(NEO-)ADJUVANT THERAPY FOR HER-2+ EBC · 1694 1 1 72 885 532 268 127 220 1 year trastuzumab Observation 0 No. at risk Events HR 95% CI p value 0.54 0.43, 0.67

(NEO-)ADJUVANT THERAPY FOR HER-2+ EBC

F. Cardoso, MDDirector, Breast Unit, Champalimaud Clinical Center, Lisbon, Portugal

ESO Breast Cancer Program CoordinatorESMO Board of Directors & NR Committee Chair

EORTC Breast Group Past-Chair

www.abc-lisbon.org

DISCLOSURES

Consultant/Ad Board:

Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo,

Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics,

Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer,

Pierre-Fabre, Roche, Sanofi, Seattle Genetics, Teva

MANAGEMENT OF HER-2 + BC: Lessons learned & Questions unanswered

• HER-2 + BC is a well identified subtype

• Quality of HER-2 testing essential

• Crucial role of patient selection

• Several efficacious anti-HER-2 agents available (challenge: the best sequence and/or combinations)

• Lack of predictive markers beyond HER-2 (particularly to select among different anti-HER-2 agents)

• Even with target/targeted drug resistance occurs

SABCS 2005

100

80

60

40

20

0

Patients

(%)

Months from randomisation

6 12 18 24

1740 1567 1353 1083 779

1646 1466 1256 1005 703

138

170

1 year trastuzumab

Observation

0

No.

at risk

Events HR 95% CI p value

0.88 0.71, 1.11 0.29

2-year

DFS

93.4

92.5

Disease-free survival

HER-2 Pos & Her-2 Neg Patients

Median follow-up: 1.8 yearsHR, hazard ratio; CI, confidence interval

Simulation by Aparna Keshaviah, Sc.M.

SABCS 2005

100

80

60

40

20

0

Patients

(%)

Months from randomisation

6 12 18 24

1693 1108 767 445 224

1694 1172 885 532 268

127127

220220

1 year trastuzumab

Observation

0

No.

at risk

Events HR 95% CI p value

0.54 0.43, 0.67

MANAGEMENT OF HER-2 + EBC: Lessons learned from the trastuzumab era &

Questions unanswered

• Consistent & significant benefit of adjuvant trastuzumab

• Optimal duration

•Neoadjuvant or adjuvant setting

•Concomitant vs. sequential with CT

• Optimal CT regimen (anthracyclines: to give or not give!)

• The principle of dual blockade (neo and adjuvant)

• Without CT or less CT in certain cases?

• Extended anti-HER2 therapy

Adjuvant chemotherapy + trastuzumab: 6 large adjuvant

BC trials, all N+ or high risk N (>13,000 patients)

AC/FEC Paclitaxel

Docetaxel (D)

Carbo+DTrastuzumab (T)

D or Vinorelbine Standard chemotherapy (CTX)FEC or ED

NSABP-B31

(n=1960)

AC for 4 cycles, followed by

paclitaxel for 4 cycles

+ Weekly T for 1 y

Reference

Romond

2005

NCCTG N9831

(n=3046)

AC q 3w for 4 cycles, followed by

12 weekly doses of paclitaxel

+Weekly T for 1 y

+Weekly T for 1 y

Romond

2005

HERA

(global ex-US)

(n=5090)

Standard CTX + observation only

Standard CTX + T 3-wkly for 1 y

Standard CTX + T 3-wkly for 2 y

Piccart-

Gebhart

2005

BCIRG 006

(global)

(n=3222)

AC for 4 cycles, followed by

docetaxel for 4 cycles

+ T 3-wkly for 1 y

Carbo + docetaxel for 6 cycles,

+ T 3-wkly for 1 y

Slamon

2006

FinHer

(n=232)

Docetaxel or vinorelbine for 3

cycles, followed by FEC for 3

cycles

+ Weekly T for 9 weeks

Joensuu

2006

PACS 04

(n=528)

FEC or ED for 6 cycles

+ Weekly T for 1 year

Spielmann

2007

See Glossary on last slide for explanations of all abbreviations here, unless previously defined.

210

Combined US (n=3968)b

HERA (n=3401)

BCIRG AC-DT (n=1074)

BCIRG DCarboT (n=1075)

FinHER (n=232)

PACS-04 (n=528)

aAbsolute difference in percentage of patients with DFS at 4 or 3 yearsbCombined US: Joint analysis of NSABP B-31 and NCCTG N9831

A, doxorubicin; C, cyclophosphamide; Carbo, carboplatin; D, docetaxel; T, trastuzumab;

DFS, disease-free survival; FU, follow-up; HR, hazard ratio

Absolute

benefit at

4y/3ya

Median

FU yrsHR

30.49 12.8%

20.64 6.3%*

30.61 6%

30.67 5%

0.42 11% 3

40.86 –0.5%

p

HR

210

0.63

0.66

0.59

0.66

0.41

1.27

3.2%

2.7%*

6%

5%

6.6%*

Difference at

4y/3ya

–1.5%

3

Median

FU yrs

3

3

2

3

p

0.004

0.017

0.0115

0.07

n.s.

* Benefit at

3 y

4

Favours trastuzumab Favours chemotherapy only

Combined US (n=3969)b

HERA (n=3401)

BCIRG AC-DT (n=1074)

BCIRG DCarboT (n=1075)

FinHER (n=232)

PACS-04 (n=528)

Reference

Smith 2007

Slamon 2006

Joensuu 2006

Spielmann 2007

0.0004

aAbsolute difference in percentage of patients with OS at 4 or 3 yearsbCombined US: Joint analysis of NSABP B-31 and NCCTG N9831

Perez 2007

*Benefit at 3y

Adjuvant chemotherapy ± trastuzumab trials: overall survival

Slamon 2006

REDUCTION IN MORTALITY RISK: 34%-59% IN EBC

COST TRASTUZUMAB: 2.300 €/cycle (s.c T)

MCBS: A

Copyrights for this presentation are held by the author/presenter. Contact for permission to reprint and/or distribute.

8th European Breast Cancer Conference

21̶-24 March 2012, Vienna, Austria

Abstract 1BA

11

HannaH Phase III Study

Objective:

Show non-inferiority of SC vs. IV based on co-primary endpoints• PK: observed trastuzumab Ctrough pre-dose Cycle 8 (pre-surgery)

• Efficacy: pathological complete response (pCR) in the breast

HER2-

positive

EBC

(N=596)*

SC trastuzumab

IV trastuzumab

Su

rgery

Fo

llo

w-u

p:

24

mo

pCR

18 c

ycle

s/

1 y

ear

Trastuzumab SC 600 mg/5 mL q3w

(fixed dose)

Trastuzumab IV

6 mg/kg q3w

(8 mg/kg loading dose)

Docetaxel75 mg/m2

FEC500/75/500

Neoadjuvant Adjuvant

R

1:1

Clinical stage Ic to IIIc

including IBC

IBC, inflammatory breast cancer. FEC, 5-fluorouracil, epirubicin and cyclophosphamide

* Central HER2 testing was carried out by TARGOS Molecular Pathology GmbH

C Jackisch et al, EBCC 2012

Copyrights for this presentation are held by the author/presenter. Contact for permission to reprint and/or distribute.

8th European Breast Cancer Conference

21̶-24 March 2012, Vienna, Austria

Abstract 1BA

18

Summary and Conclusions

• HannaH provides the first demonstration that comparable

trastuzumab drug exposure and efficacy can be achieved for

trastuzumab SC and IV

• Efficacy is robust and consistent across subgroups and analysis

populations

• pCR rate is independent of body weight or trastuzumab trough level

• Trastuzumab trough levels are higher in SC, but exposure (AUC) is

comparable between IV and SC

• Overall, the safety profiles of the trastuzumab SC and IV

formulations are comparable and consistent with the known

safety profile of trastuzumab

• SC trastuzumab 600 mg fixed dose administered q3w in

approximately 5 minutes provides a valid treatment alternative to

the q3w IV regimen

C Jackisch et al, EBCC 2012





Neoadjuvant or adjuvant setting•

Concomitant vs. sequential with CT•





TRIALS EVALUATING ADJUVANT TRASTUZUMAB DURATION

1 vs. 2 years: HERA

9 weeks: FinHER (Finland)

1 year vs. 3 ms: E 2198 (US)

1 year vs. 9 weeks: ShortHER

1 year vs. 9 weeks: SOLD

1 year vs. 6 ms: PHARE (France)

1 year vs. 6 ms: HeCOG (Greece)

1 year vs. 6 ms: Persephone (UK)

OBSERVATIONn=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 Trastuzumab8 mg/kg – 6 mg/kg3 weekly schedule

n=1703

2 years Trastuzumab8 mg/kg – 6 mg/kg3 weekly schedule

n=1701

After ASCO 2005, option of switchto Trastuzumab

HERA TRIAL DESIGNACCRUAL 2001 – 2005 (N=5102)

CT, chemotherapy; RT, radiotherapy Goldhirsch & Gelber et al, ESMO 2012, LBA 6

Dis

ease-f

ree s

urv

ival

(%)

Years from randomization

89.1%

86.7%81.0%

81.6%

75.8%

76.0%

DFS FOR 2 YEARS VS. 1 YEAR TRASTUZUMAB AT 8 YRS MEDIAN FU & 734 DFS EVENTS

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

Goldhirsch & Gelber et al, ESMO 2012, LBA 6

Ov

era

ll S

urv

ival

(%)

Years from randomizationNo. at risk

Trastuzumab 2 years 1553 1553 1525 1485 1438 1382 1317 1193 708 208

Trastuzumab 1 year 1552 1552 1513 1461 1413 1364 1329 1218 732 225

100

80

60

40

20

0

0 1 2 3 4 5 6 7 8 9

97.4%

96.5%91.4%

92.6%86.4%

87.6%

Trastuzumab 1 year

Trastuzumab 2 years

Pts Events HR (2 vs 1) 95% CI p-value

2 years 1553 196 1.05 (0.86-1.28) 0.63

1 year 1552 186

OS FOR 2 YEARS VS. 1 YEAR TRASTUZUMAB AT 8 YRS MEDIAN FU & 734 DFS EVENTS

Goldhirsch & Gelber et al, ESMO 2012, LBA 6

•No added benefit for 2 years•Independent of ER status•Higher cardiac toxicity for 2 years

www.esmo2012.org

PHARE Study design

trastuzumab 6 months

trastuzumab up to 12 months1690 patients

stop trastuzumab (i.e. 6 months)1690 patients

Clinical examLVEF

3

Mammography

6 9 12 15 18 21 24 30 mos

…

0

R

R: Randomization after informed consent

Up to 60 mos…

Stratification1. ER pos / neg2. Chemo: conco/ seq

3384 ptsrandomised

Pivot et al, ESMO 2012, LBA 5

Protocol of Herceptin®

Adjuvant withReduced Exposure

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

* Cox model stratified by ER status and concomitant chemotherapy

95.5 91.2 87.8 84.9

97.0 93.8 90.7 87.8

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


www.esmo2012.org

0.00

0.25

0.50

0.75

1.00

Pro

bab

ility

1690 1645 1438 1016 566 25H 6m1690 1662 1463 1042 583 19H-12m

At risk

0 12 24 36 48 60Months

H-12m H-6m

Overall Survival

* Cox model stratified by ER status and concomitant chemotherapy

42.5mos. median FU

99.3 97.2 95.2 93.1

99.9 98.7 96.9 95.0

Events HR 95%CI p-valueH 12m 66H 6m 93 1.47 (1.07 – 2.02)


www.esmo2012.org

Equivalent

Superior

Non Inferior

Inferior

A

B

C

D

E

.85 1 1.15 1.3 1.45 1.6HR

Primary endpoint scenarii

PHARE trial


Presented by: Carey K. Anders, MD

Short-HER: Study Design

Stratification factors: HR status, Nodal statusRadiotherapy and hormonal therapy started at the completion of ChemoRx, when indicated

EUDRACT number: 2007-004326-25

NCI ClinicalTrials.gov number: NCT00629278

Non-inferiority study:

HR = 1.29,

Alpha: 0.05 (one tail)

Power: 80%

n = 1250 pts

SHORTHer Primary Objective of DFS


5.2 yrs Follow-up

N = 1253

0.0

00

.25

0.5

00

.75

1.0

0

626 601 576 554 476 351 233 120 46B short627 608 592 566 482 374 239 132 43A long

Number at risk

0 12 24 36 48 60 72 84 96Months from randomization

A long B short

HR = 1.15 (0.91 – 1.46); 0.78 probability

5yr DFS (87.5% LONG vs. 85.4% SHORT)

Subset Analyses:

HR>1.0 favors LONG

Ratio of HRs

(90%CI)

p-value

Stage

III vs I+II

2.30

(1.35, 3.94) < 0.001

Nodal status

N2+N3 vs N0+N1

2.25

(1.33, 3.83) < 0.001

No difference in 5 yr OS (95.1 vs 95%)


ShortHER: Cardiac Adverse Events

Long

N=627

Short

N=626

Grade N(%) N(%)

2 69 (11.0) 22 (3.5)

3 12 (1.9) 5 (0.8)

4 1 (0.2) 0

Total 82 (13.1) 27 (4.3)P

TAKE HOME MESSAGES

Duration of adjuvant trastuzumab: DON’T CHANGE YOUR PRACTICE

In total about 15.000 pts enrolled to answer duration question!Really needed?

Can we be smarter in trial design?Can sponsors be more flexible?

Duration of adjuvant trastuzumab: STORY NOT FINISHEDRole of concurrent administrationAny subgroup of pts needing shorter or longer duration?Wait for other trial results & longer FU of PHARE and ShortHER

Meta-analysis: Neoadjuvant

anthracyclines/taxanes with or without

trastuzumab

Von Minckwitz et al, SABCS 2008, Abstract 79

All cooperative neoadjuvant trials in Germany between 1998 and 2006

using anthra/taxanes (N=4913) plus GeparQuattro and TECHNO trials

(N=1721) using trastuzumab for HER2+ tumors

Goals:

• Overall pCR rate

• Effects according to treatment:

- Trastuzumab

- Dose-Density

- Duration

- Concurrent versus sequential

Total 6634 pts

Von Minckwitz, SABCS 2008, Abstract 79

Meta-analysis: pCR rate based on treatment

Trastuzumab

(N=671)

No Trastuzumab

(N=736)

P-value

pCR rate 41% 23%

a CT: AP x 3 followed by P x 4, followed by CMF x 3

HER2-positive LABC

(IHC 3+ or FISH+)

HER2-negative LABC

(IHC 0/1+)

ChemotherapyaChemotherapyaTrastuzumab +

chemotherapya

Surgery followed by radiotherapyb

Trastuzumab

continued to week 52

n = 115 n = 113 n = 99

19 patients crossed

over to trastuzumab

NOAH: Phase III, Open-Label Trial of Neoadjuvant Trastuzumab

Gianni L, et al. Lancet. 2010;375(9712):377-384.

bHR+ pts received adjuvant tamoxifen

NOAH: Event-Free Survival (EFS) and OS in HER2-Positive Population (ITT)

EFS OS

Gianni L, et al. Lancet. 2010;375(9712):377-384.

Neoadjuvant therapy for HER-2+ breast cancer

Anti• -HER-2 agent in neoadjuvant or adjuvant setting?

NO DIRECT COMPARISON ADJUVANT VS. NEOADJUVANT

INDIRECT EVIDENCE (Higher pCR rates!!)

Perez, SABCS 2009

Perez, SABCS 2009

There is a strong trend for a 25% reduction in the risk

of an event with starting trastuzumab concurrently with

taxane relative to sequentially:

5 yr DFS: 80% vs. 84% (final results would need too long FU)

BCIRG 006 Trial Design

HER2+(Central FISH)

N+

or high

risk N−

N=3222

Stratified by nodes and hormonal receptor status

AC→T

AC → TH

TCH

4 x AC60/600 mg/m2

4 x Docetaxel100 mg/m2

4 x AC60/600 mg/m2

4 x Docetaxel100 mg/m2

1 year Trastuzumab

6 x Docetaxel and Carboplatin75 mg/m2 AUC 6

1 year TrastuzumabSlamon D, et al. Cancer Res. 2009;69(24 Suppl): Abstract 62.

DFS in all patients

Slamon D et al. N Engl J Med 2011;365:1273-1283

DFS in patients without TOP2A co-amplification

DFS in patients with TOP2A co-amplification

Therapeutic Index for Critical Clinical Events

Slamon D et al. N Engl J Med 2011;365:1273-1283

CLINICAL IMPLICATIONS OF BCIRG 006

• We don’t know how safe it is to withhold anthracyclines and in which pts (trial not powered to show equivalence; trial hypothesis (TCH better) not proven!)

• TCH associated with less cardiotoxicity and less leukemia (associated with A or C??!!)

• ONLY POSSIBLE CLINICAL RECOMMENDATION:

TCH is a very good option and should be chosen when cardiac risk factors or c.i. for anthracyclines are present

NeoALTTO: Trastuzumab + Lapatinib

NSABP B-41: Trastuzumab + Lapatinib

CherLob: Trastuzumab + Lapatinib

NeoSphere: Trastuzumab + Pertuzumab

TRYPHAENA : Trastuzumab + Pertuzumab

TRIALS EVALUATING DUAL BLOCKADE

IN THE NEOADJUVANT SETTING

TRIALS EVALUATING DUAL HER2 BLOCKADE

Advanced DiseaseEGF104900Cleopatra PERUSE

PHEREXA

NeoSPHERE TRYPHAENAWSG-ADAPT

KRISTINE

NeoALTTOCherlob

LPT 109096 NSABP B-41

CALGB 40601

Neoadjuvant setting

ALTTO APHINITY Adjuvant setting

STRATEGY A STRATEGY B

Alvaro Moreno-Aspitia et al, ASCO 2017

Trastuzumab

Lapatinib

NeoALTTO Study Design

Baselga J, et al. Cancer Res. 2010;70(24 Suppl): Abstract S3-3.

• Invasive

operable

HER2+ BC

• T >2 cm

(inflammatory

BC excluded)

• LVEF ≥50%

N = 450

R

A

N

D

O

M

I

Z

E

S

U

R

G

E

R

Y

Lapatinib

Trastuzumab

Lapatinib

Paclitaxel

Paclitaxel

Trastuzumab

Paclitaxel

6 wks +12 wks

F

E

C

X

3

Lapatinib

Trastuzumab

52 weeks of anti-HER2 therapy

34 wks

Stratification

•T≤5 cm vs T>5 cm

•ER or PgR+ vs

ER & PgR-

•N0-1 vs N≥2

•Conservative

surgery or not

IBC exclusion criteria

NeoALTTO: Overall Clinical Responseat 6 weeks (w/o chemo) and at surgery

L = lapatinib; T = trastuzumab

At Week 6 (w/o chemo) At surgery

L

N = 154

T

N = 149

L+T

N = 152

L

N = 154

T

N = 149

L+T

N = 152

P

Landmark Analysis: OS by PCR

Tests for interaction: pCR x HR p=0.33

Results of first analysis of EFS/OS are shown in square bracketsto provide comparison with this updateDe Azambuja et al. Lancet Oncol 2014

Ove

rall

surv

ival

Ove

rall

surv

ival

NeoALTTO trial

MEDIAN FU: 6.7 yearsJens Huober et al, ESMO 2017

Overall Survival Analysis by treatment arm

Tests for interaction: L + T vs T x HR p= 0.45L vs T x HR p=0.72

Results of first analysis of EFS/OS are shown in square bracketsto provide comparison with this updateDe Azambuja et al. Lancet Oncol 2014

Ove

rall

surv

ival

NeoALTTO trial

MEDIAN FU: 6.7 yearsJens Huober et al, ESMO 2017

NSABP B-41 Schema

Operable

Breast

Cancer

HER-2 neu

Positive

R

AC → WP+T

AC → WP+L

AC →

WP+T+L

S

U

R

G

E

R

Y

Tissue for Biomarkers

Trastuzumab

for a total of

1 year

WP=Weekly Paclitaxel

Tissue for Biomarkers

Accrued 529 patients from July 16, 2007 to June 30, 2011

NSABP B-41Summary Treatment Regimens

• Neither the addition of lapatinib to trastuzumab (AC→WP+T+L) nor the substitution of lapatinib for trastuzumab (AC→WP+L) demonstrated statistical superiority to trastuzumab (AC→WP+T) for RFI or OS in protocol specified pair-wise comparisons

• Exploratory analyses suggest the three treatment arms are different in long-term outcomes (p=0.049 for RFI and p=0.07 for OS)

• Exploratory analyses of RFI by HR status showed similar trends in patients with HR-negative and those with HR-positive tumors

ALTTO trial

Presented by:

DISEASE-FREE SURVIVAL (DFS) ANALYSIS

*Bracketed data in all KM curves represent results of the Primary Analysis – ASCO 2014

*


Absolute difference: 2 to 3%

Presented by:

DFS BY CHEMOTHERAPY TIMING

Median Clinical Follow-upSequential: 7.0 yearsConcurrent: 6.0 years


Absolute difference: 1 %Absolute difference: 3-4 %

Presented by:

DFS BY HORMONE RECEPTOR STATUS

Median Clinical Follow-upHR positive: 6.9 yearsHR negative: 6.9 years


Absolute difference: 2-4 %Absolute difference: 2 %

Presented by:

OVERALL SURVIVAL (OS) ANALYSIS


ALTTO trial

SAFETY


Presented by:

Safety Analysis - Overall AE summary by Arm

Lap+Tras

(N=2061)

Tras->Lap

(N=2076)

Lap

(N=2057)

Tras

(N=2076)

Any AE 1979 (96%) 1956 (94%) 1964 (95%) 1834 (88%)

AEs related to study t reatment 1922 (93%) 1801 (87%) 1857 (90%) 1329 (64%)

AEs leading to permanent

discont inuat ion 481(23%) 261(13%) 317 (15%) 171 (8%)

AEs leading to dose reduct ions 413 (20%) 275 (13%) 448 (22%) 81(4%)

AEs leading to dose interrupt ions/ delays 945(46%) 668 (32%) 821 (40%) 419 (20%)

Any SAE 459 (22%) 391 (19%) 461 (22%) 326 (16%)

SAEs related to study t reatment 276 (13%) 191 (9%) 275 (13%) 116 (6%)

Fatal SAEs 19 (

ALTTO trial

Presented by:

DISEASE-FREE SURVIVAL (DFS) ANALYSIS

ALTTO investigators

*Bracketed data in all KM

curves represent results of

the Primary Analysis –

ASCO 2014

*

A. Moreno-Aspitia et al, ASCO 2017

DUAL BLOCKADE COST: 5.800 €/cycle

MCBS: No Evaluable Benefit

COST LAPATINIB: 3.500 €/cycle

NeoSphere Study Design

TH (n = 107)

docetaxel +

trastuzumab

Gianni L, et al. Cancer Res. 2010;70(24 Suppl): Abstract S3-2.

BC, breast cancer; FEC, 5-fluorouracil, epirubicin, and cyclophosphamide; H, trastuzumab; P, pertuzumab; T, docetaxel

*Locally advanced = T2-3, N2-3, M0 or T4a-c, any N, M0; operable = T2-3, N0-1, M0; inflammatory = T4d, any N, M0

THP (n = 107)

docetaxel +

trastuzumab +

pertuzumab

HP (n = 107)

trastuzumab +

pertuzumab

TP (n = 96)

docetaxel +

pertuzumab

S

U

R

G

E

R

Y

Patients with

operable or

locally advanced/

inflammatory*

HER2-positive

breast cancer

Chemo-naïve

and primary

tumors >2 cm

(N = 417)

FEC q3w x 3

Trastuzumab q3w cycles 5-17

FEC q3 x 3


Docetaxel q3w x 4FEC q3w x 3


FEC q3w x 3


Study dosing: q3w x 4

NeoSphere: pCR Rates (ITT Population)

CI, confidence interval; H, trastuzumab; P, pertuzumab; pCR, pathologic complete response; T, docetaxel

Gianni L, et al. Cancer Res. 2010;70(24 Suppl): Abstract S3-2.

P = .0198

P = .0141 P = .003

pC

R,

% ±

95%

CI

74The slides are the property of BIG. Permission required for reuse

APHINITY: Trial Design

Chemotherapy* + trastuzumab+ placebo

Chemotherapy* + trastuzumab+ pertuzumab

Randomisation and treatmentwithin 8 weeks of surgery

Anti-HER2 therapy for a total of 1 year (52 weeks)(concurrent with start of taxane)

Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy

Central confirmation

of HER2 status(N = 4805)

FOLLOW-UP

10

YEARS

R

S

U

R

G

E

R

Y

*A number of standard anthracycline-taxane-sequences or a non-anthracycline (TCH) regimen were allowed

G. von Minckwitz et al, ASCO 2017, NEJM 2017


APHINITY: Intent-to-Treat Primary Endpoint Analysis Invasive Disease-free Survival

Number needed to treat: 112

expected: 89.2%


Absolute difference: 2 %


APHINITY: Node-positive Subgroup


G. von Minckwitz et al, ASCO 2017


APHINITY: Node-negative Subgroup


EFFICACY BY NODAL STATUS




EFFICACY BY HR STATUS


APHINITY: Hormone Receptor-negative Subgroup




APHINITY: Hormone Receptor-positive Subgroup




Absolute difference: 1.5 %

What were the cardiac and other “costs” of pertuzumab?


Δ 9 pts

Δ 3 pts

Grade 3 diarrhea seen in 9.8% (H/P) and 3.7% (H/placebo); more in TCHP arm

12 pts = 0.05%

N (%) Pertuzumab(ptz)

n=2364

Treatmentptz vs. pla (95%

CI)

Placebo(pla)

n=2405

Primary cardiac endpoint 17 (0.7) 0.4 (0.0, 0.8) 8 (0.3)

• Heart failure NYHA III/IV + LVEF drop*

• Cardiac death**

15 (0.6)2 (0.08)

6 (0.2)2 (0.08)

• Recovered according to LVEF 7 4

Secondary cardiac endpointAsymptomatic or mildly symptomaticLVEF drop*

64 (2.7) -0.1 (-1.0, 0.9) 67 (2.8)



APHINITY: Trial Design

Chemotherapy* + trastuzumab+ placebo

Chemotherapy* + trastuzumab+ pertuzumab

Randomisation and treatmentwithin 8 weeks of surgery

Anti-HER2 therapy for a total of 1 year (52 weeks)(concurrent with start of taxane)

Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy

Central confirmation

of HER2 status(N = 4805)

FOLLOW-UP

10

YEARS

R

S

U

R

G

E

R

Y

*A number of standard anthracycline-taxane-sequences or a non-anthracycline (TCH) regimen were allowed



APHINITY: Intent-to-Treat Primary Endpoint Analysis Invasive Disease-free Survival


expected: 89.2%


APHINITY trial

DUAL BLOCKADE COST: 6.400 €/cycle

Provisional MCBS: B

COST PERTUZUMAB: 4.100 €/cycle

TRIALS EVALUATING DUAL BLOCKADE

IN THE NEOADJUVANT SETTING

Main conclusions

• In general trastuzumab + CT better than the other anti-HER-2 agent + CT

• Dual blockage beneficial particularly in ER negative disease, in terms of pCR rates

• Interesting RR of 2 anti-HER-2 agents alone (with no CT)

• NOT FULLY CONFIRMED IN THE LARGE ADJUVANT TRIALS

De-Escalation

Tolaney S, NEJM 2015

pT1-pT3 pN0 HER2+

Tolaney S, NEJM 2015

Timing of Distant Recurrences in relation to Adjuvant Trastuzumab

Romond EH, N Engl J Med 2005; 353:1673-1684. NSABP B-31 and NCCTG N9831

< 2% of patients relapse on adjuvant trastuzumab

and < 5% in the year following

Courtesy G. Curigliano

ExteNET: study design

Chan et al. Lancet Oncol 2016Clinicaltrials.gov identifier: NCT00878709

• HER2+ breast cancer

– IHC 3+ or ISH amplified (locally determined)

– Prior adjuvant trastuzumab + chemotherapy

– Lymph node +/–, or residual invasive disease after neoadjuvant therapy

• Stratified by: nodal status, hormone receptor status, concurrent vssequential trastuzumab R

and

om

izat

ion

(1

:1) Neratinib x 1 year

240 mg/day

Placebo x 1 year

2-y

ear

fo

llow

-up

for

iDFS

5-y

ear

fo

llow

-up

for

iDFS

Ove

rall

surv

ival

Part A Part B Part C

N=2840

Primary endpoint: invasive disease-free survival (iDFS)

Secondary endpoints: DFS-DCIS, time to distant recurrence, distant DFS, CNS recurrences, OS, safety

Other analyses: biomarkers, health outcome assessments (FACT-B, EQ-5D)

Endocrine adjuvant therapy given to patients with HR-positive tumors according to local practice

M. Martin et al, ESMO 2017

HR (95% CI) = 0.73 (0.57–0.92)Two-sided P = 0.008

Intention-to-treat population. Cut-off date: March 1, 2017

NeratinibPlacebo

50

60

70

80

90

0 6 12 18 24 30 36 42 48 54 60

No. at risk Neratinib Placebo

1420 1420

1316 1354

1272 1298

1225 1248

1106 1142

978 1029

965 1011

949 991

938 978

920 958

885 927

Months after randomization

Inva

sive

dis

ease

-fre

e s

urv

ival

(%

)100

95.5%∆ 2.4%

97.9%

91.7%∆ 2.6%

94.3%

90.2%∆ 2.0%

92.2%

89.1%

∆ 2.1%

91.2%

87.7%∆ 2.5%

90.2%

0

Treatment

ExteNET: 5-year analysis: iDFS

M. Martin et al, ESMO 2017

Absolute difference: 3.5 %

ExtNET: iDFS by hormone receptor status

95

Neratinib

Placebo

50

60

70

80

90

0 6 12 18 24 30 36 42 48 54 60

No. at risk

Neratinib

Placebo

816

815

757

779

731

750

705

719

642

647

571

581

565

567

558

556

554

551

544

542

523

525


HR-positive subgroup

Inva

sive

dis

ease

-fre

e s

urv

ival

(%

)

100

96.1%

98.1%

91.7%

95.4%

89.8%

93.6%

88.5%

92.6%

86.8%

91.2%

0

50

60

70

Two-sided P = 0.762

HR (95% CI) = 0.95 (0.66–1.35)

80

90

0 6 12 18 24 30 36 42 48 54 60

No. at risk

Neratinib

Placebo

604

605

559

575

541

548

520

529

464

495

407

448

400

444

391

435

384

427

376

416

362

402


HR-negative subgroup100

94.7%

97.5%

91.8%

92.8%

90.4%

90.8%

89.3%

89.9%

88.8%88.9%

0

Inva

sive

dis

ease

-fre

e s

urv

ival

(%

)

Neratinib

Placebo

Two-sided P = 0.002

HR (95% CI) = 0.60 (0.43–0.83)

Intention-to-treat population. Cut-off date: March 1, 2017M. Martin et al, ESMO 2017

Absolute difference: 5.6 % Absolute difference: 0 %

ExteNET: Side Effects

Chan i wsp. Abst.508

N % Neratinib (n=14080) Placebo (n=1408)

All grades G3-4 All grades G3-4

Diarrhea 1343 (95.4) 562 (39,9) 499 (35,4) 23 (1,6)

Dose reduction: 26%

Tx termination: 17%

What does G 3 diarrhea mean ?- > 7 stools daily- incontinence;

hospitalization- indicated- limiting self care ADL

Courtesy of Dr Aleksandra Łacko

ANTIDIARRHEAL PROPHYLAXIS REDUCES THE INCIDENCE OF SEVERE DIARRHEA

22%

24%23%

31% 25%

28%27%

20%

ExteNET

n=1408Loperamide

n=137Budesonide + Loperamide

n=64

CONTROL Trial

Colesttipol (bile acid sequestrant) cohort to be presented at SABCS 2017

ODAC presentation, 2017 Courtesy of Dr H. Rugo, ESMO 2017

OTHER NEOADJUVANT TRIALS IN HER-2+ EBC

ADAPT HER2+/HR+ TRIAL

International, prospective, randomized phase II trial•

Primary endpoint: • pCR (no invasive carcinoma in breast/nodes)

Secondary endpoints: dynamic testing evaluation, EFS, OS, safety•

Pts with ER+ and/or PgR+, HER2+, cT1c - cT4a-c, cN,

cM0 BC and adequate organ function, LVEF ≥

50%, normal ECG(N = 375)

T-DM1 3.6 mg/kg Q3W(n = 119)

Trastuzumab 8 mg/kg loading dose, then 6 mg/kg Q3W + ET*

(n = 129)

T-DM1 3.6 mg/kg Q3W + ET*(n = 127)

1. Harbeck N, et al. SABCS 2015. Abstract S5-03. 2. Hofmann D, et al. Trials. 2013;14:261.

Surgery†

Wk 12

*Tamoxifen if premenopausal; aromatase inhibitor (of investigator’s choice) if postmenopausal.†Standard chemotherapy (1-yr trastuzumab) recommended after surgery or 12-wk biopsy (if clinical non-pCR).

ADAPT Trial

Harbeck N, et al. SABCS 2015. Abstract S5-03.

• 12-wk T-DM1 increased pCR rate vs trastuzumab + ET in women with HER2+/HR+ EBC

– 41% vs 15%, respectively (P < .001)

– Addition of ET to T-DM1 did not raise pCR rate

– Menopausal status had minimal bearing on results

• Tolerable safety profile with low toxicity

• Early response significantly associated with increased pCR rate

– Detectable after 3 wks

– Authors conclude further investigation of T-DM1 in pts with EBC warranted

ADAPT HER2+/HR-: Design

• ER / PR negative ( 50%; LVEF within

normal institutional limits by

echocardiography; normal

ECG

N. Harbeck, ASCO 2016

ADAPT HER2+/HR-: Conclusions

WSG ADAPT HER• 2+/HR- is a unique phase II trial in

focusing only on HER2+ HR- early breast cancer (eBC)

90.5• % pCR rate with T+P+Pac is substantial

Adding chemotherapy to dual blockade more than •

doubles pCR rate in HER2+ HR- eBC

34.4• % pCR rate with P + T is clinically meaningful (e.g.

frail patients, small tumors)

Early response at • 3-weeks seems to be positively

correlated with pCR. Yet, missing data does not allow

any definite conclusions

N. Harbeck, ASCO 2016

Primary endpoint: pCR by local assessment (ypT0/is, ypN0)

Stratification factors: • local HR status, geographic location, and clinical stage at presentation

KRISTINE Study Design

• Centrally confirmed

HER2-positive,

operable, locally

advanced or

inflammatory

breast cancer

• Tumor >2cm

N=432

Docetaxel

Carboplatin

Trastuzumab

Pertuzumab

Pertuzumab

T-DM1

6 cycles of

neoadjuvant therapy

TCH+P

T-DM1+P

aAdjuvant chemotherapy was recommended for patients in the T-DM1+P arm who had residual disease in lymph node(s) or in the breast (>1cm).

R

A

N

D

O

M

I

Z

A

T

I

O

N

S

U

R

G

E

R

Y

F

O

L

L

O

W

-

U

P

Trastuzumab

Pertuzumab

Pertuzumab

T-DM1

12 cycles of

adjuvant

HER2-therapya

1

1

0

Difference: -11.3

95% CI: -20.5, -2.0

Stratified 2-sided P−value: 0.0155b

Primary Endpoint: pCR (ypT0/is, ypN0)

Presented by: Dr Sara

Hurvitz

123/221 99/223

apCR rate and 95% CI are shown. Patients with missing or unevaluable pCR status were considered nonresponders: TCH+P, 7 (3.2%); T-DM1+P, 18 (8.1%).

Treatment discontinuation in the neoadjuvant phase for progressive disease: TCH+P, 0% of patients; T-DM1+P, 7% of patients.bCochran-Mantel-Haenszel Chi-square.

56%44%

7

6

pCR by Central ER/PR Receptor Status

Presented by:

pC

R(%

)a

ER and PR negative ER and/or PR positive

60/82 45/83 56/128 46/131

TCH+P T-DM1+P TCH+P T-DM1+P

aypT0/is, ypN0; patients with missing or unevaluable pCR status were considered nonresponders. Twenty patients had “unknown” ER/PR status by

central analysis.

Difference (95% CI):

−19.0 (−33.3, −4.6)

Difference (95% CI):

−8.6 (−20.5, 3.2)

73%

54%

44%35%

Maintenance of HRQoL and Physical Function

Maintenance of HRQoLa

Presented by:

aData are based on the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 and QLQ-

modified breast cancer module (BR23). Maintenance of health-related quality of life (HRQoL) and physical function were assessed as the time to

deterioration defined as the time from baseline to first 10-point (or greater) decrease.

Only data from the neoadjuvant treatment phase including pre-surgery visit are used. Patients of the ITT population with a baseline assessment and at

least 1 post-treatment assessment are included in this analysis.

0 1 5

Time (mo.)

2 3 4

T-DM1+P (n=200)

TCH+P (n=191)

100

80

60

40

20

0

De

terio

ratio

n-F

ree

Su

rviv

al (%

)

HR (95% CI): 0.60 (0.46–0.78)

6

Maintenance of physical functiona

T-DM1+P (n=200)

TCH+P (n=191)

HR (95% CI): 0.47 (0.36–0.62)

0 1 5

Time (mo.)

2 3 4

100

80

60

40

20

0

De

terio

ratio

n-F

ree

Su

rviv

al (%

) 6

Conclusions

Neoadjuvant • TCH+P achieved a superior pCR rate compared with T-

DM1+P (56% vs 44%)

Neoadjuvant TCH+P was associated with a • higher BCS rate (53% vs

42%)

Neoadjuvant • T-DM1+P had a more favorable safety profile

Lower incidence of grade ≥– 3 adverse events (13% vs 64%), serious

adverse events (5% vs 29%), and adverse events leading to treatment

discontinuation (3% vs 9%)

Neoadjuvant T• -DM1+P was associated with longer maintenance of

patient-reported HRQoL and physical function

1

1

5

Upcoming phase III T-DM1 data in EBC: KATHERINE – T-DM1 vs trastuzumab adjuvant in patients without pCR;

KAITLIN – T-DM1+P vs HP+taxane adjuvant.

116

Hormone therapy (ER+)



S

u

r

g

e

r

y

TCbHP×6Group A

Group B

Group C Group C1 (T-DM1+P×2)

Group C2 (FEC×4)

CNB MRI

TCbHP×4➡T-DM1+P×4

T-DM1+P×4

cT1c–cT3, cN0–cN1, M0

T ≤7 cm

HER2+ (central assessment)

primary invasive cancer

Allocation adjustment factors

ER+ / -

Menopausal status

T1-2 / T3

N0 / N1

Institution

R1:1:2

ResponderscCR

cPR & Ki67 ≤10%no invasive cancer

Docetaxel/ carboplatin/ trastuzumab

(75 mg/m2/ AUC6/ 8 mg/kg 6 mg/kg)

Pertuzumab (840 mg/kg 420 mg/kg)

T-DM1 (3.6 mg/kg)FEC (500 / 100 / 500 mg/m2)Hormone therapy in ER+ patients

Non-Responders

N=200

JBCRG-20 TRIAL (Randomized Ph 2):

Neoadjuvant therapy with trastuzumab emtansine and pertuzumab in patients with her2-positive primary breast cancer

Norikazu Masuda et al, ESMO 2017

117

pC

Rra

te (

%)

p = 0.013p = 0.047

All ER- ER+ All ER- ER+ All ER- ER+ All ER- ER+ All ER- ER+

n 51 21 30 52 23 29 101 42 59 80 36 44 21 6 15

JBCRG-20 TRIAL Primary endpoint; pCR (ypT0/isypN0) rate

All patients

ER-negative

ER-positive

Group A(TCbHP)

Group B (TCbHP T-DM1+P)

Group C2(T-DM1+P FEC)

Group C Group C1(T-DM1+P)

Norikazu Masuda et al, ESMO 2017

OTHER ADJUVANT TRIALS IN HER-2+ EBC

Katherine (POST-NEOAJUVANT)

Neoadjuvant CT+

trastuzumab

Residual

invasive

cancerR

T-DM1

Trastuzumab

Primary endpoint : IDFS

1400 patients; recruitment ongoing

KAITLIN

122

HER2+

Node+

or

Node-, ER-

and T>2cm

R

AC x 4

or

FEC x3

AC x 4

or

FEC x3

TAXANE

TRASTUZUMAB

PERTUZUMAB

T-DM1

PERTUZUMAB

IDFS

HO

89,5%

93,1%

1300/2500 women recruited…

PUT ON HOLD AFTER MARIANNE TRIAL RESULTS

MANAGEMENT OF HER-2 + EBC: Unanswered questions

• Optimal duration for all patients

• Neoadjuvant or adjuvant setting

• Optimal anti-HER-2 agent and optimal combination with CT

Dual blockade in the adjuvant setting•

• Without CT in certain cases? Small N0 tumors; elderly pts; minor cardiac problems??

• Mechanisms of resistance & predictive markers (beyond HER-2)

The role of BIOSIMILARS•

BACK-UP

The magnitude of improvement in pCR ratedid not predict EFS and OS effect

Cortazar P et al. Pathological complete response and long-term clinical

benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014

Association between pCR and EFS by BC subtype

Cortazar P et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBCpooled analysis. Lancet. 2014

Documents

(NEO-)ADJUVANT THERAPY FOR HER-2+ EBC · 1694 1 1 72 885 532 268 127 220 1 year trastuzumab Observation 0 No. at risk Events HR 95% CI p value 0.54 0.43, 0.67