BOLERO-4: Phase 2 trial of first-line everolimus (EVE) plus letrozole (LET) in estrogen receptor–positive (ER+), human epidermal growth factor receptor 2–negative (HER2-) advanced breast cancer (BC)

Abstract

Background: 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. Methods: 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. Results: 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%). Conclusions: EVE combined with LET is an effective regimen in HR + , HER2‐ advanced BC in the first‐line setting.