ESMO 2011 Breast Cancer BOLERO-2 Authors: CARE Faculty (Drs. Anil Joy and Sunil Verma) Date posted: October 12, 2011

Everolimus in Combination with Exemestane for Postmenopausal Women with Advanced Breast Cancer Who Are Refractory to Letrozole or Anastrozole Results of the BOLERO-2 Phase III Trial. Presenter: J. Baselga Background:Pre-clinical studies have identified mammalian target of rapamycin (mTOR) pathway to be constitutively activated in hormone therapy resistant advanced breast cancer. Phase II trials with everolimus have shown efficacy both as monotherapy and in combination with endocrine therapy in patients with estrogen receptor positive (ER+) advanced breast cancer (ABC).

R Treatment A: exemestane (EXE) + everolimus (EVE) (n=485) Treatment B: exemestane alone (n=239) Patient Population 2:1 BOLERO-2 N= 724 ER+, previously non- steroidal aromatase inhibitor treated ABC patients Primary Outcome: Progression Free Survival Baseline characteristics were well balanced; median age was 62 years; 56% had visceral involvement and 84% were sensitive to prior hormone therapy. Prior therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%) and chemotherapy (68%).

RESULTS Treatment ATreatment BHRp-value PFS (interim analysis) (median, months) × PFS (central assessment) (median, months) × Grade ¾ AEs -Stomatitis -Anemia -Dyspnea -Hyperglycemia -Fatigue -pneumonitis 8% 5% 4% 3% 1% <1% 1% <1% 1% 0% Overall survival Data is immature

BOLERO-2 Perspectives ▶ There is an unmet clinical therapeutic need in endocrine resistant ER+, HER2 normal advanced breast cancer. ▶ This is the first, large phase III study of a targeted agent (everolimus) when added to endocrine therapy that has reported significantly improved PFS, response rate and a manageable safety profile. ▶ The trial results were reported earlier than expected at the first interim analysis as the outcome of combination of EVE+EXE arm had exceeded the pre-specied PFS threshold for significance. As a result, overall survival data is still immature and is eagerly anticipated. The study remains blinded. ▶ As preclinical studies supported the hypothesis that mTOR inhibition could potentially reverse resistance to endocrine therapy, future studies evaluating mTOR inhibition in combination with inhibition of compensatory or parallel pathways of mTOR (e.g. IGF1R inhibitors) will be of particular interest. ▶ Based on BOLERO2 and other supportive results, mTOR inhibition in combination with endocrine therapy will likely be considered a new therapeutic strategy for women with previously AI treated advanced breast cancer.