The present exploratory analysis examined the efficacy, safety, and quality-of-life effects of everolimus (EVE) + exemestane (EXE) in the subgroup of patients in BOLERO-2 whose last treatment before study entry was in the (neo)adjuvant setting. In BOLERO-2, patients with hormone-receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) advanced breast cancer recurring/progressing after a nonsteroidal aromatase inhibitor (NSAI) were randomly assigned (2:1) to receive EVE (10 mg/day) + EXE (25 mg/day) or placebo (PBO) + EXE. The primary endpoint was progression-free survival (PFS) by local assessment. Overall, 137 patients received first-line EVE + EXE (n = 100) or PBO + EXE (n = 37). Median PFS by local investigator assessment nearly tripled to 11.5 months with EVE + EXE from 4.1 months with PBO + EXE (hazard ratio = 0.39; 95 % CI 0.25–0.62), while maintaining quality of life. This was confirmed by central assessment (15.2 vs 4.2 months; hazard ratio = 0.32; 95 % CI 0.18–0.57). The marked PFS improvement in patients receiving EVE + EXE as first-line therapy for disease recurrence during or after (neo)adjuvant NSAI therapy supports the efficacy of this combination in the first-line setting. Furthermore, the results highlight the potential benefit of early introduction of EVE + EXE in the management of HR+, HER2− advanced breast cancer in postmenopausal patients.

Everolimus showed efficacy in reducing angiomyolipoma lesion volume in patients with SEGA associated with TSC.The trial is registered with ClinicalTrials.gov, number NCT00789828; http://clinicaltrials.gov/ct2/show/NCT00789828?term=EXIST-1&rank=1.

Everolimus as Second-line Therapy in Metastatic Renal Cell Carcinoma (RECORD-4), ClinicalTrials.gov identifier, NCT01491672.

This paper discusses multiplicity issues arising in confirmatory clinical trials with hierarchically ordered multiple objectives. In order to protect the overall type I error rate, multiple objectives are analyzed using multiple testing procedures. When the objectives are ordered and grouped in multiple families (e.g. families of primary and secondary endpoints), gatekeeping procedures are employed to account for this hierarchical structure. We discuss considerations arising in the process of building gatekeeping procedures, including proper use of relevant trial-specific information and criteria for selecting gatekeeping procedures. The methods and principles discussed in this paper are illustrated using a clinical trial in patients with type II diabetes mellitus.

EudraCT no. 2010-023032-17.