advancing adjuvant her2- targeted therapyher2 testing in clinical practice: 2007 asco/cap algorithm...

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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

• Predictive factors of response?? (p95, PTEN-, PI3K mutations, MUC4, IGF-1R, HER-3, c-MET)

HER2 Oncogene: A Biological Target

• Increased A iHER2 gene amplification Aggressiveness

• Shortened Survival

• Hormonal Resistance

HER2 protein overexpression

HER2 gene amplification

2

HER1/EGFR

HER2 HER3

HER4

EGF

TGF

AR

HRGHRG

TK

TK

TK

X

HER Family Ligands and Signaling

PI3K/AKTRas/MEK/MAPK

(STAT)

TF

CoACoR

ProliferationMigrationDifferentiationApoptosis

PP

HER2 Testing in Clinical Practice: 2007 ASCO/CAP Algorithm

Breast cancer specimen (invasive component)

HER2 testing by IHC

EquivocalIHC 2+

Negative for HER2 overexpressionIHC 0 or 1+

Positive for HER2 overexpressionIHC 3+

Wolfff A, et al. J Clin Oncol. 2007

Re-test to assess gene amplification statuse.g. FISH

Negative for HER2 amplificatione.g. FISH ratio < 1.8

Positive for HER2 amplificatione.g. FISH ratio > 2.2

Equivocal for HER2 gene amplificatione.g. FISH ratio 1.8-2.2

Per Evidence:Ratio < 2 = HER2-Negative

Per Evidence:Ratio > 2 = HER2+

2011 Clarification – trials used IHC 3+ or FISH > 2.0 as eligibility for trastuzumab trials

TrastuzumabHumanized Anti-HER2 Monoclonal Antibody

• Targets HER2 protein

• Selectively binds with

Carter P et al. PNAS1992

high affinity (Kd ≤0.5 nM)

• 95% human, 5% murine

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Adjuvant Trastuzumab Trial Designs

Summary of Trastuzumab AdjuvantTrial DFS Benefits

Study FU, yrs N

HERA1 3,387

2 3,401

NSABP B 31/ 2 3 351

HR

0.54

0.64

0.48NSABP B-31/NCCTG 9891

2 3,351

4 3,968

BCIRG 006 3 3,222

FinHer 3 231

PACS 04 4 528

0 1 2In favor of T In favor of Obs.

0.48

0.48

0.61

0.42

0.86

NSABP/NCCTG 4 Year Follow-up

Δ 12%

Δ 7.4%

Perez EA et al JCO 2011

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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


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BCIRG 0006: Disease-Free Survival by Topo IIWith Topo IIA Amplification


BCIRG 0006: DFS By Subsets


BCIRG 0006: Overall Survival


EventsAC-T 141TCH 113AC-TH 94

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Concurrent vs. Sequential Therapy: N9831

No DifferenceIn Overall Survival

Perez EA et al. JCO 2011

Concurrent vs.

Sequential Therapy:Therapy:

N9831

Cardiotoxicity

Perez EA et al. JCO 2008

Trial

HERA

B31

N9831

Arm

ControlH 1 year

ACPACPH

ACP

BaselineLVEF, %

>55

>50

>50

CHF, %

Cardiacdeath, n

10

10

1

00.6 / 2.1

0.83.8

0.3

Clinical Cardiomyopathy fromTrastuzumab Adjuvant Trials

BCIRG 006

FinHer

ACPHACPH

ACDACDHDCarboH

No HH

>50

10

000

00

Smith et al 2007; Perez et al 2008; Slamon et al 2006; Rastogi et al 2007

2.83.3

0.41.90.4

10

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

4

6

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


A Nomogram and Model to Predict Cardiac Toxicity


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

Stratification

Randomization

No further trastuzumab

6 months trastuzumab

1 year of trastuzumab

Arm 1 Arm 2

≈50% concurrent

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0 25

0.50

0.75

1.00

Pro

bab

ility

PHARE Study: Disease Free Survival

95.5 91.2 87.8 84.9

97.0 93.8 90.7 87.8

Events HR 95%CIl

0.00

0.25

1690 1586 1353 939 526 23H 6m1690 1613 1390 980 544 18H-12m

At risk

0 12 24 36 48 60Months

H-12m H-6m

* Cox model stratified by ER status and concomitant chemotherapy

p-valueH 12m 176H 6m 219 1.28 (1.05 – 1.56) 0.29

Pivot X et al. ESMO 2012

Equivalent

Superior

A

B

C

Primary Endpoint Scenarii

PHARE trial

Non Inferior

Inferior

C

D

E

.85 1 1.15 1.3 1.45 1.6HR

Pivot X et al. ESMO 2012

How Small a Tumor to Treat?T1a/b N0 Tumors5 French Centers 2000-2010Among 51 T1a, 16 treated

In other series, distant recurrence- free survival ranges from 89-98%

Peron J, et al. SABCS 2011 Kelly CM, et al. Ann Oncol 2011

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Cost Effectiveness Dependson Baseline Relapse Risk and Age

Liberato NL et al JCO 2007

Ongoing or Competed Second Generations HER2+ Adjuvant Trials

Docetaxel x 6 Bevacizumab 15mg 3 k 1

BETH Trial

Carboplatin x 6Trastuzumab x 1 y

Docetaxel x 3Trastuzumab x 1 y

5-FU x 3Epirubicin x 3Cylophos x 3

or

q3 wk x 1 y

Observation

ALLTO Adjuvant Trial

3-weeklyTrastuzumabf 52 k

Lapatinibfor 52 weeks

WeeklyTrastuzumab (12 k )

Lapatinib + 3-weeklyT t b

Chemotherapy is flexible (eg. AC-Taxane, TCH)

for 52 weeks (12 weeks) Trastuzumab for 52 weeksWashout (6 weeks)Washout (6 weeks)

Lapatinib (34 weeks)

Anti-HER2 therapy can overlap chemotherapyAnti-HER2 therapy can overlap chemotherapy

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Aphinity Adjuvant Trial

6-8 cycles of Anthracycline or non-

th li th

Trastuzumab x 52 weeks

anthracyline therapy

Trastuzumab +Pertuzumab x 52 weeks

Even Further in the Future: T-DM1, mTOR inhibitors, PI3K inhibitors, HER2/3 bispecific antibodies, heat shock/chaperone inhibitors

Personalizing CombinatorialTherapy for HER+ Breast Cancer

• E75 = immunogenic peptide (aa 369-377) of the HER2 protein

• 6 cycles monthly intradermal E75 with GM-CSF (250 mcg)

• Combined analysis of 2 trials• Trial 1: dose-escalation

trial of node+ pts with BC

HER2 Peptide Vaccine (E75)In Early Stage Breast Cancer – Non randomized

Mittendorf EA, Peoples GE et al. Cancer 2012

p• Trial 2: dose-optimization

trial of node- pts with BC)• Median F/U = 24 mo.• N = 186

• E75 vaccine = 106 (HLAA2/A3+)

• Controls = 76 (HLAA2/A3-)

• 26% HER2+

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HER2 Peptide Vaccine (E75) - NeuVaxPRESENT Trial - Phase III Randomized Adjuvant

(1 2 )and FISH-

(1-2+)

Take Home Points HER2-directed therapy in the form of trastuzumab has a

clear and sustained impact on breast cancer recurrence and mortality (best to use IHC 3+ or FISH ratio ≥2)

Cardiotoxicity is real, can be permanent

Overlap of chemotherapy with trastuzumab appears to decrease recurrence but increase cardiotoxicitydecrease recurrence but increase cardiotoxicity

Optimal duration of therapy currently appears to be 1 year

Are anthracylines necessary? (more cardiac toxicity)

Risk and size cutpoint for trastuzumab therapy remains unclear (T1b vs higher, or some T1a)?

Need better predictors of benefit and cardiac toxicity

The future is individualized and rational combinatorial therapy

advancing adjuvant her2- targeted therapyher2 testing in clinical practice: 2007 asco/cap algorithm...

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