PI3K/AKT/mTOR pathway activation due to PTEN loss may lead to trastuzumab (TRAS) resistance. mTOR inhibition has been shown to restore TRAS sensitivity in PTEN-deficient tumors. This provided the rationale for the BOLERO-3 trial which evaluated the combination of everolimus (EVE), an mTOR inhibitor, plus TRAS and a taxane in HER2+ advanced breast cancer (ABC). The addition of EVE to TRAS plus vinorelbine (VNB) led to a statistically significant prolongation of 1.2 months in median progression free survival (PFS) vs TRAS plus VNB in patients with TRAS-resistant and taxane-pretreated, HER2+ ABC (7.0 months vs 5.78 months; hazard ratio, 0.78; p=0.0067). The final overall survival (OS) analysis from this study is presented here.

Materials and methods

BOLERO-3 is a randomized, double-blind, placebo-controlled, phase 3 trial. Women with HER2+ ABC progressing on prior TRAS and taxane therapy were randomized (1:1) to receive either daily EVE (5 mg) or PBO plus weekly TRAS (2 mg/kg) and VNB (25 mg/m2), in 3-week cycles, stratified by previous lapatinib use. The primary endpoint was PFS by local investigator assessment. Overall survival was a key secondary endpoint.


Overall, 569 patients were enrolled; 284 patients received EVE and 285 patients received PBO. As of April 1, 2015, after a median follow-up of 44.7 months, 388 deaths had occurred, 191 (67.3%) in the EVE arm and 197 (69.1%) in the PBO arm. The median OS in the EVE arm vs PBO arm was 23.5 months vs 24.1 months (HR = 0.96; 95% CI, 0.79-1.17; p = 0.3392). In the HR+ subgroup, the median OS with EVE was 23.5 months (vs 25.5 months with PBO; HR = 1.03; 95% CI, 0.79-1.35); in the HR subgroup, the median OS with EVE was 22.9 months (vs 23.1 months with PBO; HR = 0.86; 95% CI, 0.64-1.17). AEs leading to treatment discontinuation were reported in 81 (28.9%) vs 46 (16.3%) patients in the EVE vs PBO arms. Serious adverse events (SAEs) were reported in 122 (43.6%) vs 58 (20.6%) patients in the EVE vs PBO arms. Overall, 14 on-treatment deaths were observed, 7 (2.5%) in the EVE arm and 7 (2.5%) in the PBO arm; on-treatment deaths due to AEs were balanced between treatment arms (0.7% in each treatment arm). Types of post-progression therapies were balanced across both treatment arms.


In BOLERO-3, EVE showed a statistically significant prolongation of PFS. OS was similar in both treatment arms. The safety profile of EVE was comparable to that observed previously with EVE in breast cancer. (Funded by Novartis; BOLERO-3 number, NCT01007942.)

Citation Format: Isaacs C, O'Regan R, Xu B, Masuda N, Arena F, Yap Y-S, Papai Z, Lang I, Armstrong A, Lerzo G, White M, Shen K, Zhang Y, Jappe A, Pacaud LB, Taran T, Ozguroglu M. Everolimus plus trastuzumab and vinorelbine for trastuzumab-resistant, taxane-pretreated, HER2+ advanced breast cancer: Overall survival results from BOLERO-3. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-12.