Everolimus Plus Exemestane vs Everolimus or Capecitabine Monotherapy for Estrogen Receptor–Positive, HER2-Negative Advanced Breast Cancer
Authors: Guy Jerusalem, Richard H. de Boer, Sara Hurvitz, Denise A. Yardley, Elena Kovalenko, Bent Ejlertsen, Sibel Blau, Mustafa Özgüroglu, László Landherr, Marianne Ewertz, Tetiana Taran, Jenna Fan, Florence Noel-Baron, Anne-Laure Louveau, Howard Burris
Journal: JAMA Oncology (2018)

<h3>Importance</h3> Everolimus plus exemestane and capecitabine are approved second-line therapies for advanced breast cancer. <h3>Objective</h3> A postapproval commitment to health authorities to estimate the clinical benefit of everolimus plus exemestane vs everolimus or capecitabine monotherapy for estrogen receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer. <h3>Design</h3> Open-label, randomized, phase 2 trial of treatment effects in postmenopausal women with advanced breast cancer that had progressed during treatment with nonsteroidal aromatase inhibitors. <h3>Interventions</h3> Patients were randomized to 3 treatment regimens: (1) everolimus (10 mg/d) plus exemestane (25 mg/d); (2) everolimus alone (10 mg/d); and (3) capecitabine alone (1250 mg/m<sup>2</sup>twice daily). <h3>Main Outcomes and Measures</h3> Estimated hazard ratios (HRs) of progression-free survival (PFS) for everolimus plus exemestane vs everolimus alone (primary objective) or capecitabine alone (key secondary objective). Safety was a secondary objective. No formal statistical comparisons were planned. <h3>Results</h3> A total of 309 postmenopausal women were enrolled, median age, 61 years (range, 32-88 years). Of these, 104 received everolimus plus exemestane; 103, everolimus alone; and 102, capecitabine alone. Median follow-up from randomization to the analysis cutoff (June 1, 2017) was 37.6 months. Estimated HR of PFS was 0.74 (90% CI, 0.57-0.97) for the primary objective of everolimus plus exemestane vs everolimus alone and 1.26 (90% CI, 0.96-1.66) for everolimus plus exemestane vs capecitabine alone. Between treatment arms, potential informative censoring was noted, and a stratified multivariate Cox regression model was used to account for imbalances in baseline characteristics; a consistent HR was observed for everolimus plus exemestane vs everolimus (0.73; 90% CI, 0.56-0.97), but the HR was closer to 1 for everolimus plus exemestane vs capecitabine (1.15; 90% CI, 0.86-1.52). Grade 3 to 4 adverse events were more frequent with capecitabine (74%; n = 75) vs everolimus plus exemestane (70%; n = 73) or everolimus alone (59%; n = 61). Serious adverse events were more frequent with everolimus plus exemestane (36%; n = 37) vs everolimus alone (29%; n = 30) or capecitabine (29%; n = 30). <h3>Conclusions and Relevance</h3> These findings suggest that everolimus plus exemestane combination therapy offers a PFS benefit vs everolimus alone, and they support continued use of this therapy in this setting. A numerical PFS difference with capecitabine vs everolimus plus exemestane should be interpreted cautiously owing to imbalances among baseline characteristics and potential informative censoring. <h3>Trial Registration</h3> ClinicalTrials.gov identifier:NCT01783444