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Everolimus did not extend PFS in HER-2–positive breast cancer
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SAN ANTONIO — The addition of the mTOR inhibitor everolimus to trastuzumab and paclitaxel failed to extend PFS in women with HER-2–positive advanced breast cancer, according to results of a randomized phase 3 study presented at the San Antonio Breast Cancer Symposium.
The combination did appear to have benefit in the subset of patients with ER-negative disease, although the difference was not statistically significant, results showed.
Trastuzumab (Herceptin, Genentech), an anti–HER-2 antibody, has improved outcomes considerably for patients with early-stage and advanced HER-2–positive breast cancer.
“However, it is not a win for everyone. Resistance to treatment still exists and remains a clinically unmet challenge,” Sara A. Hurvitz, MD, associate clinical professor of medicine and director of the breast oncology program at the University of California, Los Angeles, said during a press conference.
Hyperactivation of the PI3 kinase/mTOR pathway has been implicated in resistance to these therapies, and mTOR inhibitors have been proposed to potentially reverse this resistance.
Preclinical, phase 1 and phase 2 trials have shown everolimus (Afinitor, Novartis) is active against HER-2–positive breast cancer.
Previously released results of the BOLERO-3 study showed the addition of everolimus to trastuzumab and vinorelbine chemotherapy significantly improved PFS among patients with HER-2–positive advanced breast cancer who underwent prior treatment with a taxane-based chemotherapy. An exploratory analysis from BOLERO-3 showed patients with hormone receptor-negative disease appeared to derive greater benefit from everolimus.
In San Antonio, Hurwitz presented results of the BOLERO-1/TRIO 019 study, which included 719 women with advanced, HER-2–positive breast cancer who had not received trastuzumab or chemotherapy in the advanced-disease setting.
Researchers randomly assigned 480 patients to receive 5 mg daily everolimus (Afinitor, Novartis) plus weekly paclitaxel and trastuzumab. The other 239 patients received placebo plus paclitaxel and trastuzumab.
Investigator-assessed PFS in the entire cohort, as well as in the subset of patients with HR-negative disease, served as the primary endpoints. Secondary endpoints included OS, overall response rate, clinical benefit rate, time to response, safety and duration of response.
The analysis, performed after 425 PFS events in the entire study population, showed no difference in median PFS between patients assigned everolimus and those assigned placebo (14.95 months vs. 14.49 months; HR=0.89; 95% CI, 0.73-1.08).
In the subset of patients with hormone receptor-negative disease, median PFS was 20.27 months among those assigned everolimus and 13.08 months among those assigned placebo (HR=0.66; 95% CI, 0.48-0.91).
Hurvitz called these data “intriguing” but emphasized they did not meet pre-specified threshold of statistical significance.
Researchers reported higher rates of any-grade stomatitis (67% vs. 32%), diarrhea (57% vs. 47%), neutropenia (38% vs. 25%) and anemia (31% vs. 16%) in the everolimus arm. Rates of grade 3 stomatitis (13% vs. 1%), diarrhea (9% vs. 4%), neutropenia (21% vs. 11%) and anemia (9% vs. 3%) also were higher in the everolimus arm.
Also, 3.6% of patients assigned everolimus died due to adverse events compared to none in the placebo arm. All but one of these events occurred within the first 15 months of enrollment and tended to occur at sites or in regions that had little experience with everolimus, Hurvitz said.
“When these events occurred, the [independent data and safety monitoring committee] sent a letter to all investigators notifying them that very proactive, aggressive management of adverse events was necessary,” Hurvitz said. “Only one adverse event occurred subsequently to that, and this underscores the need for aggressive management of adverse events when combining everolimus with chemotherapy.”
For more information:
Hurvitz SA. Abstract #S6-01. Presented at: San Antonio Breast Cancer Symposium; Dec. 9-13, 2014; San Antonio.
Disclosure: The researchers report speakers’ bureau roles with Boehringer Ingelheim, Genentech/Roche and Novartis; research funding and honoraria from, employment relationships with and stock ownership in Novartis; and contracts with Amgen, Biomarin, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Genentech, GlaxoSmithKline, Novartis, OBI Pharma, Pfizer, PUMA, Roche and Sanofi.
Perspective
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Aditya Bardia, MD, MPH
The results of this trial are interesting. They also are along the lines of what was seen in BOLERO-3 with trastuzumab (Herceptin, Genentech), vinorelbine (Navelbine, Pierre Fabre) and mTOR inhibitors in that you see an improvement for PFS for the hormone receptor-negative group but not for the hormone receptor-positive group. Because patients in BOLERO-1 with hormone receptor-positive disease did not receive endocrine therapy, it will be important to see whether the results would change with the inclusion of endocrine therapy.How do these results fit in the landscape of HER-2–positive breast cancer, particularly in the first-line setting? Currently, based on the CLEOPATRA data, trastuzumab plus pertuzumab (Perjeta, Genentech) plus docetaxel is the recommended chemotherapy regimen. In BOLERO-1, the control arm was trastuzumab plus taxol, and there was no pertuzumab. So how these results fit in the current era of the trastuzumab plus pertuzumab backbone remains to be seen.
Moving forward, it would be important to identify predictive biomarkers to suggest who would respond much better to one regimen vs. another, and to help personalize treatment for women with breast cancer.
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