BOLERO-3: Everolimus Might Help Patients Overcome Trastuzumab Resistance

Published Online: Tuesday, July 23, 2013
Ruth M O'Regan MD

Ruth M. O'Regan, MD

Adding the mTOR inhibitor everolimus to conventional therapy slowed the progression of trastuzumab-resistant advanced breast cancer, and in the process, provided clues to the origin of trastuzumab resistance. The findings came from the results of the phase III BOLERO-3 trial, which were presented at the 2013 ASCO Annual Meeting.

In the study, patients treated with everolimus (Afinitor), in addition to trastuzumab (Herceptin) and vinorelbine, had a median progression-free survival (PFS) of 7 months compared with 5.78 months in patients who received trastuzumab, vinorelbine, and a placebo.

A preliminary analysis of overall survival (OS) suggested an advantage for everolimus-treated patients, but a final determination will require longer follow-up.

“This is the first phase III study showing a benefit of mTOR pathway inhibition in HER2-positive breast cancer,” said Ruth O’Regan, MD, associate professor of Medicine at Emory University in Atlanta, Georgia, who reported the findings at the ASCO meeting. “Targeting the mTOR pathway is a viable approach to maximize the benefit of trastuzumab-based therapy.

“The combination of everolimus plus vinorelbine plus trastuzumab may be considered an appropriate option in trastuzumab-resistant HER2-positive advanced breast cancer.”

Although trastuzumab has significantly improved outcomes for patients with HER2-positive breast cancer, patients who develop metastatic disease almost inevitably have trastuzumab resistance. The mechanisms by which resistance occurs remain unknown, but include the possibility of activation of the mTOR pathway, which everolimus targets.

Two small, phase Ib trials demonstrated everolimus activity in trastuzumab-resistant HER2-positive breast cancer, supporting the hypothesis that inhibiting the mTOR pathway might reverse trastuzumab resistance, said O’Regan.

Everolimus has FDA approval for use in HER2-negative breast cancer but remains investigational in HER2-positive disease.

The international BOLERO-3 trial involved 572 women with locally advanced or metastatic HER2-positive breast cancer. All of the patients had progressed during or after treatment with trastuzumab and a taxane.

Investigators in six countries randomized patients to the trastuzumab- vinorelbine combination with or without everolimus. Treatment continued until progression or development of unacceptable toxicity. The trial had a primary endpoint of PFS, and secondary outcomes included OS, overall response rate, and time to deterioration of performance status.

About half of the patients had received trastuzumab for a year or more and half for less than a year. All of the patients had received a taxane in addition to trastuzumab. A quarter of the patients in each group had a treatment history that included the anti-HER2 agent lapatinib (Tykerb). The median time from the last trastuzumab treatment to randomization was 1.4 months. More than 40% of patients had received two or more prior regimens.

Treatment continued for 24 weeks in both arms. The >1-month difference in median PFS translated into a hazard ratio of 0.78 in favor of everolimus (P = .0067). An extensive subgroup analysis showed a consistent benefit for the addition of everolimus, regardless of age, prior lapatinib therapy, nature and duration of prior trastuzumab therapy, performance status, hormone-receptor status, or visceral involvement. O’Regan noted that patients aged <65 years and those who had received prior trastuzumab early in the course of treatment seemed to derive greater benefit from everolimus.

Data have not matured sufficiently for an analysis of OS. Nonetheless, the preliminary results showed lower mortality in the everolimus group (36.3% vs 41.1%).

The treatment arms had similar response rates of 41% with everolimus and 37.2% with placebo. Additionally, 48.2% of the everolimus group had stable disease compared with 41.4% of the placebo group. Neither difference reached statistical significance.

Adverse events occurred more frequently in the everolimus group. The most common events associated with everolimus (all grades) were stomatitis (63%), fatigue (43%), pyrexia (39%), diarrhea (38%), nausea (35%), decreased appetite (33%), constipation (30%), and rash (25%). Grade 3 events were infrequent and grade 4 events rare.

The addition of everolimus did not adversely affect quality of life, as indicated by the similarity of time to deterioration of performance status in both groups, said O’Regan.


O’Regan R, Ozguroglu M, Andre F, et al. Phase III, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and vinorelbine in trastuzumab- resistant, advanced breast cancer (BOLERO-3). J Clin Oncol. 2013;31(suppl; abstr 505).


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