The final exploratory analysis of the BOLERO-1 trial showed an overall survival advantage for patients with HER2+ and HR negative advanced breast cancer treated with everolimus in combination with paclitaxel plus trastuzumab. HER2 is overexpressed in roughly 20–25% of breast cancers. Before the introduction of targeted treatments, HER2-positive breast cancer was characterised by its aggressive proliferation and poor prognosis. Trastuzumab has markedly improved outcomes in patients with both early and metastatic HER2-positive breast cancer; however, resistance to trastuzumab (de novo or acquired) presents a large clinical challenge that warrants identification of new treatment strategies. Constitutive activation of PI3K/AKT/mTOR signalling due to PTEN loss can lead to trastuzumab resistance. mTOR inhibition sensitises PTEN-deficient tumors to trastuzumab, thereby suggesting that the combination of everolimus, an mTOR inhibitor, and trastuzumab could have a role in the treatment of HER2-overexpressing breast cancer.
In the pivotal BOLERO-1 trial, the progression-free survival was not significantly different between the everolimus plus trastuzumab plus paclitaxel combination versus placebo plus trastuzumab plus paclitaxel in the full HER2+ population: 15.0 months versus 14.5 months, respectively. (HR=0.89; 95% CI: 0.73-1.08; p=0.1166).1 Although not reaching protocol defined level for statistical significance, the hormone receptor negative (HR-negative) subpopulation appeared to benefit from everolimus: 20.3 months versus 13.1 months (HR=0.66; 95% CI: 0.48-0.91; p=0.0049). At the San Antonio Breast Cancer Conference 2016 Denise Yardley and colleagues presented the final exploratory overall survival analysis from the BOLERO-1 study.
In this phase 3 randomized trial, 719 women with HER2+ advanced breast cancer without prior trastuzumab or chemotherapy in the metastatic setting were randomized 2:1 to receive either everolimus (10 mg/d) or placebo and weekly paclitaxel plus trastuzumab. Trastuzumab was given intravenously at a 4 mg/kg loading dose on day 1 with subsequent weekly doses of 2 mg/kg of each 4-week cycle. Paclitaxel was given intravenously at a dose of 80 mg/m2 on days 1, 8, and 15 of each 4 week cycle. Patients were stratified by visceral metastasis (lung, liver, peritoneal or pleural: yes versus no) and prior adjuvant or neo-adjuvant treatment with trastuzumab (yes versus no). As the primary objectives of BOLERO-1 (progression-free survival benefit on full population and on HR-negative subpopulation) were not met, the key secondary endpoint of overall survival was not formally statistically tested. However, given the results of progression-free survival, in particular in the HR-negative subpopulation, a change to the overall survival analysis plan was made by introducing one final exploratory overall survival analysis at the time of study termination.2 At data cut-off, the median duration of exposure was 40.8 weeks (range: 0.6-320.4) in the everolimus-arm and 48.1 weeks (range: 1.1-308.0) in the placebo-arm. After a median follow-up of 60.3 months, 350 deaths were recorded in the full population, 238 (49.6%) in the everolimus-arm and 112 (46.9%) in the placebo-arm. In the full population, the median overall survival was comparable in both study arms (48.6 months versus 50.0 months in the everolimus-arm versus placebo-arm, respectively; HR = 1.13; 95% CI: 0.90-1.42). In the HR- subpopulation, 138 deaths were recorded; 88 (42.3%) patients in the everolimus-arm and 50 (48.5%) patients in the placebo-arm. In the HR- subpopulation, the median overall survival in the everolimus-arm was longer compared to the placebo-arm (57.0 months versus 41.6 months respectively; HR = 0.83; 95% CI: 0.59-1.18).
Stomatitis, diarrhoea, alopecia, cough, rash, pyrexia, neutropenia, and fatigue were the most frequent adverse events reported in the everolimus-arm (≥35%). Adverse events leading to dose interruption and/or change were reported in 441 (93.4%) patients in the everolimus-arm and 165 (69.3%) patients in the placebo-arm respectively. Overall, adverse events leading to treatment discontinuation were reported in 262 (55.5%) patients in the everolimus-arm and 98 (41.2%) patients in the placebo-arm. Serious adverse events were reported in 171 (36.2%) patients in the everolimus-arm and 40 (16.8%) patients in the placebo-arm, respectively. On treatment adverse events related deaths were reported for 17 (3.6%) patients in the everolimus-arm and 0 (0%) patients in the placebo-arm.
In summary: in the BOLERO-1 study the median overall survival was similar in the everolimus- versus placebo-arms for the overall population. However, for the HR-negative subpopulation a prolongation of 15.4 months in median overall survival was observed in the everolimus- versus the placebo-arm in this exploratory analysis. Patients in the everolimus-arm had a manageable safety, consistent with the safety profile of everolimus and no new safety signals were identified.
- Hurvitz SA, Andre F, Jiang Z, et al. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. The Lancet Oncology 2015; 16: 816–829.
- Yardley D, Hurvitz S, Jiang Z-F, et al. Everolimus plus trastuzumab and paclitaxel as first-line therapy in women with HER2+ advanced breast cancer: Overall survival results from BOLERO-1. Poster presentation at the San Antonia Breast Cancer Congress 2016, abstract P4-22-13.