Everolimus Plus Letrozole for Treatment of Patients With HR ⁺ , HER2 ^– Advanced Breast Cancer Progressing on Endocrine Therapy: An Open-label, Phase II Trial

Endocrine therapy is the standard of care for treatment of patients with HR ⁺ , HER2 ⁻ ABC. However, resistance occurs frequently leading to disease progression due to dysregulation of the PI3K/AKT/mTOR pathways. This phase II trial (N = 72) of everolimus (mTOR inhibitor) plus letrozole combination demonstrated clinical benefit and could be a valid treatment option for postmenopausal women recurring/progressing on prior endocrine therapy. Purpose: In the Breast cancer trials of OraL EveROlimus-2 (BOLERO-2) trial, everolimus plus exemestane improved progression-free survival (PFS) in patients with hormone receptor-positive (HR ⁺ ), human epidermal growth factor receptor 2-negative (HER2 ⁻ ) advanced breast cancer (ABC) recurring or progressing on/after prior endocrine therapy (ET), suggesting that dual blockade using targeted therapy and ET was an effective treatment option. Here, we investigated the clinical benefit of combining everolimus with different endocrine partner, letrozole, in a similar patient population. Methods: In this phase II, open-label, single-arm, multicenter trial, postmenopausal women with HR ⁺ , HER2 ⁻ ABC who had recurrence/progression on/after prior ET received everolimus 10 mg daily and letrozole 2.5 mg daily. The primary end point was objective response rate; key secondary end points included disease-control rate, PFS, overall survival, and safety. Results: A total of 72 patients were enrolled and followed-up for a median duration of 11.4 months. Everolimus plus letrozole achieved an overall response rate of 23.3% (95% confidence interval [CI], 13.4%-36.0%). The median PFS was 8.8 months (95% CI, 6.6-11.0 months), and the overall survival was 22.9 months (95% CI, 18.5-28.9 months). Disease-control rate was achieved in 51 (85%) patients. The safety profile was consistent with previously published data: The most frequently reported any grade adverse events (AEs) were fatigue (61.1%), stomatitis (54.2%), and rash (33.4%). The most frequently reported grade 3 AEs were stomatitis and anemia (8.3% each), fatigue and diarrhea (5.6% each), and hyperglycemia (4.2%). Only 1 patient had grade 4 AE of anemia. Conclusions: Everolimus plus letrozole demonstrated clinical benefit and could be a valid treatment option for postmenopausal women recurring/progressing on prior endocrine therapy.