title: Safety of everolimus plus exemestane in patients with hormone-receptor-positive, HER2-negative locally advanced or metastatic breast cancer progressing on prior non-steroidal aromatase inhibitors: primary results of a phase IIIb, open-label, single-arm, expanded-access multicenter trial (BALLET).
abstract: This European phase IIIb, expanded-access multicenter trial evaluated the safety of EVE plus EXE in a patient population similar to BOLERO-2.
  
  
  
  Post-menopausal women aged ≥18 years with hormone receptor-positive, human epidermal growth factor-receptor-2-negative advanced breast cancer (ABC) recurring/progressing during/after prior non-steroidal aromatase inhibitors were enrolled. The primary objective was safety of EVE plus EXE based on frequency of adverse events (AEs), and serious AEs (SAEs). The secondary objective was to evaluate AEs of grade 3/4 severity.
  
  
  
  The median treatment duration was 5.1 months [95% confidence interval (CI) 4.8-5.6] for EVE and 5.3 months (95% CI 4.8-5.6) for EXE. Overall, 2131 patients were included in the analysis; 81.8% of patients experienced EVE- or EXE-related or EVE/EXE-related AEs (investigator assessed); 27.2% were of grade 3/4 severity. The most frequently reported non-hematologic AEs were (overall %, % EVE-related) stomatitis (52.8%; 50.8%) and asthenia (22.8%; 14.6%). The most frequently reported hematologic AEs were (overall %, % EVE-related) anemia (14.4%; 8.1%) and thrombocytopenia (5.9%; 4.6%). AE-related treatment discontinuations were higher in elderly (≥70 years) versus non-elderly patients (23.8% versus 13.0%). The incidence of EVE-related AEs in both elderly and non-elderly patients appeared to be lower in first-line ABC versus later lines. The incidence of AEs (including stomatitis/pneumonitis) was independent of BMI status (post hoc analysis). Overall, 8.5% of patients experienced at least one EVE-related SAE. Of the 121 on-treatment deaths (5.7%), 66 (3.1%) deaths were due to disease progression and 46 (2.2%) due to AEs; 4 deaths were suspected to be EVE-related.
  
  
  
  This is the largest ever reported safety dataset on a general patient population presenting ABC treated with EVE plus EXE and included a sizeable elderly subset. Although the patients were more heavily pretreated, the safety profile of EVE plus EXE in BALLET was consistent with BOLERO-2.
  
  
  
  EudraCT Number: 2012-000073-23.
authors.affiliation: Department of Medical Oncology, CHU Sart Tilman Liege and Liege University, Domaine Universitaire du Sart Tilman, Liege, Belgium g.jerusalem@chu.ulg.ac.be.
authors.forename: G
authors.initials: G
authors.lastname: Jerusalem
authors.affiliation: Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Mariani
authors.affiliation: Medical Oncology Department, Breast Cancer Unit, University Hospital 12 de Octubre, Madrid, Spain.
authors.forename: E M
authors.initials: EM
authors.lastname: Ciruelos
authors.affiliation: Instituto de Investigación Sanitaria Gregorio Marañón, Univesidad Complutense, Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Martin
authors.affiliation: Department of Medical Oncology, GROW, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: V C G
authors.initials: VC
authors.lastname: Tjan-Heijnen
authors.affiliation: KULeuven (University of Leuven), Department of Oncology, Multidisciplinary Breast Center, University Hospitals Leuven, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Neven
authors.affiliation: Medical Oncology Unit of Fundacion Instituto Valenciano De Oncologia, Valencia, Spain.
authors.forename: J G
authors.initials: JG
authors.lastname: Gavila
authors.affiliation: UO Oncologia Medica I, Azienda Ospedaliera Universitaria Pisana, Santa Chiara Hospital, Pisa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Michelotti
authors.affiliation: Unit of Investigative Clinical Oncology (INCO), Fondazione del Piemonte per l'Oncologia, Institute of Candiolo Cancer Center (IRCCs), Candiolo, Torino, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Montemurro
authors.affiliation: Department of Medical, Surgery and Health Sciences, University of Trieste, Trieste, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Generali
authors.affiliation: Breast Unit, Azienda Ospedaliera Spedali Civili, Brescia, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Simoncini
authors.affiliation: Medical Oncology and Clinical Pharmacology, National Institute of Oncology, Budapest, Hungary.
authors.forename: I
authors.initials: I
authors.lastname: Lang
authors.affiliation: Narodny Onkologicky Ustav Klenova 1, Bratislava, Slovakia.
authors.forename: J
authors.initials: J
authors.lastname: Mardiak
authors.affiliation: Department of Oncology, Oslo University Hospital, Oslo, Norway K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: B
authors.initials: B
authors.lastname: Naume
authors.affiliation: Novartis Farma S.p.A., Origgio, VA, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Camozzi
authors.affiliation: Novartis Farma S.p.A., Origgio, VA, Italy.
authors.forename: K
authors.initials: K
authors.lastname: Lorizzo
authors.affiliation: Novartis Farma S.p.A., Origgio, VA, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Bianchetti
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy Medical Oncology 2, Istituto Oncologico Veneto, Padova, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Conte
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000730:Androstadienes / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D047072:Aromatase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics; D000068338:Everolimus / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017698:Postmenopause; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics; D020123:Sirolimus
chemical_list: D000730:Androstadienes; D047072:Aromatase Inhibitors; D066246:ErbB Receptors; D000068338:Everolimus; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D020123:Sirolimus; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C056516:exemestane
keywords: BMI; advanced breast cancer; elderly; everolimus; hormone-receptor positive; stomatitis