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SABCS 2014: BOLERO-3: Everolimus Plus Trastuzumab/Paclitaxel Misses the Mark in First-Line HER2 Advanced Breast Cancer

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Key Points

  • In the phase III BOLERO-1/TRIO-019 trial of previously untreated advanced/metastatic HER2-positive patients, the addition of everolimus to trastuzumab/paclitaxel did not improve outcomes in the overall population.
  • In the hormone receptor–negative subset, however, progression-free survival was improved by 7 months; due to a stringent P value set for this analysis, this just missed statistical significance.

The addition of everolimus to weekly trastuzumab (Herceptin) plus paclitaxel did not improve outcomes in the phase III BOLERO-1/TRIO-019, but did provide a “signal” in the hormone receptor–negative subset. The study was reported at the 2014 San Antonio Breast Cancer Symposium by Sara A. Hurvitz, MD, of the University of California, Los Angeles (Abstract S6-01).

“Trastuzumab has dramatically improved outcomes for patients, however, it’s not a win for everyone. Resistance to treatment remains a clinically unmet challenge,” she said at a press briefing. One means of counteracting resistance could be to add a drug that would inhibit the mTOR pathway in early metastatic disease, according to Dr. Hurvitz.   

In the previously reported BOLERO-3 trial, everolimus added to trastuzumab and vinorelbine did significantly improve progression-free survival for patients with trastuzumab-resistant previously treated cancer.

“We were interested in evaluating whether inhibiting mTOR early in metastatic disease will help delay the development of resistance to HER2-targeted therapy,” she said.

BOLERO-1/TRIO-019 Study

The study enrolled 719 patients with locally advanced or metastatic HER2-positive breast cancer and no prior treatment in this setting. Patients were randomly assigned 2:1 to everolimus (10 mg orally daily) plus paclitaxel/trastuzumab or paclitaxel/trastuzumab alone, until disease progression or intolerable toxicity. The primary endpoint was investigator-assessed progression-free survival in the whole population and in the hormone receptor–negative subpopulation. Overall survival was a secondary endpoint. 

In the full study population, progression-free survival was the same in each arm: 14.95 months with everolimus and 14.49 months with placebo (hazard ratio [HR] = 0.89, P = .1166). In the hormone receptor–negative subpopulation, however, everolimus-treated patients achieved a median progression-free survival of 20.27 months vs 13.08 months with placebo (HR = 0.66; P = .0049), Dr. Hurvitz reported.

“We saw a 7-month improvement favoring the everolimus arm, and while this was intriguing it did not meet the prespecified level of significance (P = .0044),” she reported.

Adverse Events

Adverse events were similar as seen in BOLERO-3. Patients treated with stomatitis had more stomatitis, diarrhea, neutropenia, and anemia. There were also several treatment-related deaths in the everolimus arm (3.2%) and none in the control arm, though only one occurred after clinicians undertook more proactive management of toxicities.

“Safety was consistent with the known safety profile from BOLERO-3, but the increased rate of adverse events on treatment underscores the need for proactive, aggressive management of adverse events when combining everolimus with chemotherapy,” she noted.

Hormone receptor–positive patients in this study did not receive endocrine therapy. “Future and ongoing studies are evaluating the use of PI3K inhibitors in combination with trastuzumab and endocrine therapy for the hormone receptor–positive subset,” Dr. Hurvitz indicated. 

Some Benefit in Hormone Receptor–Negative Patients

The benefit in BOLERO-3 was also predominantly observed in the hormone receptor–negative subset. “Had we known about this hormone receptor–negative signal from the start, we may have done this trial in a hormone receptor–negative population or enrolled more hormone receptor–negative patients,” she commented.

This could have given BOLERO-1 more power to show benefit, at least in a certain subpopulation of HER2-positive patients, she explained.

“We came so close to meeting the prespecified level of significance. We set the bar high for the hormone receptor–negative subset because we wanted to heavily favor the full population, so we would not miss a signal. A statistical decision was made, but we are all thinking about this now and asking whether future studies should be planned in the hormone receptor–negative subset,” Dr. Hurvitz said.

The study was supported by funds from Novartis. Dr. Hurvitz has contracted research with Novartis, Genentech, and Roche.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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