1 Advancing Adjuvant HER2- Targeted Therapy Debu Tripathy, MD Professor of Medicine University of Southern California USC/Norris Comprehensive Cancer Center Ongoing Controversies Regarding Adjuvant Therapy for HER2+ Breast Cancer • Are anthracylines more effective for higher risk disease? • Can shorter duration be as effective? • Is longer duration optimal? • Should trastuzumab be used for T1a or T1b N0 disease? New Data from ESMO • Can trastuzumab be given with single agent paclitaxel or hormonal therapy for low risk disease? • Are there predictors for cardiac toxicity other than age, hypertension, use of anthracyclines? • How to handle borderline subnormal and subclinical drops in cardiac ejection fraction • Predictive factors of response?? (p95, PTEN-, PI3K mutations, MUC4, IGF-1R, HER-3, c-MET) HER2 Oncogene: A Biological Target • Increased A i HER2 gene amplification Aggressiveness • Shortened Survival • Hormonal Resistance HER2 protein overexpression HER2 gene amplification
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Advancing Adjuvant HER2- Targeted TherapyHER2 Testing in Clinical Practice: 2007 ASCO/CAP Algorithm Breast cancer specimen (invasive component) HER2 testing by IHC Equivocal IHC 2+
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Advancing Adjuvant HER2-Targeted Therapy
Debu Tripathy, MD
Professor of Medicine
University of Southern California
USC/Norris Comprehensive Cancer Center
Ongoing Controversies Regarding Adjuvant Therapy for HER2+ Breast Cancer
• Are anthracylines more effective for higher risk disease?
• Can shorter duration be as effective?
• Is longer duration optimal?
• Should trastuzumab be used for T1a or T1b N0 disease?
New Data from ESMO
• Can trastuzumab be given with single agent paclitaxel or hormonal therapy for low risk disease?
• Are there predictors for cardiac toxicity other than age, hypertension, use of anthracyclines?
• How to handle borderline subnormal and subclinical drops in cardiac ejection fraction
Europe, Canada, SA, Australia, NZ (2438) 161 vs 235 0.66 (0.54, 0.81)Asia Pacific, Japan (405) 21 vs 37 0.53 (0.31, 0.90)Eastern Europe (369) 23 vs 36 0.54 (0.32, 0.91)
Region of the world
<35 years (253) 19 vs 31 0.57 (0.32, 1.01)35-49 years (1508) 89 vs 150 0.54 (0.42, 0.70)
Age at randomisation
No. eventsT vs obs
HR (95% CI)Subgroup (no. patients)
Central + South America (189) 13 vs 13 0.98 (0.45, 2.11)
Exploratory DFS Subgroup Analysis (ITT):1 year Trastuzumab vs Observation - HERA Trial
0.0 0.5 1.0 1.5
HR
50-59 years (1096) 71 vs 97 0.71 (0.52, 0.97)>60 years (544) 39 vs 43 0.91 (0.59, 1.41)
Premenopausal (491) 43 vs 49 0.80 (0.53, 1.21)Uncertain (1373) 70 vs 135 0.48 (0.36, 0.64)Postmenopausal (1535) 105 vs 137 0.75 (0.58, 0.97)
Neoadjuvant CT (372) 39 vs 50 0.66 (0.43, 1.00)Negative (1099) 34 vs 58 0.59 (0.39, 0.91)1-3 positive nodes (976) 50 vs 80 0.61 (0.43, 0.87)
Nodal status
Menopausal status at randomisation
>4 positive nodes (953) 95 vs 132 0.64 (0.49, 0.83)All patients (3401) 218 vs 321 0.64 (0.54, 0.76)
HROverall Result
Smith I, et al. Lancet 2007
BCIRG 0006: Disease-Free Survival
Events
All Patients
Slamon D et al. NEJM 2011
AC-T 257TCH 214AC-TH 185
BCIRG 0006: Disease-Free Survival by Topo IIWithout Topo IIA Amplification
Slamon D et al. NEJM 2011
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BCIRG 0006: Disease-Free Survival by Topo IIWith Topo IIA Amplification
Smith et al 2007; Perez et al 2008; Slamon et al 2006; Rastogi et al 2007
2.83.3
0.41.90.4
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H = Trastuzumab; A = Doxorubicin; C = Cyclophosphamide; P = Paclitaxel; D = Docetaxel
Any Chemo
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Physiology of Trastuzumab-RelatedCardiac Dysfunction
• HER2 expressed at low levels on adult myocytes
• HER2 knock out mice exhibit embryonic lethal neural and cardiac developmental anomalies
• Cre-Lox ventricular-targeted knockoutCre Lox ventricular targeted knockout model (Crone, et al 2002)
Stress-induced progressive wall dilitation, thinning and decreased contractility
Rescued with Bcl-xL expression
• Cultured myocytes (J Schneider, et al)
• Trastuzumab and other HER2 Abs--> myopathic changes
Reversed with neuregulin 2b (HER4 ligand)
Chien KR, NEJM 2005
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N=830, 30 CHFs,No Cardiac Deaths
NSABP-31: Cumulative Incidence of Cardiac Events in the Evaluable Cohort
4.1%
Arm 2: AC → T+H
3/48 (6 3%) 9/47 (19 1%)
Relationship of CHF to Age and Baseline LVEF
50 54%)
AGE<50 ≥ 50
Tan-Chiu E et al JCO 2005; Romond E ASCO 2005
Cohort Arm 1 Evaluable CohortArm 2 Evaluable Cohort
%
0
2
Years Post Day 1 Cyc 50.0 0.5 1.0 1.5 2.0 2.5 3.0
Arm 1: AC → T
N=794, 3 CHFs, 1 Cardiac Death
HR=7.2
0.7%
3/48 (6.3%)5/229 (2.2%)1/160 (0.6%)
9/47 (19.1%)10/194 (5.2%)2/159 (1.3%)
50-5455-6465+LV
EF
(%
P (Age) = 0.04P (LVEF) <0.0001
7 Year Follow Up NSABP B31
Romond E et al. JCO 2012
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Histograms of Cohorts with LV Dysfunction – NSABP B31and Repeat LVEF > 6 Months after Nadir Ejection Fraction
Romond E et al. JCO 2012
A Nomogram and Model to Predict Cardiac Toxicity
Romond E et al. JCO 2012
Within Normal Limits Cont.
Relationship of LVEF to LLN
Absolute Decreaseof < 10%
Absolute Decrease
of 10 - 15%
Absolute Decrease of 16%
Hold *Cont.
Asymptomatic PatientsRules for Trastuzumab Continuation
Based on Serial LVEF
Within Normal Limits
1- 5 % below LLN
6 % below LLN
Hold *
Hold *
o d
Hold *
Hold *
Cont.
Cont.*
* Repeat LVEF assessment after 4 weeks - If criteria for continuation met – resume trastuzumab - If 2 consecutive holds, or total of 3 holds occur – discontinue
trastuzumab
Russell S, et al. JCO 2010; Procter M, et al. JCO 2010
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HERA 2-Year Trial: Study Design
Study Sites: Global (33 countries)
Primary endpoint
• Disease-free survival:
o 1-year trastuzumab vs. b ti
Study Details Study Design
Nodal status adjuvant chemotherapy regimen hormone
HER2-positive invasive EBC (N ~ 5000)
Stratification
Surgery + (neo)adjuvant chemotherapy ± radiotherapy
observation
o 2-year trastuzumab vs. observation
Secondary endpoint
• Disease-free survival
o 1-year trastuzumab vs. 2-year trastuzumab
o Overall survival
Nodal status, adjuvant chemotherapy regimen, hormone receptor status and endocrine therapy, age, region
Observation(n = ~1700)
Randomization
1 years trastuzumab8 mg/kg → 6 mg/kg3-weekly schedule
(n ~ 1700)
2 year trastuzumab8 mg/kg → 6 mg/kg3-weekly schedule
(n ~ 1700)
Arm 2Arm 1 Arm 3
fre
e s
urv
iva
l (%
)
89.1%
86.7%81.0%
81.6%75.8%
76.0%
100
80
60
40Trastuzumab 1 year
Trastuzumab 2 years
HERA 2-Year Trial: DFS Results
Dis
ea
se
-f
Years from randomization
40
20
00 1 2 3 4 5 6 7 8 9
No. at riskTrastuzumab 2 years 1553 1553 1442 1361 1292 1223 1153 1051 633 194Trastuzumab 1 year 1552 1552 1413 1319 1265 1214 1180 1071 649 205
Pts Events HR (2 vs 1) 95% CI p-value
2 years 1553 367 0.99 (0.85-1.14) 0.86
1 year 1552 367
Gelber R et al. ESMO 2012
PHARE Trial: Study Design
HER2-positive EBC (N ~ 3500)
Trastuzumab x 6 mosA h dj t i
Study Sites: France (~150 sites)
Primary endpoint (non-inferiority)
• Disease-free survival
o 6 months of trastuzumab vs. 1 f b
Surgery + (neo)adjuvant chemotherapy ± radiotherapy
Study Details Study Design
≈50% sequential50% tAny chemo adjuvant regimen
Chemotherapy and trastuzumab timing: sequential vs. concurrent, Hormonal therapy, Recruiting center