SABCS 2011 BOLERO-2 Updated Results Everolimus for postmenopausal women with advanced breast cancer: updated results of the BOLERO-2 phase III trial Presented by Dr. Gabriel Hortobagyi Reviewer: Dr. Sunil Verma Date posted: December 12th, 2011

BACKGROUND The average survival of patients with Metastatic Breast Cancer (MBC) remains around 24-28 months. The general approach is to treat metastatic HR+ve MBC with sequential anti-estrogen agents Though some patients may have a durable response, most patients will develop resistance to these agents and many go on to receive salvage chemotherapy One of the key pathways of resistance is the pI3k-AKT pathway and hence mTor inhibitors such as Everolimus may be ideal agents to help overcome this resistance

R BOLERO-2 Treatment B: exemestane + placebo (n=239) Randomized 2:1 N= 724 ER+, previously non-steroidal aromatase inhibitor treated MBC 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 for metastatic disease (25%). Treatment A: exemestane (EXE) + everolimus (EVE) (n=485) R Treatment B: exemestane + placebo (n=239) Randomized 2:1

RESULTS Median follow up of 12.5 months EVE + EXE PBO + EXE HR p-value PFS (interim analysis) (median, months) 7.4 3.2 0.44 (95% CI: 0.36-0.53) <1 x 10-16 PFS (central assessment) 11.0 4.1  0.36 (95% CI: 0.28-0.45) Overall survival interim analysis planned after 182 deaths (December 2011) 23.1% in everolimus arm 29.3% in placebo arm

BOLERO-2 Key Conclusions The addition of Everolimus to Exemestane leads to a substantial improvement in PFS OS Data is premature Main Toxicity Events Stomatitis (Grade 3 – 8%) Pneumonitis (Grade 3 – 3%) Rash No improvement in Quality of Life

BOLERO-2 Bottom Line for Oncologists This is one of the most significant trials in the management of breast cancer The differences seen in progression free survival are clinically meaningful and will help delay the use of chemotherapy for our patients This approach may not be suitable for some HR+ve MBC, such as patients with durable response with first line NSAI, slow growing indolent disease or frail/elderly patients. We still need to consider chemotherapy for some patients who have very aggressive disease despite HR+ve status The toxicity is concerning and we need to be aware and be educated on the management of stomatitis and monitoring for pneumonitis and hyperglycemia prior to the use of this agent in clinical practice