Everolimus plus exemestane improves PFS, appears safe in advanced breast cancer

Everolimus plus exemestane resulted in a greater PFS benefit versus everolimus alone in patients with estrogen receptor-positive, HER-2-negative advanced breast cancer who experienced disease progression after treatment with nonsteroidal aromatase inhibitors, according to findings presented at the ASCO Annual Meeting.

Perspective from Aditya Bardia, MD (MBBS), MPH

The BOLERO-6 trial follows results from BOLERO-2, which demonstrated an improvement in median PFS with the combination of everolimus plus exemestane vs. everolimus alone.

Guy Heinrich Maria Jerusalem, MD, PhD, of CHU Sart Tilman Liège and Liège University in Liège, Belgium, and colleagues enrolled 309 postmenopausal women with ER-positive, HER-2-negative metastatic or recurrent breast cancer in this open-label, phase 2 study. Recurrence or progression occurred following treatment with anastrozole (Arimidex, AstraZeneca) or letrozole (Femara, Novartis). Eligible patients had measurable disease per RECIST 1.1 criteria or bony lesions and an ECOG performance status of 0 to 2.

Researchers randomly assigned patients 1:1:1 to receive everolimus 10 mg plus exemestane 25 mg orally once per day, everolimus alone, or capecitabine 1250 mg/m² twice per day. Estimation of the HR for PFS with everolimus plus exemestane vs. everolimus alone served as the trial’s primary objective. Secondary objectives included OS and safety.

Following randomization, 104 patients received treatment with everolimus plus exemestane, 103 patients received everolimus and 102 patients received capecitabine. Baseline characteristics in the different arms were similar, although patients in the capecitabine arm tended to be younger compared with the everolimus plus exemestane arm; 68% of patients in the capecitabine arm were aged less than 65 years compared with 63% of patients in the everolimus plus exemestane arm. Patients in the capecitabine arm had more bone-only lesions (24% vs. 13%) and less visceral disease (62% vs. 66%) and were more likely to be Caucasian (89% vs. 75%) and fully active (56% vs. 52%). Patients in the capecitabine arm were also less likely to have three or more sites of metastatic disease (44% vs. 50%).

Median follow-up was 37.6 months. The estimated HR for PFS with everolimus plus exemestane vs. everolimus was 0.74 (90% CI, 0.57–0.97). The estimated HR for PFS with everolimus plus exemestane vs. capecitabine was 1.26 (90% CI, 0.96-1.66), but a stratified multivariate Cox regression model adjusted for prognostic factors and baseline covariates with imbalances between arms resulted in a HR closer to 1 (HR = 1.15; 90% CI, 0.86-1.52).

Median OS was 23.1 months in the everolimus plus exemestane arm and 29.3 months in the everolimus arm (HR = 1.27; 90% CI, 0.95-1.7) and 25.6 months with capecitabine (HR = 1.33; 90% CI, 0.99-1.79). Grade 3 to 4 adverse events occurred most frequently in the capecitabine arm and serious adverse events occurred more often with everolimus plus exemestane.

“The estimated HR [for] PFS [with] everolimus plus exemestane vs. everolimus is indicative of a treatment benefit,” the researchers wrote. “While the estimated HR [for] PFS [with] everolimus plus exemestane vs. capecitabine was 1.26, the capecitabine arm may have been favored by baseline imbalances and potential informative censoring. The safety profile of exemestane vs. everolimus was consistent with the known profile of this combination.” – by Julia Ernst, MS

Reference:

Jerusalem GHM, et al. Abstract 1005. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.

Disclosures: Heinrich reports serving in a consultant or advisory role for Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Eli Lilly, Novartis, Pfizer, Puma Biotechnology and Roche, and receiving honoraria from Amgen, Bristol-Myers Squibb, Eli Lilly, Novartis, Pfizer and Roche, research funding from Novartis and Roche, and travel, accommodations and expenses from Eli Lilly, Novartis, Pfizer and Roche. Please see the study for all other authors’ relevant financial disclosures.

Perspective

Aditya Bardia, MD (MBBS), MPH

While endocrine therapy is the mainstay of management for metastatic HR-positive breast cancer, patients eventually experience disease progression. The median PFS with first-line endocrine monotherapy such as aromatase inhibitors ranges from 14 to 16 months. The BOLERO-6 clinical trial evaluated the use of everolimus plus exemestane vs. everolimus alone or capecitabine in patients who progressed on nonsteroidal aromatase inhibitors. Three things should be noted regarding the clinical trial.

First, the study results confirm that everolimus plus exemestane is the standard of care for patients who experience disease progression on an aromatase inhibitor and underscore the fact that everolimus should probably not be used as a single agent; it should be used in combination with endocrine therapy. Second, while chemotherapy has similar efficacy compared with everolimus plus exemestane, the incidence of grade 3/4 adverse events was more common with capecitabine compared with everolimus plus exemestane, highlighting higher toxicity associated with chemotherapy compared with targeted therapies. Third, the landscape of breast cancer has changed over the past few years. CDK4/6 inhibitors in the first-line setting can nearly double PFS for patients with metastatic, HR-positive breast cancer. When the BOLERO-6 trial was designed, CDK4/6 inhibitors had not yet been approved, but we now routinely use these agents in first and later lines of therapy. Unfortunately, we don’t have data yet on whether everolimus provides the same benefit in patients treated previously with CDK4/6 inhibitors, although I suspect that it would have the same general benefit. Further research is needed to evaluate the benefit of everolimus in patients who experience disease progression after treatment with a CDK4/6 inhibitor.

Aditya Bardia, MD (MBBS), MPH

Harvard Medical School

Massachusetts General Hospital

Disclosures: Disclosure: Bardia reports serving as a consultant for Genentech, Novartis and Pfizer.