Everolimus combination prolongs PFS in HER2-positive advanced breast cancer

The addition of everolimus, an mTOR inhibitor, to trastuzumab and vinorelbine in heavily pretreated advanced breast cancer patients led to a 22% reduction in the risk of disease progression in the first phase 3 study showing that inhibition of human epidermal growth factor receptor-2 positive (HER2+) receptor and mTOR provides significant benefit in HER2+ advanced breast cancer.

“Trastuzumab has markedly improved outcomes for patients with all stages of HER2+ breast cancer. However, in the metastatic setting, the majority of patients eventually develop resistance to trastuzumab,” said lead author Ruth O’Regan, MD, professor and vice-chair for educational affairs, department of hematology and medical oncology at Emory University School of Medicine, at the American Society of Clinical Oncology annual meeting in Chicago.

BOLERO-3 (Breast cancer trials of OraL EveROlimus-3) is a phase 3, randomized, double-blind study of everolimus plus trastuzumab and vinorelbine conducted at 159 clinical trial sites globally. The trial included 569 women with HER2+ locally advanced or metastatic breast cancer who were previously treated with a taxane and were resistant to trastuzumab. Participants were randomly assigned to receive either everolimus 5 mg/day orally (284 patients) or placebo (285 patients), plus weekly vinorelbine 25 mg/m² intravenously and weekly trastuzumab 2 mg/kg intravenously following a loading dose of 4 mg/kg. All patients had prior taxane therapy, and 27% of patients in each group had received prior lapatinib.

The study met its primary end point of improved PFS, Dr O’Regan said, with a median time to progression of 7.0 months in the everolimus combination arm and 5.8 months in the placebo combination arm. Overall survival data are not yet mature, and will be available next year.

Dr O’Regan noted that in subgroup analyses everolimus seemed to have a greater effect on PFS among patients under aged 65 years, those with hormone receptor-negative cancers, and those who had received prior adjuvant or neoadjuvant trastuzumab. The overall response rate was not significantly different between the 2 groups.

Adverse events were consistent with the known safety profile of everolimus, she said, and were “quite manageable.” The most common all-grade adverse reactions were neutropenia, stomatitis, anemia, leukopenia, fatigue, pyrexia, diarrhea, nausea, decreased appetite, and constipation. The most common Grade 3-4 adverse reactions were neutropenia, leukopenia, anemia, stomatitis, fatigue, febrile neutropenia, diarrhea, pyrexia, nausea, hyperglycemia, and thrombocytopenia.

In conclusion, Dr O’Regan said “the addition of everolimus to trastuzumab and vinorelbine significantly prolongs PFS in patients with trastuzumab-resistant and taxane-pretreated HER2+ advanced breast cancer, resulting in a 22% decrease in risk of disease progression or death. The data support earlier clinical trials that inhibition of the mTOR pathway reverses resistance to trastuzumab, and shows the potential role of everolimus in treating these women.”

She noted that 2 agents, pertuzumab and trastuzumab emtansine (T-DM1), have been approved for advanced breast cancer in the last 18 months. “This everolimus combination would be the third line after those agents in the metastatic setting,” she said. “With more mature survival data, I hope it will become another treatment option for advanced breast cancer.”