Everolimus Does Not Overcome Trastuzumab Resistance

Neil Osterweil

December 16, 2014

SAN ANTONIO — The addition of everolimus (Afinitor, Novartis Pharmaceuticals Corporation) to a weekly chemotherapy and targeted therapy regimen did not improve progression-free survival of women with advanced breast cancer positive for the HER2 receptor.

Although preclinical data had suggested that activation of the PI3 kinase/mTOR (mammalian target of rapamycin) pathway could lead to tumor resistance to trastuzumab (Herceptin, Genentech, Inc) and that PI3K/mTOR inhibitors such as everolimus might be able to overcome that resistance, clinical trials that have put this theory to the test have been largely disappointing.

Results of the latest trial to miss the bar, BOLERO-1/TRIO 019, were presented here at San Antonio Breast Cancer Symposium (SABCS) 2014. They showed a nearly identical median progression-free survival (PFS) between patients treated with weekly paclitaxel (multiple brands) and trastuzumab alone, and patients treated with the same regimen plus daily everolimus, said Sara A. Hurvitz, MD, associate clinical professor of medicine and director of the Breast Oncology Program, Division of Hematology, University of California, Los Angeles, School of Medicine.

The trial failed to meet its two primary endpoints: neither the overall PFS, as noted above, nor PFS in the subpopulation of patients with hormone receptor (HR)–negative disease. Although women with HR tumors who received everolimus had a median PFS of 20.27 months, compared with 13.08 months in the group who did not receive it, the difference was not statistically significant (P = .0049, which was higher than the prespecified statistical threshold for significance of P ≤ .0044).

"These data are consistent with the preliminary observation from the BOLERO-3 study that the hormone receptor–negative subpopulation of HER2-positive breast cancer may have a differential response to everolimus, keeping in mind that neither of these studies used or allowed endocrine therapy for hormone receptor–positive disease," Dr Hurvitz said at a briefing prior to her presentation of the data.

Data from BOLERO-3, reported at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO), showed that in women with HER2-positive advanced breast cancer who had received prior taxane therapy and whose tumors were resistant to trastuzumab, the addition of everolimus to the combination of trastuzumab and vinorelbine was associated with a 22% relative reduction in risk for disease progression, but only a small improvement in the median time to progression (7.0 months for the combination plus everolimus vs 5.8 months without, P < .01).

Study Details

In BOLERO-1/TRIO 019, investigators enrolled 719 women with locally advanced or metastatic HER2-positive breast cancer not previously treated with an advanced-cancer regimen except for endocrine therapy. Prior trastuzumab and/or chemotherapy in the neoadjuvant or adjuvant setting was allowed. The presence of measurable disease or bone lesions was required for study entry.

The patients were randomly assigned in a 2:1 ratio, stratified by prior trastuzumab use and visceral metastases, to receive oral everolimus 10 mg daily plus paclitaxel and trastuzumab, or paclitaxel and trastuzumab alone.

As noted above, the trial failed to meet either of its primary endpoints of PFS benefit in the overall or HER2-negative populations.

The safety analysis showed that the addition of everolimus was associated with 13 cases of grade 3 stomatitis compared with one in the control arm, and nine cases of grade 3 diarrhea vs four cases among control patients. Grade 3 and 4 neutropenia was seen in 25 patients on everolimus vs 15 among patients who did not receive it. Respective numbers of grade 3 or 4 anemia were 10 and 3.

In all, 4.7% of patients in the everolimus arm and 0.8% in the control arm died on study. Of the patients receiving everolimus, 1.1% died from disease progression, and 3.6% from adverse events. There were no deaths attributable to adverse events in the control arm; all of the deaths were due to disease progression.

These findings are consistent with studies previously reported by Medscape Medical News at SABCS, which showed that the addition of everolimus was associated with additional toxicity without additional benefit.

C. Kent Osborne, MD, director of the Dan L. Duncan Cancer Center and the Lester Sue Smith Breast Center at Baylor College of Medicine, in Houston, Texas, told Medscape Medical News that he would be unlikely to use everolimus in similar patients.

"This is an area where we're doing a lot of research, and I think that there are other studies that have suggested how resistance can be overcome in this population," he said.

He explained that therapies targeting multiple members of the human epidermal growth factor receptor (HER) family, HER 1, 2, 3, and 4, have been shown to reduce resistance, particularly when combined with estrogen-receptor blockade in patients whose tumors are ER-positive.

"The most important part of this study [BOLERO-1] will be to analyze the tumors to see if we can really pinpoint who are those who are really benefiting from everolimus," he said.

Dr Osborne moderated the briefing where the data were presented, but he was not involved in the study.

The study was funded by Novartis. Dr Hurvitz has disclosed that she has contracted research/grants paid to her institution by Genentech/Roche. Dr Osborne has disclosed serving on an advisory board for Novartis.

San Antonio Breast Cancer Symposium (SABCS) 2014: Abstract S6-01, presented December 12, 2014.

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