Overall survival data BOLERO-1: benefit everolimus in HR-negative patients

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.

References

1. 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.
2. 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.