Treatment of Early Stage HER2-positive Breast Cancer (One size...

Treatment of Early Stage HER2-positive

Breast Cancer

(One size does not fit all)

8 November 2014

Edward H. Romond, M.D.

Professor of Medicine

Lucille Parker Markey Cancer Center

University of Kentucky

Lexington, KY

Slamon, et al. Science 1987;235:177-182

Amplified

Not Amplified

Amplified

Not Amplified

Focal HER2 Amplified Clones

Fig. 2 Epitope binding of HER2 and EGFR therapeutic antibodies.(A) Trastuzumab.

M X Sliwkowski, and I Mellman Science 2013;341:1192-1198

Published by AAAS

Large Phase III Adjuvant Trastuzumab Trials

B31/N9831 AC → T

AC → TH

CIRG 006

AC → T*

AC → T*H

T*C*H

HERA: Chemo

± XRT

Observation

H x 1 year

H x 2 years

A = doxorubicin

C = cyclophosphamide

T = paclitaxel

H = trastuzumab

T* = docetaxel

C* = carboplatin

(AC → T → H)

NSABP B-31

NCCTG N9831

Arm 1

Arm 2

Arm A

Arm B

Arm C

= doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4

= paclitaxel (T) 175 mg/m2 q 3 wk x 4

= paclitaxel (T) 80 mg/m2/wk x 12

= trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51

Control: AC→T

Investigational: AC→T+H

N9831/B-31 Disease-Free Survival

2028 1959 1848 1747 1675 1611 1514 1293 910 619 350

2018 1887 1689 1529 1423 1329 1232 1027 705 449 255

% E

ve

nt-

Fre

e

Years from Randomization No. at risk

AC P

AC P+H

N Events

AC→P 2018 680

AC→P+H 2028 473 HRadj=0.60 (95% CI: 0.53-0.68)

P<0.0001

62.2%

73.7%

64.9%

76.8% 81.4%

69.5%

11.5%

San Antonio Breast Cancer Symposium, December 4-8, 2012

Perez, E et al. , J Clin Oncol, 2014

B-31/N9831 Overall Survival

2028 1995 1959 1897 1843 1785 1709 1506 1085 735 439

2018 1962 1883 1806 1730 1640 1534 1336 944 604 353

Years from Randomization

% S

urv

iva

l

No. at risk

AC P

AC P+H

84.0% 87.0% 89.8%

75.2%

79.4% 84.3%

HRadj=0.63 (95% CI 0.54-0.73)

P<0.0001

N Events

AC→P 2018 418

AC→P+H 2028 286

90.3%

93.2%

∆=2.9% ∆=5.5% ∆=7.6% ∆=8.8%

8.8%


Perez, E et al. , J Clin Oncol, 2014

OS According to Subgroups ACTH vs. ACT (reference group)

Factor N

No. of Events

ACT ACTH HR

<40 years

40-49

50-59

60+ years

ER- and PR-

ER+ or PR+

0-2cm

2.1-5.0cm

5.1cm+

LN 0

LN 1-3

LN 4-9

LN 10+

Good

Intermediate

Poor

654

1373

1336

683

1828

2215

1598

2096

345

282

2144

1084

536

76

1123

2801

65

121

129

103

212

206

129

239

50

11

161

133

113

8

108

299

45

87

90

64

149

137

67

176

42

9

104

103

70

1

59

219

0.67

0.65

0.68

0.51

0.65

0.61

0.51

0.68

0.58

0.94

0.59

0.72

0.56

0.11

0.52

0.67

HR with 95% CI

0.5 1 1.5 2

Age

Hormone

Receptor

Tumor Size

Nodal

Status

Histologic

Grade

0.0

ER and PR Negative

AC P

AC P+H

N Events

AC→P 911 175

AC→P+H 917 103

21.5%

11.9%

B-31/N9831 Cumulative Incidence of Distant Recurrence as a First Event

ER and/or PR Positive

AC P

AC P+H

Cu

mu

lati

ve

In

cid

en

ce

(%

)

N Events

AC→P 1105 216

AC→P+H 1110 124

22.3%

12.7%

Years from Randomization

Δ= 9.6%


Δ=9.6%

Does the degree of HER2 amplification correlate

with the degree of benefit from trastuzumab?

Reinholz M, SABCS 2007, abstr 36

Hazard Ratio of Benefit to Trastuzumab by HER2 FISH Ratio in NCCTG N9831

0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00

11.0-15.0 (328)

< 2.0 (156)

2.0-5.0 (253)

5.0-8.0 (515)

8.0-11.0 (473)

≥ 15.0 (70)

p = 0.12

p = 0.05

p = 0.03

p = 0. 04

p = 0.96

p = 0.004

Ratio (N) p-value

Hazard ratio

What is the benefit of using trastuzumab with a

non-anthracycline containing regimen?

4 x AC 60/600 mg/m2

4 x Docetaxel 100 mg/m2

6 x Docetaxel and Carboplatin 75 mg/m2 AUC 6

1 Year Trastuzumab

N=3,222

1 Year Trastuzumab

ACT

ACTH

TCH

Her2+ (Central FISH)

N+

or high

risk N-

4 x AC 60/600 mg/m2

4 x Docetaxel 100 mg/m2

BCIRG 006

Stratified by Nodes

and Hormonal

Receptor Status

BCIRG 006 Disease Free Survival (median follow-up 65 months)

Slamon D, et al. NEJM 365:1273-1283, 2011

Patients Events HR P

AC-TH 1074 185 .64 <0.001

TCH 1075 214 .75 0.04

AC-T 1073 257

What is the benefit of using trastuzumab after

chemotherapy is finished?

OBSERVATION n=1698

Women with locally determined HER2-positive invasive early breast cancer

Surgery + (neo)adjuvant CT ± RT

Centrally confirmed IHC 3+ or FISH+ and LVEF ≥ 55%

Randomization

1 year Trastuzumab 8 mg/kg – 6 mg/kg 3 weekly schedule

n=1703

2 years Trastuzumab 8 mg/kg – 6 mg/kg 3 weekly schedule

n=1701

After ASCO 2005, option of switch to Trastuzumab

HERA TRIAL DESIGN Accrual 2001 – 2005 (n=5102)

CT, chemotherapy; RT, radiotherapy

HERA: Disease Free Survival

Goldhirsch A, et al. Lancet 382:1021-1028,2013 53% of Observation received trastuzumab

Median follow-up

(% follow-up time

after selective crossover)

No. of DFS events

1 year trastuzumab

vs observation

127 vs 220

P<0.0001

218 vs 321

P<0.0001

369 vs 458

P<0.0001

DFS benefit

Favours 1 year trastuzumab Favours observation 0 1 2

HR (95% CI)

SUMMARY OF DFS ITT ANALYSES FOR 1 YEAR

TRASTUZUMAB VS. OBSERVATION

ACROSS ANALYSIS TIME POINTS

2005

(0%)

2006

(4.3%)

2008

(33.8%)

1 yr MFU

4 yrs MFU

2 yrs MFU

0.54

0.64

0.76

471 vs 570

P<0.0001

2012

(48.5%) 8 yrs MFU

0.76

Goldhirsch A, et al. Lancet 382:1021-1028,2013

Favours 1 year trastuzumab Favours observation 0 1 2

HR (95% CI)

OS benefit

SUMMARY OF OS ITT ANALYSES FOR 1

YEAR TRASTUZUMAB VS. OBSERVATION

ACROSS ANALYSIS TIME POINTS


Median follow-up

(% follow-up time

after selective crossover)

No. of deaths

1 year trastuzumab

vs observation

29 vs 37

P=0.26

59 vs 90

P=0.0115

182 vs 213

P=0.1087

2005

(0%)

2006

(4.1%)

2008

(30.9%)

0.76

0.66

0.85

1 yr MFU

4 yrs MFU

2 yrs MFU

278 vs 350

P=0.0005

2012

(45.5%)

0.76

8 yrs MFU

So is it better to start trastuzumab sequentially

after completion of chemotherapy or concurrently

with taxane chemotherapy?

NCCTG N9831 Trial Incorporating

Trastuzumab in Adjuvant Therapy

R

A

N

D

O

M

I

Z

E

HER2 positive

(FISH ratio ≥2

or

IHC 3+ >10%)

Arm A

Arm C

Arm B

AC T

AC T

H

H

AC T

= AC (doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4)

= T (paclitaxel 80 mg/m2/wk × 12)

= H (trastuzumab 4 mg/kg loading + 2 mg/kg/wk × 51)

n=3,505

N9831: Sequential (B) vs. Concurrent (C)

Perez EA et al. J Clin Oncol 29:4491-4497, 2011

Efficacy Summary

Randomized Adjuvant Trastuzumab Trials

TRIAL Pts TREATMENT

DFS

(%) HR P

OS

(%) HR P

B31/N9831 2028

2018

AC→TH

AC→T

74*

62 0.60 <0.001

84*

75 0.63 <.001

CIRG 006 1074

1075

1073

AC→TH

TCH

AC→T

84**

81

75

0.64

0.75

<0.001

0.04

92**

91

87

0.63

0.77

0.001

0.038

HERA 1703

1698

chemo→H

chemo→obs

71*

65 0.76 <0.0001

83*

77 0.76 0.0005

FinHER 115

116

V/T+H→FEC

V/T→FEC

89†

78 0.42 0.01

96†

90 0.41 0.07

PACS04 260

268

FEC/ET→H

FEC/ET

73*

73 0.86 0.42

92*

93 1.27 NR

† - at 3 years * - at 8 years ** - at 5.5years

How long should trastuzumab be given in the

adjuvant setting?

Current Trials Assessing

Duration of Trastuzumab

SOLD

(Finland)

Docetaxel + Trast (nine weeks) → FEC X 3

Docetaxel + Trast (nine weeks) → FEC X 3 → Trast (total 1

year)

PHARE

(France)

Chemotherapy + Trast X 12 months


Short-HER

(Italy)

Docetaxel + Trast (nine weeks) → FEC X 3

AC/FEC X 4 → Taxane + Trast X 4 → Trast (18 weeks)

Hellenic

Group

(Greece)

FEC X 4 → Docetaxel + Trast → Trast (total 12 months)

FEC X 4 → Docetaxel + Trast → Trast (total 6 months)

Persephone

(Great Britain)



HERA Chemotherapy → Trast X 1 year

Chemotherapy → Trast X 2 years

Dis

ease-f

ree s

urv

ival

(%)

Years from randomization

89.1%

86.7% 81.0%

81.6%

75.8%

76.0%

HERA: DFS FOR 2 YEARS VS. 1 YEAR

TRASTUZUMAB AT 8 YRS MFU

100

80

60

40

20

0

0 1 2 3 4 5 6 7 8 9

No. at risk

Trastuzumab 2 years 1553 1553 1442 1361 1292 1223 1153 1051 633 194

Trastuzumab 1 year 1552 1552 1413 1319 1265 1214 1180 1071 649 205

Trastuzumab 1 year

Trastuzumab 2 years

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


PHARE* Study design

trastuzumab 6 months

trastuzumab up to 12 months

1690 patients

stop trastuzumab

1690 patients

Clinical exam

LVEF 3

Mammography

6 9 12 15 18 21 24 30 mos

…

0

R

Up to 60 mos…

Stratification

1. ER pos / neg

2. Chemo: concurrent/sequential

* Protocol of Herceptin Adjuvant with Reduced Exposure

Pivot X, et al, Lancet Oncol 14:741-748, 2013

www.esmo2012.org

0.00

0.25

0.50

0.75

1.00

Pro

babili

ty

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

Disease Free Survival

95.5 91.2 87.8 84.9

97.0 93.8 90.7 87.8

Events HR 95%CI p-value H 12m 176 H 6m 219 1.28 (1.05 – 1.56) 0.29


Equivalent

6 month Superior

6 month Non Inferior

6 month Inferior

A

B

C

D

E

.85 1 1.15 1.3 1.45 1.6 HR

Primary endpoint scenarii

PHARE trial


Cardiac Risk Assessment with

Anthracycline based regimens

Control

AC x 4 Paclitaxel

Investigational

AC x 4 Trastuzumab + Paclitaxel

0 mo.

18 mos.

6 mos.

9 mos.

3 mos.

0 mo.

18 mos.

6 mos.

9 mos.

3 mos.

B-31/N9831 LVEF Evaluation Schedule

Cont.

Hold*

Hold*

Relationship of LVEF to LLN

Absolute decrease of < 10%

Absolute decrease of 10%–15%

Absolute decrease of 15%

Hold*

Hold*

Hold*

Cont.

Cont.

Cont.*

*Repeat LVEF assessment after 4 weeks

– If criteria for continuation is met then resume trastuzumab • If 2 consecutive holds (or a total of 3 holds occur) then

discontinue trastuzumab

LLN = lower limit of normal.

Asymptomatic Patients

Rules for Trastuzumab Continuation

Based on Serial LVEF

Within normal limits

1%–5% below LLN

≥ 6% below LLN

0 1 2 3 4 5 6 7

01

23

45

Years Post Day 1 Cyc 5

%

HR=3.30;P-value- =0.00038

ACPH arm; 4.0%

ACP arm; 1.3%

NSABP B-31: 7 year cumulative incidence of cardiac events

Romond et al. J Clin Oncol 30:3792-3799, 2012

Risk Factors No. of

Pts

No. with CHF

(%)

P

value

Relative risk

(95% CI)

Age

< 50 486 11 (2.3%)

0.03

Ref. group

50-59 313 16 (5.1%) 2.3 (1.1-4.9)

60+ 148 8 (5.4%) 2.4 (1.0-6.0)

B-31: Potential Risk Factors for Congestive Heart Failure

Hypertension

medications

No 732 22 (3.0%) 0.02 2.3 (1.2 - 4.6)

Yes 192 13 (6.8%)

Baseline

LVEF

<54 70 9 (12.9%)

0 .0003

Ref. group

55-64 452 17 (3.8%) 0.3 (0.1 – 0.6)

65+ 425 9 (2.1%) 0.2 (0.1 – 0.4)

Left-sided tumor

& radiation

No 587 23 (3.9%) 0.71 0.9 (0.4-1.8)

Yes 351 12 (3.4%)

Cardiac Risk Score (based on evaluable cohort in NSABP B-31)

[7.0 + (0.04 x Age in years) – (0.1 x Baseline percent LVEF)] x 100

4.76


0 20 40 60 80 100

0.0

0.1

0.2

0.3

0.4

Cardiac Risk Score

Pre

dic

ted

Pro

ba

bili

ty o

f CE

0 %

1

0 %

2

0 %

3

0 %

4

0 %

NSABP B-31 Cardiac Risk Assessment


Examples:

(a)age 45, LVEF=65%, CRS=48.3

(b)age 65, LVEF=55, CRS=86.1

0 20 40 60 80 100

0.0

0.1

0.2

0.3

0.4

Cardiac Risk Score

Pre

dic

ted

Pro

ba

bili

ty o

f CE

0 %

1

0 %

2

0 %

3

0 %

4

0 %

a

b

NSABP B-31: Examples of Cardiac Risk Assessment

Summary of Cardiac Dysfunction in the

Large Adjuvant Trastuzumab Trials

Trial

Median

Follow-up

(years) Treatment Arms

Class III/IV

CHF (%)

Cardiac

Deaths

NSABP B-

31 7

AC→P + Trast

AC→P

4.0

1.3

1

1

NCCTG

N9831 5

AC→P+Trast

AC→P→Trast

AC→P

3.3

2.8

0.3

1

0

0

HERA 8 Chemo→Trast

Chemo→Observation

0.8

0

0

1

BCIRG 006 5

AC→D+Trast

D+Carboplatin+Trast

AC→D

2.0

0.4

0.7

0

0

0

A: doxorubicin; C: cyclophosphamide; P: paclitaxel; D: docetaxel

Low Risk and Node Negative Cancers

British Columbia Tumor

Registry

HER2

status

n 10 yr

RFS (%)

HER2- 1128 78.7

HER2+ 117 71.6

Stage I Only (T1N0)

Chia S et al. J Clin Oncol 2008 26:5697-5704

P=0.21

Valero et al, ASCO 2011, Abstr 553

BCIRG 006 Node Negative Patients

BCIRG 006 Disease Free Survival

Valero et al, ASCO 2011, Abstr 553

US Oncology Phase II Adjuvant Trial

Docetaxel + Cyclophosphamide + Trastuzumab

• Open label, Phase II

• 493 patients registered

• “Low risk” HER2 positive operable breast cancer: T1-2, N0-1a

• LVEF ≥ 50% by MUGA or echo

• Treatment regimen: (4 chemotherapy cycles)

– Docetaxel 75 mg/m² day 1

– Cyclophosphamide 600 mg/m² day 1

– Trastuzumab 4 mg/kg (loading) then 2mg/kg day 1,8,15

– Following completion of chemo: trastuzumab 6mg/kg q 21 days

to complete 1 year targeted therapy

Jones SE, et al. Lancet Oncol 14:1121-1128, 2013

Baseline Patient Characteristics

Jones SE, et al. Lancet Oncol

14:1121-1128, 2013

Disease-free Survival Overall Survival


US Oncology Phase II Adjuvant Trial

Docetaxel + Cyclophosphamide + Trastuzumab

Study Design

(APT Trial)

Tolaney S, et al. SABCS 2013, abstr S1-04

HER2+

ER+ or ER-

Node Negative

< 3 cm

Enroll

T

P

T

P

T

P

T

P

T

P

T

P

T

P

T

P

T

P

T

P

T

P

T

P

PACLITAXEL 80 mg/m2 + TRASTUZUMAB 2 mg/kg x 12

T T T T T T T T T T T T T

FOLLOWED BY 13 EVERY 3 WEEK DOSES

OF TRASTUZUMAB (6 mg/kg)*

Planned N=400

*Dosing could alternatively be 2 mg/kg IV weekly for 40 weeks

** Radiation and hormonal therapy was initiated after completion of paclitaxel

Patient Characteristics N %

Age

<50

50-70

≥70

132

233

41

33

57

10

Size of Primary Tumor

T1a ≤0.5 cm

T1b >0.5-≤1.0

T1c >1.0-≤2.0

T2 >2.0-≤3.0

77

124

169

36

19

31

42

9

Histologic Grade

I Well differentiated

II Moderately differentiated

III Poorly differentiated

44

131

228

11

32

56

HR Status (ER and/or PR)

Positive

Negative

272

134

67

33


San Antonio Breast Cancer Symposium- Cancer Therapy and Research Center at UT Health Science Center--December 10-14, 2013

50%

50%

San Antonio Breast Cancer Symposium- Cancer Therapy and Research Center at UT Health Science Center- December 10-14, 2013

Time (Months)

Re

curr

en

ce-F

ree

Su

rviv

al (

Pro

ba

bili

ty)

0 12 24 36 48 60

0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60

0.0

0.2

0.4

0.6

0.8

1.0

All patientsNumber at risk

406 390 382 307 126 27

Recurrence-Free Interval


3-year RFI 95% Conf. Interval

99.2% 98.3% to >99.9%

Recurrence Free Interval=

•Invasive Local/Regional Recurrence

•Distant Recurrence

•Death from Breast Cancer

What about really small node negative breast

cancers ≤ 1.0 cm (T1a/b)?

Subset DFS and OS results

US Oncology Phase II Trial of TC + Trastuzumab


T1abN0M0 HER2+ Breast Cancers

Kaiser Permanente Northern California

• 3.3 million members

• 16,975 new Breast Cancers diagnosed

from 1/1/2000 to 12/31/2006

• HER2, ER, PR IHC mandatory on all cases

• 2,168 HER2+ (IHC 3+ or FISH ratio >2.0)

• 237 T1a or T1b

Fehrenbacher L, et al. J Clin Oncol 32:2151-2158, 2014

Recurrences:T1a+bN0 HER2+

Median F/U 5.8 yrs

N#

T1aN0

116

T1bN0

121

T1abN0

237

Invasive Cancer Recurrence

(%)

(4)

3.5%

(11)

9.1%

(15)

6.3%

Invasive Cancer Local

Recurrence Only (%)

(3)

2.6%

(4)

3.3%

(7)

2.9%

Invasive Cancer Distant

Recurrence (%)

(1)

0.9%

(7)

5.8%

(8)

3.4%

5 year Relapse Free Interval

(K-M) 97.4%

(95% CI, 92.1.,99.1)

91.1% (95% CI ,83.2,95.3)

94.2% (95% CI, 89.9, 96.7)

5 year Distant Relapse Free

Interval (K-M) 99.1%

(95% CI,93.9, 99.9)

94.0% (95% CI, 87.1, 97.3)

96.5% (95% CI, 92.8, 98.3)


Treatments Received by T1abN0M0

Received

Chemo

Received

Trastuzumab

Distant Recur

No Chemo

Distant Recur

with Chemo

All T1abN0 59/237 (24.9%) 20/237(8.4%) 5/178 (2.8%) 3/59 (5.1%)

Pre 2005 4/153 (2.6%)

2005-2006 16/84 (19.0%)

T1aN0* 15/116 (12.9%) 8/116 (6.8%) 1/101 (1.0%) 0/15(0%)

T1bN0 44/121 (36.3%) 12/121 (9.9%) 4/77 (5.2%) 3/44(6.8%)


*Note:48% ER negative

NCCN Breast Cancer Guidelines (v.1.2011)

T1/N0, HER2-positive

Tumor Size Recommendation

> 1cm Chemotherapy + trastuzumab*

0.6-1.0 cm Consider chemotherapy +

trastuzumab*

≤ 0.5cm No adjuvant therapy*

* endocrine therapy if HR +

Recently Reported Adjuvant Trials

TCH ± B

Node-Positive or High Risk Node-

Negative Breast Cancer HER2 Positive by

Central Testing

STRATIFICATION

• Number of positive Nodes (0, 1-3 4+)

• Hormone Receptor Status

BETH TRIAL

FEC → TH ± B

NSABP/CIRG CONTACT

Does improved neo-adjuvant response predict

improved disease-free and overall survival?

Collaborative Trials in

Neoadjuvant Breast Cancer (CTNeoBC): Association of pCR with EFS in Her2+ Subtype

pCR=ypT0/is ypN0

HR=0.39, P* < 0.001 HR=0.58, P* = 0.001 HR=0.25, P* < 0.001

Cortazar P, et al. Lancet 384:164–72,2014

Lapatinib

• Works intracellularly

• Binds reversibly to the

cytoplasmic ATP-binding site of

the kinase, thereby preventing

receptor phosphorylation and

activation

Lapatinib is an oral small-molecule

dual inhibitor of ERBB1 and ERBB2

tyrosine kinase:

Downstream signaling

cascade

1 + 1 2 + 2 1 + 2

Phase III NeoALTTO Trial

Baselga J et al. Lancet 379: 633–40,2012

Eligibility criteria:

• Operable HER2+

breast cancer

• T > 2 cm

• LVEF ≥ 50%

Stratify by:

• Tumor size (≤ 5 cm vs.

> 5 cm)

• HR status (positive vs.

negative)

• N status (0/1 vs. ≥ 2)

R

A

N

D

O

M

I

Z

E

S

U

R

G

E

R

Y

Lapatiniba 1000 mg/day

Trastuzumab 2 mg/kg/week (4-mg/kg

loading dose) × 18 cycles

Paclitaxel 80 mg/m2/week × 12 cycles

starting at week 7

Lapatinib 1500 mg/day


starting at week 7

Trastuzumab 2 mg/kg/week (4-mg/kg

loading dose) × 18 cycles


starting at week 7 a 750 mg/day with paclitaxel

(n = 455)

NeoALTTO: Efficacy

All differences between lapatinib/trastuzumab and trastuzumab alone are significant (P < .05).

Baselga J et al. Lancet 379: 633–40,2012 .

Lapatinib/

Trastuzumab

(n = 152)

Lapatinib

(n = 154)

Trastuzumab

(n = 149)

Pathologic CR, Breast 51% 25% 29.5%

By hormone receptor status

Positive 42% 16% 23%

Negative 61% 34% 36.5%

(n = 145) (n = 150) (n = 145)

Total Pathologic CR,

Breast +Nodes 47% 20% 28%

Objective Response (n = 152) (n = 154) (n = 149)

At week 6 67% 53% 30%

At surgery 80% 74% 70.5%

WILL DUAL ANTI-HER2 BLOCKADE IMPROVE DISEASE-FREE AND OVERALL SURVIVAL IN THE ADJUVANT SETTING?

ALTTO Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization

All patients: radiotherapy, if indicated (concomitant with targeted therapy). Hormone receptor-positive patients: endocrine therapy for at least 5 years. *The L alone arm was closed on 18 Aug 2011 following IDMC recommendation

Lapatinib*

34 weeks 6 wks 12 weeks

3-weekly Trastuzumab

All (neo)adjuvant

chemo prior to

anti-HER2 therapy

Lapatinib + 3-weekly Trastuzumab

Lapatinib Weekly

Trastuzumab

wash out

DESIGN 1: SEQUENTIAL ANTI-HER2 THERAPY AFTER ALL CHEMOTHERAPY (N= 4,613)

52 weeks


Tras alone: 8 mg/kg 6 mg/Kg iv, q21 days Lap alone: 1500 mg po qd Tras Lap: T 4 mg/kg 2 mg/Kg iv q7 days; L 1500 mg po qd Tras + Lap: T 8 mg/kg 6 mg/Kg iv, q21 days; L 1000 mg po qd

Weekly

Trastuzumab

Lapatinib*



Anthracycline-

based chemo first

52 weeks


Lapatinib wash out

DESIGN 2: CONCURRENT ANTI-HER2 THERAPY AFTER ANTHRACYCLINE-BASED CHEMOTHERAPY (N= 3,337)

w-P or 3-w D

w-P or 3-w D

w-P or 3-w D

w-P or 3-w D

w-P: weekly paclitaxel (80 mg/m2); 3-w D: q3 weeks docetaxel (75-100 mg/m2) All patients: radiotherapy, if indicated (concomitant with targeted therapy). Hormone receptor-positive patients: endocrine therapy for at least 5 years. *The L alone arm was closed on 18 Aug 2011 following IDMC recommendation


Tras alone: 4 mg/kg 2 mg/Kg iv, q7 days 6 mg/Kg iv, q21 days Lap alone: 750 mg po qd 1500 mg qd Tras Lap: T 4 mg/kg 2 mg/Kg iv q7 days; L 1500 mg po qd Tras + Lap: T 4 mg/kg 2 mg/Kg iv, q7 days 6 mg/Kg iv, q21 days; L 750 mg po qd 1000 mg qd

Weekly

Trastuzumab

Lapatinib*



Non-

anthracycline-

based chemo with

anti-HER2 therapy

52 weeks


Lapatinib wash out

DESIGN 2B: CONCURRENT ANTI-HER2 THERAPY WITH A NON-ANTHRACYCLINE CHEMOTHERAPY (N= 431)

3-w D + carbo

3-w D + carbo

3-w D + carbo

3-w D + carbo

3-w D: q3 weeks docetaxel (75 mg/m2); carbo: carboplatin (AUC 6) All patients: radiotherapy, if indicated (concomitant with targeted therapy). Hormone receptor-positive patients: endocrine therapy for at least 5 years. *The L alone arm was closed on 18 Aug 2011 following IDMC recommendation


Tras alone: 4 mg/kg 2 mg/Kg iv, q7 days 6 mg/Kg iv, q21 days Lap alone: 750 mg po qd 1500 mg qd Tras Lap: T 4 mg/kg 2 mg/Kg iv q7 days; L 1500 mg po qd Tras + Lap: T 4 mg/kg 2 mg/Kg iv, q7 days 6 mg/Kg iv, q21 days; L 750 mg po qd 1000 mg qd

DISTRIBUTION OF THE STRATIFICATION FACTORS BY TREATMENT ARM

L + T

(N = 2,093)

T → L

(N = 2,091)

T

(N = 2,097)

Hormone Receptor Status

Positive 1,203 (57%) 1,205 (58%) 1,200 (57%)

Negative 890 (43%) 886 (42%) 897 (43%)

Timing of chemotherapy

Sequential (Design 1) 1,155 (55%) 1,143 (55%) 1,147 (55%)

Concurrent (Design 2 and 2B) 938 (45%) 948 (45%) 950 (45%)

Lymph Node Status

Not applicable (neoadjuvant chemotherapy) 168 (8%) 170 (8%) 181 (9%)

Node negative 845 (40%) 842 (40%) 844 (40%)

1-3 positive nodes 617 (29%) 617 (30%) 603 (29%)

>=4 positive nodes 463 (22%) 462 (22%) 469 (22%)

DISTRIBUTION OF PATIENT CHARACTERISTICS BY TREATMENT ARM

76

L + T

(N = 2,093)

T → L

(N = 2,091)

T

(N = 2,097)

Menopausal Status

Premenopausal 908 (43%) 929 (44%) 908 (43%)

Postmenopausal or male 1,185 (57%) 1,162 (56%) 1,189 (57%)

Pathological primary tumor size - largest diameter of invasive component

Missing 27 41 38

≤ 2cm 937 (45%) 938 (46%) 942 (46%)

> 2cm to ≤ 5cm 1,002 (49%) 980 (48%) 990 (48%)

> 5cm 127 (6%) 132 (6%) 127 (6%)

Histologic grade

Missing 10 7 9

Gx: Differentiation cannot be assessed 79 (4%) 61 (3%) 59 (3%)

G1: Well differentiated 51 (2%) 59 (3%) 48 (2%)

G2: Moderately differentiated 774 (37%) 793 (38%) 744 (36%)

G3: Poorly differentiated/undifferentiated 1,179 (57%) 1,171 (56%) 1,237 (59%)

DISEASE-FREE SURVIVAL (DFS) ANALYSIS

MFU = 4.5 yrs

*

* 97.5% CI

**

**p-value ≤ 0.025 required for statistical significance Piccart-Gebhart M. ASCO 2014, LBA 4

Fig. 2 Epitope binding of HER2 and EGFR therapeutic antibodies.(B) Pertuzumab.


Published by AAAS

Randomized Phase II Study of Neoadjuvant

Pertuzumab Plus Trastuzumab: NeoSphere

Gianni et al. SABCS 2010; abstract S3-2.

Eligibility criteria:

• Operable or

locally advanced/

inflammatory

HER2+ breast

cancer

• Chemonaive

• Primary tumors >

2 cm

Primary endpoint: pCR rates

Secondary endpoints including: clinical response

R

A

N

D

O

M

I

Z

E

S

U

R

G

E

R

Y

Docetaxel (T)

Trastuzumab (H)

FEC q 3 weeks × 3

H q 3 weeks, cycles

5-17

Docetaxel (T)

Trastuzumab (H)

Pertuzumab (P)

FEC q 3 weeks × 3

H q 3 weeks, cycles

5-17

Trastuzumab (H)

Pertuzumab (P)

T q 3 weeks × 4 →

FEC q 3 weeks × 3

H q 3 weeks, cycles

5-17 Docetaxel (T)

Pertuzumab (P) FEC q 3 weeks × 3

H q 3 weeks, cycles

5-21

All q 3 weeks × 4 FEC: 5-fluorouracil/epirubicin/

cyclophosphamide

(n = 107)

(n = 96)

(n = 107)

(n = 107)

NeoSphere: Efficacy of Neoadjuvant

Pertuzumab Plus Trastuzumab

Gianni et al. SABCS 2010; abstract S3-2.

Pathologic Complete

Response

TH

(n = 107)

THP

(n = 107)

HP

(n = 107)

TP

(n = 96)

pCR in Breast 29% 46% 17% 24%

By Hormone Receptor

Status

ER+/PgR+ 20% 26% 6% 17%

ER–/PgR– 37% 63% 29% 30%

By Nodal Status

Node negative 21.5% 39% 11% 18%

Node positive 7.5% 6.5% 6% 6%

CR + PR + SDa 107 (100%) 106 (99%) 99 (92.5%) 94 (98%)

a Investigator assessed

T = docetaxel H = trastuzumab P = pertuzumab

TRYPHAENA

HER2-positive

EBC

centrally confirmed

(n = 225)

FEC

Trastuzumab

to complete

1 year

S

u

r

g

e

r

y

• All 3 arms were experimental

• Study dosing q3w: − FEC: 500 mg/m2, 100 mg/m2, 600 mg/m2

− Carboplatin: AUC 6

− Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance

− Pertuzumab: 840 mg loading dose, 420 mg maintenance

− Docetaxel: 75 mg/m2 (escalating to 100 mg/m2 if tolerated, in Arms A and B only)

Docetaxel

Cycles 1‒3 4‒6

Pertuzumab + trastuzumab

Pertuzumab + trastuzumab

FEC Docetaxel

Carboplatin

Docetaxel

Pertuzumab + trastuzumab C

B

A

Schneeweiss, et al. Annals Onc 24:2278-2284,2013

TRYPHAENA: Pathologic complete response

FEC, 5-fluorouracil, epirubicin, cyclophosphamide; H, trastuzumab; P, pertuzumab;

T, docetaxel; TCH, docetaxel/carboplatin/trastuzumab

Path

olo

gic

co

mp

lete

resp

on

se (

%)

FEC+H+P x3

T+H+P x3

(n = 73)

FEC x3

T+H+P x3

(n = 75)

TCH+P x6

(n = 77)

50.7

45.3

51.9

ypT0/is ypT0 ypN0

61.6

66.2

57.3


Pathologic complete response by hormone

receptor status

ER, estrogen receptor; FEC, 5-fluorouracil, epirubicin, cyclophosphamide;

H, trastuzumab; P, pertuzumab; PR, progesterone receptor; T, docetaxel;

TCH, docetaxel/carboplatin/trastuzumab

Path

olo

gic

co

mp

lete

resp

on

se (

%)

ER- and PR-negative ER- and/or PR-positive

79.4

65.0

46.2 48.6

83.8

50.0

ypT0/is

FEC+H+P x3

T+H+P x3

(n = 73)

FEC x3

T+H+P x3

(n = 75)

TCH+P x6

(n = 77)


Fig. 2 Epitope binding of HER2 and EGFR therapeutic antibodies.(D) T-DM1.


Published by AAAS

NSABP B-50-I/GBG 77/Roche BO27938 Katherine: Study Schema

Residual Invasive HER2 Positive Breast Cancer in Breast and/or Axillary Nodes after Neoadjuvant

Taxane/Trastuzumab ± Anthracycline

Randomization

T-DM1 3.6 mg/kg q3wk x 14 doses

Accrual goal - 1484 patients

Trastuzumab 6 mg/kg q3wk x 14 doses

Radiation per standard guidance; hormone therapy if ER or PgR pos

A Final Question: Does the standard definition of

HER2 positivity mean the same thing as a

predictor of response to trastuzumab +

chemotherapy in the adjuvant setting as it does

for metastatic breast cancer?

B-31: distribution of cases according

to central HER2 assay

IHC=0 IHC=1 IHC=2 IHC=3 unk

FISH- 25 87 62 31 2

FISH+ 9 32 84 1457 6

“Central assay negative”

Paik, ASCO 2007, abstr 511

N #Event HR p-value 92 25 0.64 0.16

81 19

0 1 2 3 4 5 6 7

020

4060

8010

0

NSABP B-31:FISH Negative, IHC 0,1+,2+

Time from Randomization

% D

isea

se-F

ree

ACT

ACTH

NSABP B-31 Updated 2009 Disease Free Survival

FISH Negative, IHC 0, 1+, 2+ Breast Cancer Pts.

HR=0.64, p=0.16

0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000

Case

6

7

8

9

10

11

12

13

14

15

HE

R2

by

RT

-PC

R (

rela

tive

to r

ef g

en

es;

log

2)

Cut-off

Based on

IHC/FISH

0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000

Case

6

7

8

9

10

11

12

13

14

15

HE

R2

by

RT

-PC

R (

rela

tive

to r

ef g

en

es;

log

2)

Cut-off

Based on

IHC/FISH

HER2 expression is a continuous variable

Hard to imagine that these two tumors

respond differently to trastuzumab

Slide courtesy of S Paik

Summary of take-home messages

• Virtually all invasive breast cancers should be tested for HER2.

HER2 testing must be done in laboratories with rigorous quality

controls.

• Addition of one year of trastuzumab to adjuvant chemotherapy

decreased the rate of breast cancer events by 25-40% in the large

adjuvant trials. Focally positive cancers also derive similar benefit.

• The inclusion of pertuzumab along with trastuzumab and

chemotherapy in pre-operative treatment of early stage disease is

now a FDA approved standard of care. NCCN 2014 guidelines also

provide for option to include pertuzumab concurrent with

chemotherapy and trastuzumab in the adjuvant AC-TH and TCH

regimens.

Summary of take-home messages

• Cardiac monitoring must be done in all patients treated with adjuvant

trastuzumab with appropriate holds when indicated. Most patients

recover normal ejection fractions if holding rules are followed.

• In B-31 the combination of age and baseline LVEF correlates with

risk of CHF when trastuzumab/paclitaxel is used following AC.

• Radiation and hormone therapy may be given after chemotherapy

concurrently with trastuzumab.

• Neo-adjuvant trials are appropriate for studying new targeted agents

for specific patient subsets but appropriate patient selection for

incorporating new agents in adjuvant trials is critical.

• The criteria of HER2 positivity for discerning adjuvant trastuzumab

benefit is being studied further in a prospective randomized trial

(NSABP B=47).

Thank you!

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