Everolimus-Exemestane Combination Prolongs Remission by 4 Months in Metastatic Breast Cancer

Caroline Helwick

October 2011, Vol 2, No 6 - ESMO 2011 Conference

José Baselga, MDStockholm, Sweden—The use of everolimus (Afinitor) together with the aromatase inhibitor exemestane (Aromasin) more than halved the risk for disease progression in patients with advanced breast cancer, adding an average of 4 disease-free months, investigators reported at the 2011 European Society for Medical Oncology European Multidisciplinary Cancer Congress.

Lead investigator José Baselga, MD, of Massachusetts General Hospital, Boston, predicted that this combination “could represent a new therapeutic option” for postmenopausal women who have received previous hormonal therapy.

The hypothesis is that the mTOR inhibitor could reverse the resistance to endocrine therapy that inevitably develops in hormone receptor–positive patients, a concept based on strong preclinical evidence.

Fabrice André, MD, PhD, of the Institut Gustav Roussy, Villejuif, France, commented on the results, saying, “I would consider the efficacy of everolimus in the range of the most important advances in medical oncology.”


The phase 3 trial BOLERO-2 was halted early after an interim analysis showed a 57% reduced risk for progression in postmenopausal patients with estrogen receptor–positive, HER2- negative disease.

In earlier phase 2 trials, the mTOR inhibitor everolimus—approved for the treatment of renal-cell carcinoma— was effective as monotherapy and in combination with hormonal therapy. A double-blind, placebo-controlled phase 3 trial then evaluated the combination in women who had previously received letrozole (Femara) or anastrozole (Arimidex) whose disease continued to progress.

The 724 patients were randomized to either everolimus 10 mg/day or placebo; all patients also received exemestane daily.

At an interim analysis, investigators observed significantly better progression- free survival (PFS) for the combined treatment group versus placebo: median 6.9 months versus 2.8 months, respectively (P <.001), according to local investigator assessment. By central review, the benefit was even greater, with median PFS, 10.6 months versus 4.1 months, respectively, a 64% risk reduction (P <.001).

Overall survival data are immature, but Dr Baselga said there had been 83 deaths overall, including 13% in the placebo arm and 10% in the combination therapy arm.

Future analyses will determine the effects on bone metabolism, because everolimus is expected to counteract the bone problems that have been associated with aromatase inhibitors. Numerically, there were more grade 3- 4 side effects with the combination, but these were very uncommon in both arms and did not worsen quality of life for patients taking the 2 drugs, he said.

“Our results could represent a paradigm shift in the management of patients with hormone receptor– positive breast cancer,” Dr Baselga concluded.

Dr André said the study was well designed, used an appropriate control arm, and appeared to be molecularly enriched for mTOR activation on the basis of the subjects’ resistance to endocrine therapy. “Everolimus not only improves outcomes but opens perspectives in the field of kinase inhibitors in general. I think this is the most important advance in breast cancer since trastuzumab [Herceptin].”