secondary endpoints. Safety findings showed a greater incidence of diarrhea (40, 51, and 12 % for AZD8931 20, 40 mg, and placebo, respectively), rash (32, 48, and 12 %), dry skin (19, 25, and 2 %), and acneiform dermatitis (16, 28, and 2 %) in patients treated with AZD8931 versus placebo. Conclusions: AZD8931, in combination with endocrine therapy, does not appear to enhance endocrine responsiveness and is associated with greater skin and gastrointestinal toxicity.
KW - AZD8931
KW - Endocrine therapy
KW - Hormone-sensitive advanced breast cancer
KW - PFS
KW - Phase II
KW - Tyrosine kinase inhibitor
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U2 - 10.1007/s10549-016-3979-5
DO - 10.1007/s10549-016-3979-5
M3 - Article
C2 - 27654971
AN - SCOPUS:84988644187
VL - 160
SP - 91
EP - 99
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
SN - 0167-6806
IS - 1
ER -