Everolimus/Letrozole Combination Shows Clinical Benefit in Advanced Breast Cancer

Melanie Royce, MD, details recent studies into hormone receptor-positive (HR+) and HER2-advanced breast cancer treatment.

Melanie Royce, MD

Co-targeting the estrogen receptor (ER) and mTOR pathways with combined letrozole and everolimus significantly improved outcomes in postmenopausal patients with hormone receptor-positive (HR+)/HER2-advanced breast cancer, according to findings from the BOLERO-4 phase II trial presented at the 2016 ESMO Annual Congress. This was the first trial to evaluate adding everolimus to endocrine therapy as first-line treatment for these patients.

The overall response rate (ORR) for the combination was 42.6% in patients with advanced breast cancer, and the ORR was 51.8% in patients with measurable disease. The best overall response was complete response (CR) in 3 patients who all had measurable disease. In the overall cohort, partial response (PR) was achieved by 83 (41.1%) and stable disease (SD) was reported for 91 (45.0%) patients. Progressive disease occurred in 14 patients; outcome was undetermined for 11 patients. The clinical benefit rate (CBR) with the combination was 74.3% in the overall population and 75.5% in the cohort of patients with measurable disease.

The mammalian target of rapamycin (mTOR) pathway plays a vital role in the pathogenesis of breast cancer and the BOLERO trials have established the efficacy of the mTORC1 inhibitor everolimus. The BOLERO-2 trial demonstrated superior progression-free survival (PFS) with combined exemestane, which targets the estrogen receptor, plus everolimus over placebo in postmenopausal patients with HR+, HER2−advanced breast cancer progressing on endocrine therapy. BOLRERO-2 results supported the approval of everolimus plus exemmestane for treatment of postmenopausal women with HR+, advanced breast cancer who progressed on a non-steroidal aromatase inhibitor (NSAI).

Melanie Royce, MD, professor, Department of Internal Medicine, University of New Mexico, presented results on behalf of colleagues from the phase 2 BOLERO-4 trial, evaluating the efficacy and safety of first-line everolimus and exemestane in patients with ER-positive, HER2 metastatic or locally advanced breast cancer.

Patients were required to have measurable disease or presence of bone lesions and and to have received no prior treatment for advanced disease. All 202 patients in BOLERO-4 received daily everolimus at 10 mg plus letrozole at 2.5 mg. Patients were eligible to receive everolimus plus exemestane upon disease progression.

Patients developing stomatitis completed the Oral Stomatitis Daily Questionnaire (OSDQ) and were randomized to local standard of care or alcohol-free dexamethasone 0.5 mg/5 ml oral rinse, where commercially available. The median patient age was 65 years. ECOG performance status was 0 in 52.5% of patients; 1 in 43.1%; and 2 in 5.4% of patients; 154 patients had metastatic disease and 38 patients had locally advanced cancer.

The primary endpoint was progression-free survival (PFS) in the first-line setting by local assessment and secondary endpoints included ORR, CBR, overall survival (OS), PFS in the second line, safety in the first and second line, and change in stomatitis severity and duration.

Efficacy findings from the combination treatment administered in the first-line were presented at ESMO.

"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 and confirm that dual inhibition is an effective treatment approach regardless of progression on prior NSAI therapy," Royce said.

At a median follow-up of 17.5 months, median PFS had not been reached; the estimated 6-month and 12-month PFS rates were 83.6% (95% CI 77.3, 88.2) and 71.4% (95% CI 64.0, 77.5), respectively.

No new safety signals were raised in combination everolimus and letrozole, which both demonstrated safety profiles similar to previous reports. One hundred percent of patients experienced an adverse event (AE), of which 99% were suspected to be study related. Stomatitis was reported in 67.8% of patients, weight loss in 42.6%, and diarrhea occurred in 36.1% of patients. Serious AEs were reported for 56 patients; 15 patients discontinued the study due to a grade 3 AE, and 5 patients discontinued due to a grade 4 AE.

Royce pointed out: "BOLERO-4 is ongoing. Additional data on second-line progression-free survival, overall survival and stomatitis will be reported, and first-line efficacy results will be updated at a later date."


M Royce, C Villanueva, M Ozgurogluc, et al. BOLERO-4: Phase 2 trial of first-line everolimus (EVE) plus letrozole (LET) in estrogen receptor—positive (ER+), human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (BC). Presented at: 2016 ESMO Congress; October 7-11 2016; Copenhagen, Denmark. Abstract 222O (BC)

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