SABCS 2014 Abstract S6-01 - HER2+ Advanced Breast Cancer: BOLERO-1

San Antonio Breast Cancer Symposium 2014

S6-01. Phase 3, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus (EVE) plus weekly trastuzumab and paclitaxel as first-line therapy in women with HER2+ advanced breast cancer (ABC): BOLERO-1

Hurvitz SA, Andre F, Jiang Z, et al.

Background: Resistance to trastuzumab presents a clinical challenge in the management of HER2+ ABC.  Hyperactivation of the PI3K/AKT/mTOR pathway can lead to resistance towards HER2-targeted therapies.  Everolimus (EVE) is a mTOR inhibitor and has shown activity in HER2+ ABC in pre-clinical and clinical studies. In the BOLERO-3 trial2 (vinorelbine/trastuzumab +/- EVE) clinical benefit was also noted to be more pronounced in the Hormone Receptor (HR)-negative subpopulation.

In BOLERO-1 a total of 719 patients with locally advanced or metastatic HER2+ breast cancer were treated with weekly paclitaxel (80 mg/m2) and weekly trastuzumab (4 mg/kg loading followed by 2 mg/kg) and randomized 2:1 (double blinded) to receive either EVE (10 mg daily) (n=480) or placebo (n=239).  Treatment was administered until disease progression or unacceptable toxicity.  The primary endpoint of was initially set as investigator-assessed PFS in the overall population and was later amended to include PFS in the HR-negative subpopulation as a co-primary endpoint.

Results: Baseline characteristics overall were similar between the two groups, with 57% having HR+ disease, visceral involvement in ~70%, neo-adjuvant trastuzumab ~11%, prior endocrine therapy in ~25%.  Median dose intensity in the EVE treated group was ~50%. 

No major differences were seen with either response rates or clinical benefit rates, overall or in the HR-negative subgroup.  No difference was seen in the overall population with investigator assessed median PFS with EVE treatment was 14.95 months versus placebo 14.49 months  (HR 0.89; 95%CI [0.73, 1.08], log rank p value = 0.1166), or with central assessment EVE median PFS 20.37 m vs. 18.30 m placebo (HR 0.86).  In the HR negative subpopulation investigator assessed median PFS with EVE treatment was 20.27 months versus 13.08 months placebo (HR 0.66; 95%CI [0.48, 0.91], log rank p value = 0.0049), and central assessment EVE noted median PFS 23.06 m vs. 14.82 m placebo (HR 0.61; 95%CI[0.42, 0.87], log rank p value = 0.0030). 

The most significant grade 3/4 toxicities in the EVE treated patients compared to placebo were stomatitis (13/0% vs. 1/0%) diarrhea (9/0% vs. 4/0%), neutropenia (21/4% vs. 11/4%) and anemia (9/1% vs. 3/0%). Deaths due to adverse events (AE) were 3.6% on EVE (primarily due to respiratory events including pneumonitis, pneumonia, and cardiopulmonary arrest) versus 0% on placebo. All but one on-treatment death due to AE occurred within the 15m-recruitment start, with higher rates noted from regions with limited clinical experience with EVE.


CARE Faculty Canadian Perspective:

·   The primary objective of PFS improvement in BOLERO-1 was not met with the addition of EVE to weekly paclitaxel/trastuzumab in HER2+ ABC.  Although median PFS was prolonged by 7 months in the HR-negative subpopulation (20 vs. 13m, HR 0.66, p=0.0049), this did not cross the pre-specified statistical significance threshold  (p=0.0044).  Overall survival follow-up is still ongoing.

·   The adverse event profile of EVE was consistent with those as previously reported in other EVE trials including BOLERO-3 (stomatitis, diarrhea, cytopenias).  A higher rate of AE on-treatment deaths for the EVE treated arm however was observed (3.6%).  It is interesting to note that although the EVE 10 mg/day dose was used in BOLERO-3, the median dose intensity was only 50% (5 mg/day) which was the same dose used of EVE used in BOLERO-1.  This further stresses the critical importance of vigilant toxicity monitoring and proactive treatment of EVE related toxicities.

·   Given the BOLERO-1 results, it is unlikely that the combination of everolimus, trastuzumab and paclitaxel will be used in clinical practice particularly when other anti-HER2 therapeutic options exist with overall survival benefit and superior toxicity profile3.

·   BOLERO-1 data however does further support the preliminary observation of preferential treatment effect of EVE in HR- HER2+ patients in BOLERO-3.  Furthermore as a mutated PIK3CA in HER2+ disease has been consistently demonstrated to be associated with a worse prognosis, it will be interesting to see the translation component of BOLERO-1. As such, consideration for prospective confirmatory studies of PI3K/mTOR pathway inhibition with trastuzumab and chemotherapy are still warranted. 


- CARE Breast Cancer Faculty

1.  Hurvitz SA, Andre F, Jiang Z, et al. Phase 3, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and paclitaxel as first-line therapy in women with HER2+ advanced breast cancer: BOLERO-1. Presented at: 2014 SABCS; December 9-12, 2014; San Antonio, TX. Abstract: S6-01

2.  Andre F et al. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014 May;15(6):580-91. doi: 10.1016/S1470-2045(14)70138-X. Epub 2014 Apr 14.

3.  Swain SM, Kim SB, Cortés J et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study.  Lancet Oncol. 2013 May;14(6):461-71. doi: 10.1016/S1470-2045(13)70130-X. Epub 2013 Apr 18.

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