Everolimus Plus Endocrine Therapy for Postmenopausal Women With Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: A Clinical Trial

Abstract

Importance: Cotargeting the mammalian target of rapamycin pathway and estrogen receptor may prevent or delay endocrine resistance in patients receiving first-line treatment for advanced breast cancer.

Objective: To investigate the combination of everolimus plus endocrine therapy in first-line and second-line treatment settings for postmenopausal women with estrogen receptor-positive, human epidermal growth receptor 2-negative advanced breast cancer.

Design, setting, and participants: In the multicenter, open-label, single-arm, phase 2 BOLERO-4 (Breast Cancer Trials of Oral Everolimus) clinical trial, 245 patients were screened for eligibility; 202 were enrolled between March 7, 2013, and December 17, 2014. A median follow-up of 29.5 months had been achieved by the data cutoff date (December 17, 2016).

Interventions: Patients received first-line treatment with everolimus, 10 mg/d, plus letrozole, 2.5 mg/d. Second-line treatment with everolimus, 10 mg/d, plus exemestane, 25 mg/d, was offered at the investigator's discretion upon initial disease progression.

Main outcomes and measures: The primary end point was investigator-assessed progression-free survival in the first-line setting per Response Evaluation Criteria in Solid Tumors, version 1.0. Safety was assessed in patients who received at least 1 dose of study medication and at least 1 postbaseline safety assessment.

Results: A total of 202 women treated in the first-line setting had a median age of 64.0 years (interquartile range, 58.0-70.0 years) with metastatic (194 [96.0%]) or locally advanced (8 [4.0%]) breast cancer. Median progression-free survival was 22.0 months (95% CI, 18.1-25.1 months) with everolimus and letrozole. Median overall survival was not reached; 24-month estimated overall survival rate was 78.7% (95% CI, 72.1%-83.9%). Fifty patients started second-line treatment; median progression-free survival was 3.7 months (95% CI, 1.9-7.4 months). No new safety signals were observed. In the first-line setting, the most common all-grade adverse event was stomatitis (139 [68.8%]); the most common grade 3 to 4 adverse event was anemia (21 [10.4%]). In the second-line setting, the most common adverse events were stomatitis and decreased weight (10 [20.0%] each); the most common grade 3 to 4 adverse event was hypertension (5 [10.0%]). There were 50 (24.8%) deaths overall during the study; 40 were due to study indication (breast cancer).

Conclusions and relevance: The results of this trial add to the existing body of evidence suggesting that everolimus plus endocrine therapy is a good first-line treatment option for postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer.

Trial registration: clinicaltrials.gov Identifier: NCT01698918.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Royce received research funding from Novartis Pharmaceuticals Corporation, was a consultant for Celltrion and BCI Pharma, and received honoraria from Novartis Pharmaceuticals Corporation and Syndax. Dr Bachelot received research funding from Roche and Novartis Pharmaceuticals Corporation and was a consultant for and received travel expenses from AstraZeneca, Roche, Novartis Pharmaceuticals Corporation, and Pfizer. Dr Villanueva was an advisory board member for Novartis Pharmaceuticals Corporation. Dr Melo Cruz received research funding from Novartis Pharmaceuticals Corporation, Janssen, Roche, and Celgene; and received travel, accommodation, and expenses from Janssen Pharmaceuticals. Dr Toyama received research funding from Eisai, Chugai, Novartis Pharmaceuticals Corporation, Nippon Kayaku, Kyowa Hakko Kirin, Daiichi Sankyo, and Takeda. Dr Falkson received research funding from Novartis Pharmaceuticals Corporation, Cascadian Therapeutics, Genentech, and EMD Serono, and was a consultant for and received honoraria from Biotheranostics. Dr Jeong received research funding from Dong-A, Boryung, LG Life Sciences, and Antigen, and received honoraria from Roche, Alvogen, Novartis Pharmaceuticals Corporation, Pfizer, and Covidien. Ms Arce is a Novartis Pharmaceuticals Corporation employee and reported stock ownership with BD. Ms Ridolfi is a Novartis Pharma S.A.S. employee. Dr Lin is a Novartis Pharmaceuticals Corporation employee and reported stock ownership with Novartis Pharmaceuticals Corporation. Dr Cardoso received research funding for clinical trials by institution and was a consultant for Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GSK, MacroGenics, Merck, Merus BV, Novartis Pharmaceuticals Corporation, Pfizer, Pierre Fabre, Roche, Sanofi, and Teva. No other disclosures are reported.

Figures

Figure 1.. Patient Enrollment and Disposition

Between March 7, 2013, and December 17, 2014, this open-label, phase 2 study screened 245 patients for eligibility, 202 of whom were enrolled and provided first-line treatment with everolimus plus letrozole.

Figure 2.. Progression-Free Survival (PFS) in First- and Second-Line Settings per Local Investigator Review (Full Analysis Set)

A, Total of 108 PFS events with everolimus plus letrozole in the first-line setting; median PFS, 22.0 months (95% CI, 18.1-25.1 months). B, Total of 31 PFS events with everolimus plus exemestane in the second-line setting; median PFS, 3.7 months (95% CI, 1.9-7.4 months).

Figure 3.. Overall Survival (OS) in the First-Line Setting, per Local Investigator Review (Full Analysis Set)

Total of 50 OS events with everolimus plus letrozole; median OS, NE (95% CI, 37.0-NE). NE indicates not estimable.