Everolimus in first-line treatment of advanced premenopausal breast cancer: Results from MIRACLE (everoliMus trIal foR AdvanCed premenopausaL brEast cancer) study

Background:Everolimus is the first approved mTOR inhibitor in breast cancer to overcome endocrine resistance in post-menopausal patients after BOLERO-2 study. However, different from western countries, majority (55-60%) of patients are premenopausal women in Asia including China. Benefit of everolimus plus endocrine therapy in premenopausal women has not yet been well delineated. In addition, the feasibility of patients who progressed on the endocrine therapy continuing to receive the same endocrine agent plus everolimus is unclear. Thus, Miracle study was designed as a national multicenter randomized phase ll trial comparing letrozole versus letrozole plus everolimus for hormone receptor-positive HER2-negative premenopausal women with recurrent or metastatic breast cancer on goserelin treatment after progession on selective estrogen receptor modulator (SERMs). Patients: Advanced HR positive, HER2 negative premenopausal breast cancer patients who were resistant to SERMs (Tamoxifen or Toremifen) were randomly assigned to receive either letrozole plus everolimus or letrozole single agent together with goserelin. Endocrine resistance was defined as either progression on SERMs if it was for advanced disease or recurrence during adjuvant treatment of SERMs or within 2 years of completion of SERMs. Patients in the control group will be cross-overed to test group by adding everolimus to letrozole after progression. This is to verify whether everolimus can truly reverse endocrine resistance. The primary endpoint is the Progression-Free Survival (PFS) of letrozole plus everolimus versus letrozole monotherapy. Secondary endpoints included PFS of letrozole plus everolimus after progression on letrozole, Overall Response Rate (ORR), Clinical Benefit Rate (CBR), Duration of Response (DOR), Overall Survival (OS), safety. Exploratory biomarker analyses were also planned to identify proper prognostic and predictive biomarkers. Results: Totally 199 patients (101 in everolimus group and 98 in control group) were included in the intention-to-treat population. Patients were well balanced in terms of baseline demographics such as previous endocrine therapy, history of previous chemotherapy, percentage of visceral metastases etc. Addition of everolimus to letrozole resulted in significantly longer progression-free survival (PFS) than letrozole alone. As of Jun 30th 2019, PFS was 19.2 months (95%CI: 13.8-20.2 months) in the everolimus group and 11.0 months (95%CI: 7.3-15.7 months) in the control group [HR: 0.60, 95%CI:(0.42-0.86), P=0.0053]. ORR was 34.4% (1CR and 32PR among 96 evaluable patients) in everolimus group versus 28.2% in control group (1CR and 23 PR among 85 patients) (P=0.375). CBR (CR+PR+SD) was higher in everolimus group than control group (67.7% vs 49.4%, P=0.0125). 50 patients from control group were cross-overed to receive addition of everolimus, 7(14%) had Partial response and 23(46%) had stable disease. Median PFS after cross-over was 5.5 months (95% CI: 3.8-8.2months). OS data was quite immature, 4 years survival rate was 97.0% in everolimus group and 91.8% in control group (HR=0.36, P=0.127). Toxicity was similar to what has been observed in other everolimus study. Conclusions: This is the first randomized trial demonstrating a much longer PFS with mTOR inhibitor plus endocrine therapy than endocrine therapy alone among premenopausal patients with advanced hormone receptor-positive, HER2-negative breast cancer. The results support the use of everolimus plus letrozole in this population. Furthermore, everolimus can indeed overcome endocrine resistance, addition of everolimus to the same endocrine agent can still be effective even after previous progression. Citation Format: Ying Fan, Tao Sun, Zhimin Shao, Qingyuan Zhang, Quchang Ouyang, Zhongsheng Tong, Shusen Wang, Yang Luo, Yuee Teng, Xiaojia Wang, Shu Wang, Qiang Liu, Jifeng Feng, Kunwei Shen, Yanqiu Song, Jiayu Wang, Fei Ma, Qing Li, Pin Zhang, Binghe Xu. Everolimus in first-line treatment of advanced premenopausal breast cancer: Results from MIRACLE (everoliMus trIal foR AdvanCed premenopausaL brEast cancer) study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD7-08.