SAN ANTONIO—Adding everolimus to paclitaxel and trastuzumab does not significantly prolong progression-free survival (PFS) in patients with breast cancer, according to a final analysis of outcomes and safety for the randomized, double-blind, placebo-controlled multicenter phase 3 Breast Cancer Trials of Oral Everolimus-1 (BOLERO-1) study presented at the 2014 San Antonio Breast Cancer Symposium.

“The primary objective of PFS was not met,” reported lead study author Sara A. Hurvitz, MD, of the University of California, Los Angeles in Los Angeles, CA.

BOLERO-1/TRIO 019 studied daily everolimus, an m-TOR inhibitor, plus weekly trastuzumab and paclitaxel as a first-line therapy in women with HER2-positive (HER2+) advanced breast cancer.

Study participants included a total of 719 women with locally advanced or metastatic HER2+ breast cancer and no prior therapy for advanced or metastatic disease other than endocrine therapy. They were randomly assigned 2:1 to receive everolimus (10 mg orally, daily) or placebo, plus paclitaxel and trastuzumab. Therapy was continued until disease progression or intolerable toxicity.

At a median follow-up of 14.9 months, PFS among all patients in the everolimus group was not statistically different from placebo, Dr. Hurvitz reported.

Among the hormone receptor (HR)-negative subgroup, everolimus was associated with a median PFS of 20 months compared with 13 months among women in the placebo group (hazard ratio [HR]: 0.66; 95% CI: 0.48,0.91; =0.0049), but this failed to cross the study protocol’s prespecified threshold of statistical significance of P=0.0044, and was therefore deemed a statistically nonsignificant finding.

The safety profile was consistent with previous results in BOLERO-3, and included grade 3 stomatitis and diarrhea, and grade 3/4 neutropenia and anemia, Dr. Hurvitz noted.

Importantly, toxicity-related deaths attributable to pulmonary adverse events such as pulmonary embolism and edema, respiratory failure, and pneumonia, did occur among patients in the treatment group (3.6% vs. 0 in the placebo group).

“All but one on-treatment death due to AEs occurred within 15 months of recruitment,” Dr. Hurvitz noted. “This may be associated with a lack of experience in managing AEs of everolimus when combined with chemotherapy. There was a higher rate of on-treatment deaths in regions with limited experience with everolimus and in some cases protocol defined AE management guidelines were not followed.”

Proactive monitoring and early management of AEs is “crucial” for patients receiving everolimus in combination with chemotherapy, she emphasized.


  1. Hurvitz SA, Andre F, Jiang Z, et al. S6-01. Presented at: San Antonio Breast Cancer Symposium 2014. Dec. 9-13, 2014; San Antonio, TX.