In a previous phase 3 trial (BOLERO-2), the efficacy of everolimus plus exemestane was established in postmenopausal patients with estrogen receptor–positive (ER+)/human epidermal growth factor receptor 2–negative (HER2–) breast cancer that was progressing on endocrine therapy. In these patients, everolimus plus exemestane showed a statistically significant 4.6-month increase in median progression-free survival (PFS) when compared with placebo plus exemestane. This open-label, single-arm phase 2 trial, BOLERO-4 (NCT01698918), is the first trial to evaluate the efficacy and safety of first-line everolimus plus letrozole in postmenopausal patients with ER+/HER2– metastatic or locally advanced breast cancer. Secondary objectives of BOLERO-4 include the efficacy of everolimus plus exemestane as second-line therapy after progression, and the reduction in severity and duration of oral stomatitis (a common side effect of everolimus treatment).
Eligible patients for this study were postmenopausal women with ER+/HER2– metastatic or locally advanced breast cancer who had no prior treatment for metastatic breast cancer. All patients received everolimus 10 mg/day plus letrozole 2.5 mg/day. For patients with disease progression, patients were offered everolimus 10 mg/day plus exemestane 25 mg/day until further progression or unacceptable toxicity. Patients 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. The primary end point of this study was a local assessment of PFS in the first-line setting; secondary end points included overall response rate (ORR), clinical benefit rate (CBR), overall survival, second-line PFS, safety (in both the first and second line), and change in stomatitis severity and duration.
Included in this study were 202 patients (median age, 64 years) from 13 countries. A total of 194 (96%) patients had metastatic breast cancer and 8 (4%) patients had locally advanced breast cancer. Prior therapies in these patients included hormonal therapy (46%) and chemotherapy in a (neo)adjuvant setting (43%). Despite a median duration of follow-up of 17.5 months, the median PFS was not yet reached at data cutoff (12 months after the last patient’s first visit). Estimated PFS rates were 83.6% (95% confidence interval [CI], 77.3%-88.2%) and 71.4% (95% CI, 64.0%-77.5%) at 6 months and 12 months, respectively. ORR and CBR were 42.6% (95% CI, 35.7%-49.7%) and 74.3% (95% CI, 67.7%-80.1%), respectively. The combination of everolimus and letrozole was generally well tolerated. The most common adverse events (occurring in ≥35% of patients) were stomatitis (67.8%), weight loss (42.6%), and diarrhea (36.1%). No new safety signals were observed for these drugs.
This study has shown that everolimus combined with letrozole is a safe and effective first-line regimen in HR+/HER2– advanced breast cancer. “Given results from past studies, [the] BOLERO-4 results support the rationale for mTOR inhibition with everolimus in combination with various endocrine therapies for the treatment of postmenopausal women with HR+ advanced breast cancer,” said Dr Melanie Royce of Albuquerque, NM, who was affiliated with this study. Results regarding second-line PFS, overall survival, and the stomatitis substudy data will be reported at a later date, along with updated first-line efficacy results.
Royce M, et al. ESMO 2016. Abstract 222O.