1. 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

2. 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.

3. 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

4. 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.

5. 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.

6. 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

7. 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

8. 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

9. 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

10. 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)

11. 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 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

12. 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)

13. 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

14. 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

15. 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

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

17. Thank you
Medical questions for Dr. Chavez- MacGregor and Dr. Priya Rastogi:
Eligibility questions: