222O - BOLERO-4: Phase 2 trial of first-line everolimus (EVE) plus letrozole (LET) in estrogen receptor–positive (ER+), human epidermal growth factor rece...

Date 08 October 2016
Event ESMO 2016 Congress
Session Breast cancer, metastatic
Topics Breast Cancer
Presenter Melanie Royce
Citation Annals of Oncology (2016) 27 (6): 68-99. 10.1093/annonc/mdw365
Authors M. Royce1, C. Villanueva2, M. Ozguroglu3, T. Bachelot4, S. Azevedo5, F. Melo Cruz6, R. Hegg7, M. Debled8, W.J. Gradishar9, C. Manlius10, A. Ridolfi11, J. Lin12, F. Ringeisen13, F. Cardoso14
  • 1Department Of Internal Medicine, University of New Mexico, 87131-0001 - Albuquerque/US
  • 2Department Of Medical Oncology, CHU Besançon, Hôpital Jean Minjoz, Besançon/FR
  • 3Medical Oncology, Istanbul University Institute of Oncology, 34093 - Istanbul/TR
  • 4Service Oncologie Medicale, Centre Léon Bérard, Lyon/FR
  • 5Oncology, Hospital de Clinicas de Porto Alegre Universidade Federal Do Rs, Porto Alegre/BR
  • 6Oncology, Instituto Brasileiro de Controle do Cancer, Sao Paulo/BR
  • 7Department Of Medicine, Hospital Perola Byington, Sao Paulo/BR
  • 8Medical Oncology, Institute Bergonié, Bordeaux/FR
  • 9Hematology/oncology, Northwestern University Feinberg School of Medicine, Chicago/US
  • 10Oncology, Novartis Pharma AG, Basel/CH
  • 11Oncology, Novartis Pharma S.A.S., Rueil-Malmaison/FR
  • 12Oncology, Novartis Pharmaceuticals Corporation, East Hanover/US
  • 13Oncology, Novartis Pharma, CH-4002 - Basel/CH
  • 14Breast Unit, Champalimaud Clinical Centre, 1400-038 - Lisbon/PT



Efficacy of EVE + exemestane (EXE) in postmenopausal patients (pts) with hormone receptor–positive, HER2− advanced BC progressing on endocrine therapy was established in the phase 3 BOLERO-2 trial (statistically significant 4.6-month increase in median progression-free survival [PFS; local assessment] vs placebo + EXE). BOLERO-4 (NCT01698918) is the first trial to evaluate first-line EVE + LET efficacy and safety in postmenopausal pts with ER + , HER2− metastatic or locally advanced BC. Efficacy of EVE + EXE upon disease progression and a stomatitis therapeutic intervention are secondary objectives.


Postmenopausal pts with ER + , HER2− metastatic or locally advanced BC with no prior advanced disease therapy received EVE 10 mg/day + LET 2.5 mg/day. At disease progression, pts were offered EVE + EXE 25 mg/day until further progression or unacceptable toxicity. Pts with stomatitis completed the Oral Stomatitis Daily Questionnaire and were randomized to local standard of care or alcohol-free dexamethasone 0.5 mg/5 mL oral rinse, where commercially available. Primary endpoint: PFS (first-line setting; local assessment); secondary endpoints: overall response (ORR), clinical benefit (CBR) rate, overall survival, PFS (second line), safety (first and second line), and change in stomatitis severity and duration.


202 pts (median age, 64 years) in 13 countries participated: 194 pts (96%) with metastatic BC and 8 pts (4%) with locally advanced BC. 93 (46%) and 87 (43%) pts received prior hormonal therapy and chemotherapy (neo-/adjuvant setting). The median duration of follow-up was 17.5 months. The median PFS was not yet reached at data cutoff (12 months after the last patient's first visit). The estimated PFS rates (95% CI) were 83.6% (77.3%-88.2%) and 71.4% (64.0%-77.5%) at 6 and 12 months, respectively. ORR and CBR were 42.6% (35.7%-49.7%) and 74.3% (67.7%-80.1%), respectively. The most common adverse events were stomatitis (67.8%), weight loss (42.6%), and diarrhea (36.1%).


EVE combined with LET is an effective regimen in HR + , HER2− advanced BC in the first-line setting.

Clinical trial identification

CRAD001Y24135 Release date: 10 Aug 2015 (Amendment 4)

Legal entity responsible for the study

Novartis Pharmaceuticals Corporation


Novartis Pharmaceuticals Corporation


M. Royce: Research funding from Novartis and Angiochem. C. Villanueva: A consulting or advisory role with Roche, Novartis and Genentech. T. Bachelot: Membership on the board for Roche, Novartis, Zeneca and Pfizer; research funding from Roche and Novartis; speaker fees from Novartis. C. Manlius: Employment with Novartis Pharma AG. A. Ridolfi: Employment with Novartis Pharma S.A.S. J. Lin: Discloses employment with Novartis Pharmaceuticals Corporation. F. Ringeisen: Employment and stock ownership in Novartis Pharma AG. F. Cardoso: Honoraria from Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, Merck-Sharp, Merus BV, Novartis, Pfizer, Pierre-Fabre, Roche, Sanofi, Teva. All other authors have declared no conflicts of interest.