STOCKHOLM – Coupling everolimus with exemestane has produced such dramatic disease control in women with advanced hormone resistant, estrogen receptor-positive breast cancer that it is expected to transform the management of these patients.
A preplanned interim analysis of the phase III BOLERO-2 trial found that everolimus (Afinitor) increased the primary end point of progression-free survival, by local assessment, from a median of 2.8 months with exemestane (Aromasin) alone to 6.9 months. This corresponds to a 57% risk reduction (hazard ratio 0.43; P less than .0001).
Based on central assessment, everolimus produced a 64% reduction in the risk of progression or death (10.6 months vs. 4.1 months; HR = 0.36; P less than .0001). The trial was stopped early based on the benefit shown in the interim data.
"Everolimus is the first agent to enhance the clinical benefit of hormonal therapy in refractory estrogen receptor (ER)–positive patients," lead author Dr. José Baselga said at the European Multidisciplinary Cancer Congress.
"Our results could represent a paradigm shift in the management of patients with hormone receptor-positive breast cancer," he added
Invited discussant Dr. Fabrice André, from the Institut Gustave Roussy in Villejuif, France, called everolimus the most important advance in breast cancer since trastuzumab (Herceptin).
"The efficacy of everolimus in the BOLERO-2 trial is in the range of the most important advances in medical oncology," he said.
Novartis plans to submit the data for worldwide regulatory approval of everolimus as a treatment for ER-positive advanced breast cancer by year’s end, although the medical oncology community could embrace off-label use in this indication since both drugs are already available.
Everolimus is approved in the United States for progressive neuroendocrine tumors of pancreatic origin, subependymal giant cell astrocytoma associated with inoperable tuberous sclerosis and advanced renal cell carcinoma after sunitinib (Sutent) or sorafenib (Nexavar) treatment failure. Exemestane, an aromatase inhibitor, is approved as neoadjuvant therapy for hormone receptor–positive disease in postmenopausal women.
Everolimus was evaluated because the mammalian target of rapamycin (mTOR) pathway is activated in hormone therapy–resistant advanced breast cancer. Phase II everolimus trials suggested that the mTORC1 inhibitor could reverse resistance to endocrine therapy, said Dr. Baselga, chief of hematology/oncology and associate director of the Massachusetts General Hospital Cancer Center, Boston.
BOLERO-2 enrolled 724 women postmenopausal women with advanced ER-positive, HER2-negative breast cancer who were refractory to letrozole (Femara) or anastrozole (Arimidex). Prior treatment also included chemotherapy for metastatic disease in roughly 25%, tamoxifen in 48% and fulvestrant (Faslodex) in about 16%. Patients were randomized to everolimus 10 mg daily or placebo, with both arms receiving exemestane 25 mg daily.
The overall response rate was 9.5% for the everolimus arm and 0.4% for the placebo arm (P less than .0001).
The clinical benefit rate was 33.4% and 18%, respectively (P less than .0001), Dr. Baselga said at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society of Radiotherapy and Oncology.
A progression-free survival subgroup analysis showed consistent results across all subgroups.
At the time of the interim analysis, 83 deaths had occurred (10.6% in the everolimus arm and 13% in the placebo arm), but the data are immature, he said.
Adverse events were consistent with previous everolimus experience including stomatitis, fatigue, noninfectious pneumonitis, and hyperglycemia, Dr. Baselga said.
Dr. Fabrice André
Dr. André said BOLERO-2 provides robust and clinically relevant data, but added that "preclinical data suggest we can do even better." He pointed out that inhibiting mTORC1 alone is not optimal because of the activation of alternative compensatory or parallel pathways, and he suggested moving to combination trials to inhibit alternative pathways and reverse resistance.
"BOLERO-2 is just part of the iceberg coming," Dr. Jean-Charles Soria, cochair of the Congress scientific program and a cancer specialist at Institut Gustave Roussy in Villejuif, France, said in an interview. "The whole question now is about building a triplet combination that is not too toxic and that is feasible."
He referenced the ongoing phase III BOLERO-1 and BOLERO-3 trials assessing everolimus in combination with paclitaxel and trastuzumab in HER2-positive metastatic breast cancer and the triple combination of everolimus, vinorelbine, and trastuzumab in HER2-positive, locally advanced, taxane-pretreated disease resistant to trastuzumab (Herceptin).
"I’m pretty convinced from what I’ve seen in phase I and II, that the phase IIIs in combination with Herceptin might also come out as positive," he said. "So, the way we think about breast cancer is probably going to change with mTOR inhibitors."
Dr. Baselga reports consulting for several pharmaceutical companies including the study sponsor, Novartis. Dr. André has previously reported no conflicts. Dr. Soria has previously reported consulting for Boehringer Ingelheim, Roche, AstraZeneca Pharmaceuticals, and Pfizer.