title: Paclitaxel, bevacizumab, and everolimus/placebo as first-line treatment for patients with metastatic HER2-negative breast cancer: a randomized placebo-controlled phase II trial of the Sarah Cannon Research Institute.
abstract: Amplified PI3K/Akt/mTOR signaling is common in metastatic breast cancer (MBC). The mTOR inhibitor everolimus improves progression-free survival (PFS) when added to steroidal aromatase inhibitor therapy. This randomized phase II trial compares the efficacy of paclitaxel/bevacizumab/everolimus and paclitaxel/bevacizumab/placebo as first-line treatment for MBC. Patients with untreated HER2-negative MBC were randomized (1:1) to receive 28-day cycles of paclitaxel 90 mg/m(2) IV (days 1, 8, and 15) and bevacizumab 10 mg/kg IV (days 1, 15) with either everolimus 10 mg (Arm 1) or placebo (Arm 2) daily. Treatment continued (evaluation every 8 weeks) until progression or unacceptable toxicity. Treatment of 110 patients allowed detection of an improvement in median PFS from 11 to 16 months (70 % power, α = 0.10). Between August 2009 and June 2011, 113 patients (median age 58 years; 88 % ER or PR positive) were randomized (Arm 1, 56; Arm 2, 57). Patients in both arms received a median of six treatment cycles. Median PFS (95 % CI) was 9.1 months (6.8-18.8) for Arm 1, and 7.1 months (5.6-10.8) for Arm 2 (p = 0.89). Comparisons of other efficacy endpoints were also similar in the two treatment arms. Patients receiving everolimus had more anemia, stomatitis, diarrhea, rash, and arthralgia/myalgia, although the overall incidence of severe (grade 3/4) toxicity was similar. The addition of everolimus did not improve the efficacy of weekly paclitaxel/bevacizumab as first-line treatment for patients with HER2-negative MBC. These results contrast with the demonstrated efficacy of adding everolimus to either hormonal or HER2-targeted therapy in previously treated patients.
authors.affiliation: Sarah Cannon Research Institute, 3322 West End Ave, Suite 900, Nashville, TN, 37203, USA. dyardley@tnonc.com.|Tennessee Oncology, PLLC, 250 25th Avenue North, Nashville, TN, 37203, USA. dyardley@tnonc.com.
authors.forename: Denise A
authors.initials: DA
authors.lastname: Yardley
authors.affiliation: Wilshire Oncology Medical Group, La Verne, CA, USA.
authors.forename: Linda D
authors.initials: LD
authors.lastname: Bosserman
authors.affiliation: Baylor Sammons Cancer Center and Texas Oncology, Dallas, TX, USA.
authors.forename: Joyce A
authors.initials: JA
authors.lastname: O'Shaughnessy
authors.affiliation: Sarah Cannon Research Institute, 3322 West End Ave, Suite 900, Nashville, TN, 37203, USA.|Florida Cancer Specialists, Fort Myers, FL, USA.
authors.forename: William N
authors.initials: WN
authors.lastname: Harwin
authors.affiliation: Sarah Cannon Research Institute, 3322 West End Ave, Suite 900, Nashville, TN, 37203, USA.|Florida Cancer Specialists, Fort Myers, FL, USA.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Morgan
authors.affiliation: The Center for Cancer and Blood Disorders, Bethesda, MD, USA.
authors.forename: Victor M
authors.initials: VM
authors.lastname: Priego
authors.affiliation: Sarah Cannon Research Institute, 3322 West End Ave, Suite 900, Nashville, TN, 37203, USA.|Tennessee Oncology, PLLC, 250 25th Avenue North, Nashville, TN, 37203, USA.
authors.forename: Nancy W
authors.initials: NW
authors.lastname: Peacock
authors.affiliation: Sarah Cannon Research Institute, 3322 West End Ave, Suite 900, Nashville, TN, 37203, USA.
authors.forename: J David
authors.initials: JD
authors.lastname: Bass
authors.affiliation: Sarah Cannon Research Institute, 3322 West End Ave, Suite 900, Nashville, TN, 37203, USA.|Tennessee Oncology, PLLC, 250 25th Avenue North, Nashville, TN, 37203, USA.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.affiliation: Sarah Cannon Research Institute, 3322 West End Ave, Suite 900, Nashville, TN, 37203, USA. john.hainsworth@scresearch.net.|Tennessee Oncology, PLLC, 250 25th Avenue North, Nashville, TN, 37203, USA. john.hainsworth@scresearch.net.
authors.forename: John D
authors.initials: JD
authors.lastname: Hainsworth
mesh_terms: D000328:Adult; D000368:Aged; D000068258:Bevacizumab / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D000068338:Everolimus / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics
chemical_list: D000068258:Bevacizumab; D000068338:Everolimus; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases
keywords: Bevacizumab; Everolimus; HER2-negative; Metastatic breast cancer; Paclitaxel; Randomized