title: Inhibition of EGFR, HER2, and HER3 signaling with AZD8931 in combination with anastrozole as an anticancer approach: Phase II randomized study in women with endocrine-therapy-naïve advanced breast cancer.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  AZD8931, in combination with endocrine therapy, does not appear to enhance endocrine responsiveness and is associated with greater skin and gastrointestinal toxicity.
authors.affiliation: The Royal Marsden NHS Foundation Trust, The Royal Marsden Hospital, Fulham Road, Chelsea, London, SW3 6JJ, UK. Stephen.Johnston@rmh.nhs.uk.
authors.forename: Stephen
authors.initials: S
authors.lastname: Johnston
authors.affiliation: Jewish General Hospital, Montreal, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Basik
authors.affiliation: Hospital Perola Byington, São Paulo, Brazil.
authors.forename: Roberto
authors.initials: R
authors.lastname: Hegg
authors.affiliation: National Cancer Institute of Thailand, Bangkok, Thailand.
authors.forename: Wirote
authors.initials: W
authors.lastname: Lausoontornsiri
authors.affiliation: Magodent Sp. z o.o. Grupa Lux Med, Warsaw, Poland.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Grzeda
authors.affiliation: The Ottawa Hospital Cancer Center, Ottawa, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Clemons
authors.affiliation: University of Pretoria and Steve Biko Academic Hospital, Pretoria, South Africa.
authors.forename: Lydia
authors.initials: L
authors.lastname: Dreosti
authors.affiliation: AstraZeneca, Macclesfield, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Mann
authors.affiliation: AstraZeneca, Macclesfield, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: Stuart
authors.affiliation: Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Cristofanilli
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077384:Anastrozole; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D003131:Combined Modality Therapy; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009570:Nitriles / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D019233:Retreatment; D015398:Signal Transduction / Q000187:drug effects*; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage
chemical_list: D000077384:Anastrozole; D066246:ErbB Receptors; D009570:Nitriles; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D014230:Triazoles; C548875:AZD 8931
keywords: AZD8931; Endocrine therapy; Hormone-sensitive advanced breast cancer; PFS; Phase II; Tyrosine kinase inhibitor