S1207: Phase III randomized, placebo-controlled trial adding 1 year of everolimus to adjuvant endocrine therapy for patients with high-risk, HR+, HER2- breast cancer Mariana Chavez-MacGregor, MD Eleftherios Mamounas, MD

e3 Primary Objective Determine if the addition of one year of everolimus to standard adjuvant endocrine therapy improves IDFS in high-risk patients with HR+, HER2- negative breast cancer.

e3 Secondary Objectives Overall Survival Distant Recurrence-Free Survival Evaluate safety and toxicities Evaluate adherence QOL (patient-reported fatigue and symptoms, fatigue-related biomarkers) To collect specimens in order to evaluate biomarkers of therapeutic efficacy

e3 Background Abnormalities of the PI3kinase/AKT/mTOR signaling network are some of the most common molecular anomalies in breast cancer. This pathway has been associated with resistance to endocrine therapies among HR-positive breast tumors. Everolimus, an mTOR-inhibitor, has been shown to increase the biological activity of aromatase inhibitors.

e3 Background (cont.) In the metastatic setting, everolimus in combination with tamoxifen or exemestane increased the progression-free survival in patients previously treated with endocrine therapy. S1207 proposes to evaluate the role of everolimus used in combination with endocrine therapy in the adjuvant setting.

e3 Clinical Trial Design SWOG/NSABP randomized phase III double-blind, placebo-controlled clinical trial Parallel randomization design with equal allocation to two treatment groups (everolimus vs. placebo) Patients stratified by risk group

e3 Clinical Trial Design Adjuvant/ Neoadjuvant Chemotherapy Surgery Radiation Therapy Registration Randomization Everolimus for 1 year + Appropriate endocrine therapy for 5 years Placebo for 1 year + Appropriate endocrine therapy for 5 years

e3 Key Eligibility Criteria Histologically confirmed HR+, HER2- negative breast cancer Patient must complete chemotherapy before registration (within past 21 weeks) When RT is indicated, patient must complete radiation therapy before registration (at least 21 days before and recovered to ≤ grade 1 from XRT effects) Patient may have started endocrine therapy before registration

e3: 4 High-Risk Groups Node-negative, primary tumor ≥ 2cm, OncotypeDX RS > 25, and completed adjuvant chemotherapy 1-3 positive nodes, RS > 25, and completed adjuvant chemotherapy RS screened via S1007 RxPONDER or otherwise ≥ 4 positive nodes and completed adjuvant chemotherapy ≥ 4 positive nodes and completed neoadjuvant chemotherapy

e3 Treatment Plan Patients randomized to either: Everolimus 10mg/PO daily for one year + adjuvant endocrine therapy (selected by treating physician) OR Matched placebo daily for one year + adjuvant endocrine therapy (selected by treating physician)

e3 Statistical Considerations Randomize 3,500 patients over 3.5 years 90% power (with 2-sided α=0.05) to detect an effective hazard ratio of 0.75 for everolimus vs placebo, corresponding to a gain in IDFS of approximately 4.3% at 5 years All patients will be followed for 10 years to assess OS and late adverse events Expected trial duration from activation to reporting of IDFS is about 7 years

e3 Schema HR-positive and HER2-negative breast cancer Recurrence Score evaluation by OncotypeDX Surgery: Number of positive nodes? 1 - 3 positive > 4 positive Adjuvant Chemotherapy RANDOMIZATION Stratification factors: Node negative 1 - 3 positive nodes > 4 positive nodes Adjuvant > 4 positive nodes Neoadjuvant RS > 25 Everolimus for 1 year + endocrine therapy for 5 years Placebo for 1 year + endocrine therapy for 5 years Neoadjuvant chemotherapy Node-negative & tumor > 2 cm Radiation therapy if indicated RS < 25: Not eligible > 4 positive lymph nodes Surgery (may be eligible for S1007 RxPONDER if 1-3 positive nodes)

e3 and RxPONDER Two trials are mutually exclusive S1007 screens patients with 1-3 positive nodes using OncotypeDX RS ≤ 25 may be eligible for S1007 RS > 25 are ineligible for S1007, but may be eligible for S1207 Keep S1207 in mind when screening patients for S1007 RxPONDER

S1207-E01: Behavioral and Health Outcomes Study (BAHO) Patients at CCOPs may take part in BAHO study Patients who have already started endocrine therapy are not eligible Objectives: Determine severity of symptoms (fatigue, stomatitis, MSK complaints) and QOL by treatment arm Determine if fatigue and anemia are associated with proinflammatory cytokines and biomarkers of inflammation N = 492 to have 90% power to detect a difference of 1/3 standard deviation between treatment groups for any primary endpoint with α level at 0.05

e3 Translational Studies Blood is mandatory Tissue is mandatory if available 1 paraffin block of primary tumor Positive lymph node Negative lymph node Tissue from biopsies at time of recurrence will be collected

e3 Activation November 2012: active, not recruiting September 2013: accrual start

Thank you Medical questions for Dr. Chavez- MacGregor and Dr. Priya Rastogi: s1207medicalquery@swog.org Eligibility questions: breastquestion@crab.org