S1207 An Upcoming Trial for High-Risk Breast Cancer - SWOG

4/22/2013
S1207: Endocrine +/- Everolimus
Phase III randomized, placebo-controlled trial
adding 1 year of everolimus to adjuvant endocrine
therapy for patients with high-risk, HR+, HER2-
breast cancer
Chair: Mariana Chavez-MacGregor, MD
co-Chair: Eleftherios Mamounas, MD
The Problem
1’384,155 women diagnosed with breast cancer in one year
458,503 women died of breast cancer in one year
Globocan, 2008
Survival is improving
Giordano S, et al. Cancer. 2004;100(1):44-52.
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4/22/2013
Breast Cancer is a heterogeneous disease
Perou, Nature 2000;406:747-752.
Perou, The Oncologist 2010.
Mechanisms of ER action in breast cancer
Osborne, Annual Reviews 2011.
BOLERO-2 Schema
N = 724
• Postmenopausal
2
• ER+ HER2- MBC
2:1
• Recurrence or
1
progression to
letrozole or
anastrozole
Everolimus 10 mg/day +
Exemestane 25 mg/day
(N = 485)
Placebo +
Exemestane 25 mg/day
(N = 239)
PFS
OS
ORR
Bone Markers
Safety
QOL
PK
• Stratification:
1. Sensitivity to prior hormonal therapy
2. Presence of visceral disease
No cross-over
Baselga et al. ESMO 2011; Hortobagyi G et al. SABCS 2011, Baselga et al NEJM 2012.
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4/22/2013
BOLERO‐2: Response & Clinical Benefit
Exemestane + Everolumis
Exemestane + Placebo
50.5%
(%)
Patients (
12.0%
P < 0.0001
P < 0.0001
25.5%
1.3%
Response
Clinical Benefit
Baselga et al. ESMO 2011; Hortobagyi G et al. SABCS 2011, Baselga et al NEJM 2012, Piccart ASCO abstract 551.
BOLERO ‐2: Primary Endpoint, PFS
(18‐Month Follow‐up, Local)
Probability (% %) of Event
100
80
60
40
20
EVE 10 mg + EXE
PBO + EXE
0
EVE 10 mg + EXE (n/N=310/485)
PBO + EXE (n/N=200/239)
HR=0.45 (95% CI: 0.38-0.54)
Log-rank p value: < .0001
EVE 10 mg + EXE: 7.82 months
PBO + EXE: 3.19 months
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120
Time (week)
Number of patients still at risk
485 436 366 304 257 221 185 158 124 91 66 50 35 24 22 13 10 8 2 1 0
239 190 132 96 67 50 39 30 21 15 10 8 5 3 1 1 1 0 0 0 0
Piccart ASCO abstract 551.
BOLERO ‐2: Primary Endpoint, PFS
(18‐Month Follow‐up, Central)
(%) of Event
100
80
60
HR=0.38 (95% CI: 0.31-0.48)
Log-rank P value: < .0001
Kaplan-Meier medians
EVE 10 mg + EXE: 11.01 months
PBO + EXE: 4.14 months
Probability
40
20
0
EVE 10 mg + EXE (n/N=188/485)
PBO + EXE (n/N=132/239)
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108
Time (week)
Number of patients still at risk
EVE 10 mg + EXE
PBO + EXE
485 427 359 292 239 211 166 140 108 77
239 179 114 76 56 39 31 27 16 13
62
9
48
6
32
4
21
1
18
0
11
0
10
0
5
0
0
0
Piccart ASCO abstract 551.
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4/22/2013
BOLERO‐2
• Addition of everolimus to exemestane prolongs
PFS in patients with ER+ HER2‐ breast cancer
refractory to nonsteroidal aromatase inhibitors.
◦ Local: median 7.4 vs. 3.2 months (HR = 0.44, P < 1 x 10 ‐16)
◦ Central: median 11.0 vs. 4.1 months (HR = 0.36, P < 1 x 10 ‐16)
• Benefit is observed in all subgroups.
• QOL was similar in the two arms.
• Adverse events were consistent with previous
experience with everolimus.
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Benefit of Systemic Therapy- Oxford Overview
Oxford Overview, 2006
S1207 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 HRpositive
breast tumors.
• Everolimus, an mTOR-inhibitor, has been
shown to increase the biological activity of
aromatase inhibitors.
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S1207
• 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.
S1207 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.
◦ STEEP definition: Time from registration to
date of first invasive recurrence (local,
regional or distant), second invasive primary
cancer (breast or not) or death due to any
cause.
S1207 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
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4/22/2013
S1207 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
S1207 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
S1207 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
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4/22/2013
S1207: 4 High-Risk Groups
1. Node-negative, primary tumor ≥ 2cm,
OncotypeDX RS > 25, and completed
adjuvant chemotherapy
2. 1-3 positive nodes, RS > 25, and completed
adjuvant chemotherapy
• RS screened via S1007 RxPONDER or otherwise
3. ≥ 4 positive nodes and completed adjuvant
chemotherapy
4. ≥ 4 positive nodes and completed
neoadjuvant chemotherapy
S1207 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)
S1207 Schema
HR-positive and HER2-negative breast cancer
Neoadjuvant chemotherapy
Surgery: Number of positive nodes?
Surgery
Node-negative & tumor > 2 cm
1 - 3 positive > 4 positive
> 4 positive lymph nodes
Recurrence Score evaluation by OncotypeDX
RS < 25: Not eligible
RS > 25
Adjuvant
Chemotherapy
(may be eligible for
S1007 RxPONDER if
1-3 positive nodes)
Radiation therapy if indicated
RANDOMIZATION
Stratification factors:
• Node negative
• 1 - 3 positive nodes
• > 4 positive nodes Adjuvant
• > 4 positive nodes Neoadjuvant
Everolimus for 1 year +
endocrine therapy for 5 years
Placebo for 1 year +
endocrine therapy for 5 years
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4/22/2013
S1207 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
S1207 Statistical Considerations
• Primary analysis will be a stratified log-rank test
of treatment effect on IDFS with stratification on
the 4 risk levels.
◦ Interaction between treatment and risk level
◦ Separate subset analyses are planned for node+ and
node- patients
• 295 event are expected in the standard treatment
arm.
◦ 1 st interim analysis would be after 39% of the events
in the control arm have been observed (3.5 years
after initiation.
◦ There will be annual interim analysis (60 and 801%
expected events) with final analysis 3 years after last
patient was enrolled or 6.5 years after activation.
Study calendar
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S1207 and S1007 (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
• Cost effectiveness substudy
S1207 Translational Studies
• Blood is mandatory
• Lavender tube 7.5mL (EDTA tube)
• Red top tube 10mL (serum separator)
• Tissue is mandatory if available
◦ Paraffin block, punch biopsy or 20 slides from:
• Primary tumor
• Positive lymph node
• Negative lymph node
• Tissue from biopsies at time of recurrence
will be collected
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4/22/2013
S1207 Activation
• May 15 th , 2013: expected accrual start
Thank you
• Medical questions for Dr. Chavez-
MacGregor:
s1207medicalquery@swog.org
• Eligibility questions:
breastquestion@crab.org
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