Everolimus plus Endocrine Therapy: Effective 1st Line Option for Postmenopausal Women with HR+/HER2- Advanced Breast Cancer

MedicalResearch.com Interview with:

Melanie E. Royce, MD, PhD Division of Hematology/Oncology University of New Mexico Comprehensive Cancer Center Albuquerque

Dr. Royce

Melanie E. RoyceMDPhD
Division of Hematology/Oncology
University of New Mexico Comprehensive Cancer Center

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: BOLERO-4 is an open label, single-arm, Phase II study that evaluates the combination of everolimus plus letrozole as a first-line treatment for hormone receptor (HR)-positive/human epidermal growth factor receptor (HER2)-negative advanced breast cancer patients, as well as the use of everolimus plus exemestane beyond initial progression. Results of the BOLERO-4 trial published in JAMA Oncology showed that everolimus in combination with endocrine therapy is an effective first-line treatment option for postmenopausal women with HR+/HER2- advanced breast cancer.

A total of 202 patients received everolimus in combination with letrozole as first-line treatment between March 7, 2013 and December 17, 2014. Median progression-free survival (PFS) in the first-line setting was 22.0 months (95% CI 18.1-25.1) with an overall response rate of 45% (95% CI 38.1-52.2) and clinical benefit rate of 74% (95% CI 67.7-80.1). A total of 152 (75%) discontinued treatment, primarily due to disease progression (51%) or adverse events (16%).

Data from a smaller number of patients in BOLERO-4 also show limited efficacy with continued everolimus, combined with exemestane, following disease progression.
Second-line treatment was ongoing in 16 (32%) patients, while 34 (68%) had discontinued. The most frequent reason for second-line treatment discontinuation was disease progression (56%). In the second-line setting, median PFS was 3.7 months (95% CI 1.9-7.4) with an overall response of 6% (95% CI 1.3-16.5) and clinical benefit rate of 28% (95% CI 16.2-42.5).

Safety findings from BOLERO-4 are consistent with previous studies of Afinitor in advanced breast cancer. The most common (≥ 20% incidence) first-line all-grade adverse events were stomatitis (69%), weight loss (44%), nausea (37%) and anemia (35%). Most were ‘low grade’ in severity (grade 1 or 2) and generally well managed. Safety findings show the most common (≥ 10% incidence) second-line adverse events were stomatitis (20%) and weight loss (20%). Lower rates of stomatitis in second-line were noted. 

MedicalResearch.com: What should readers take away from your report?

Response: The findings of BOLERO-4 support the rationale for dual inhibition of the mTOR pathway and estrogen receptor in the first-line setting. The median PFS achieved in this study was particularly compelling given the heavy baseline disease burden of the patient population; 96% had metastatic disease, 68% had three or more metastatic sites, and 61% had visceral metastases.

The treatment landscape for HR+/HER2- advanced breast cancer has been evolving in recent years with the licensing of cyclin-dependent kinase (CDK4/6) inhibitors. Despite this, combinations of mTOR inhibitors and endocrine therapy remain important and effective options.

While combinations of aromatase inhibitors and CDK4/6 inhibitors are a preferred first-line option in many countries, they are not universally accessible. The PFS benefit demonstrated by everolimus plus letrozole in BOLERO-4 exceeded that observed with letrozole alone in previous Phase III studies of postmenopausal women with HR+ advanced breast cancer (median PFS 9.0-9.4 months) suggesting there may be a place for everolimus in combination with letrozole as first-line treatment for these women. 

MedicalResearch.com: What recommendations do you have for future research as a result of this work?

Response: Following the arrival of CDK4/6 inhibitors, there is an interest in determining the optimal sequence of therapies. Despite the challenges posed by the patient population, our findings are insightful and provide data describing everolimus in areas of the advanced breast cancer landscape where existing data are scarce. Furthermore, with new and emerging phosphatidylinositol 3-kinase (PI3K) inhibitors receiving significant attention, there is sufficient evidence to suggest that the PI3K/mTOR pathway remains important and warrants further exploration in the treatment of HR+, HER2– advanced breast cancer.

Another area that we should increase research efforts around is working to find effective biomarkers that help identify which subsets of patients may benefit from a specific treatment/combination. Even if all the research uncovers is which type of patient should not be exposed to certain treatment – helping to spare them from therapy toxicities and unnecessary expense of treatment(s) – this remains in my opinion, a worthy endeavor. 

MedicalResearch.com: Is there anything else you would like to add?

Response: Similar to BOLERO-2, the most common adverse event associated with mTOR inhibition in BOLERO-4 was stomatitis (mouth sores). In BOLERO-4, the incidence of stomatitis was primarily grade 1 or 2. Additional studies have shown that stomatitis can be significantly minimized or prevented making this treatment option more tolerable.

Disclosures: research funding from Novartis Pharmaceuticals Corporation; consultant for Celltrion and BCI; and honoraria from Novartis Pharmaceuticals Corporation and Syndax.


Royce M, Bachelot T, Villanueva C, Özgüroğlu M, Azevedo SJ, Cruz FM, Debled M, Hegg R, Toyama T, Falkson C, Jeong J, Srimuninnimit V, Gradishar WJ, Arce C, Ridolfi A, Lin C, Cardoso F. Everolimus Plus Endocrine Therapy for Postmenopausal Women With Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast CancerA Clinical Trial. JAMA Oncol. Published online March 22, 2018. doi:10.1001/jamaoncol.2018.0060

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