Adjuvância para o Câncer de Mama HER-2 Positivo de Acordo ...

Adjuvância para o Câncer de Mama

HER-2 Positivo de Acordo com Risco

Dr Antonio C Buzaid

Diretor, Centro Oncológico Antonio Ermírio de Moraes, Beneficência Portuguesa de São Paulo

Membro do Comitê Gestor, Centro de Oncologia Dayan-Daycoval, Hospital Israelita Albert Einstein

De acordo com a resolução do Conselho Federal de Medicina nº 1595/2000 e Resolução da

Diretoria Colegiada da ANVISA nº 96/2008, eu declaro os seguintes potenciais conflitos de

interesse:

Pesquisa Clínica – Como investigador: Roche, MSD, BMS, Novartis, Pfizer

Apresentações científicas – Como palestrante: Roche, MSD, BMS, Novartis, Pfizer, United

Medical, AstraZeneca, Sanofi

Atividades de Consultoria – Como membro de Advisory Boards: Roche, MSD, BMS, Novartis,

Pfizer, United Medica, AstraZeneca, Sanofi, Blau

Declaro não ter ações em bolsa de valores das empresas supracitadas.

Meus pré-requisitos para participar destas atividades são o intercâmbio científico, a

autonomia do pensamento científico, independência de opinião e liberdade de expressão,

aspectos estes respeitados pela Novartis.

Esta apresentação pode conter informações que não constam nas bulas aprovadas dos

produtos Novartis . Estas informações têm o intuito de fornecer a você os dados científicos

pertinentes para tirar suas próprias conclusões e para tomar suas próprias decisões. A

Novartis não corrobora a promoção de seus produtos de uma forma que não esteja de

acordo com suas bulas aprovadas.

Disclaimer

Estudos de Adjuvância com Trastuzumabe

1. Gianni L, et al. Lancet Oncol 2011; 12:236244;

2. Slamon D, et al. N Engl J Med 2011; 365:12731283;

3. Perez EA, et al. J Clin Oncol 2011; 29:33663373.

DFS and OS Benefits Demonstrated with Addition of Trastuzumab

Study Follow-up (years)

DFS OS

N HR p value HR p value

HERA1–4

CT+/–RTH vs. CT+/–RT

1 3387 0.54 < 0.0001 0.76 0.26

2 3401 0.64 < 0.0001 0.66 0.0115

4 3401 0.76 < 0.0001 0.85 0.1087

8 3401 0.76 < 0.0001 0.76 0.0005

NCCTG N9831/

NSABP B-315–7

ACTHH vs. ACT

2 3351 0.48 < 0.0001 – –

4 4045 0.52 < 0.001 0.61 < 0.001

8.4 4046 0.60 < 0.0001 0.63 < 0.0001

BCIRG 0068

ACTHH vs. ACT5.5 3222

0.64 < 0.001 0.63 < 0.001

TCH vs. ACT 0.75 0.04 0.77 0.04

CT, chemotherapy; DFS, disease-free survival; H, trastuzumab;

HR, hazard ratio; OS, overall survival; RT, radiotherapy; T, taxane.

1. Piccart-Gebhart MJ, et al. N Engl J Med. 2005;353:1659-1672; 2. Smith I, et al. Lancet. 2007;369:29-36;

3. Gianni L, et al. Lancet Oncol. 2011;12:236-244; 4. Goldhirsch A, et al. Lancet. 2013 [Epub ahead of print];

5. Romond EH, et al. N Engl J Med. 2005;353:1673-1684; 6. Perez EA, et al. J Clin Oncol. 2011;29:3366-3373;

7. Romond EH, et al. SABCS 2012 (abstract S5-5; oral presentation); 8. Slamon D, et al. N Engl J Med. 2011;365:1273-1283.

BCIRG 006

Phase III Trial Comparing

AC→T with AC→TH and with TCH

in the Adjuvant Treatment of

HER2-Amplified Early Breast Cancer Patients:

ACT-TH vs TCH

Third Planned Efficacy Analysis

Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Rolski J, Chan A, Mackey J, Liu M, , Pinter T, Valero V,

Falkson C, Fornander T, Shiftan T, Olsen S, Buyse V, Falkson C, Fornander T, Shiftan T, Olsen S, Buyse M, Kiskartalyi T,

Landreau V, Wilson V, Press M, Crown J, on behalf of the BCIRG 006 Investigators.

Study sponsored by Sanofi

Support from Genentech

Slamon et al. SABCS abstr S5-04, 2015

BCIRG006: Braço sem antraciclina


BCIRG-006 Disease Free Survival Final Analysis (10.3yrs)

1

0.9

0.8

0.7

0.6

0.5

0.40 12 24 36 48 60 72 84 96 108 120 132

Time (months)

% a

live

and

dis

ease

-fre

e

AC-TAC-THTCH

Patients107310741075

Events328269279

HR (95% C.I.)1 (reference)

0.72 (0.61 – 0.85)0.77 (0.65 – 0.90)

P

< 0.00010.0011

67.9%

74.6%

73.0%


Diferença em toxicidade

Therapeutic Index – Most Recent 006 Data

AC → TH TCH

DFS Events 269 279

Grade 3 / 4 CHF 21 4

Totals 290 283

RX-Related

Leukemias

7 (8)*

*Only in AC-Rx

patients

0(1)**

**Leukemia developed after

CHOP Rx

Sustained LVEF

Loss > 10%200 97


Descalonamento da Adjvância

Paclitaxel semanal e Trastuzumabe (de-escalonando)

Primary tumor

Size

T1mic: ≤ 0.1 cm 9 (2.2)

T1a: > 0.1 to ≤ 0.5 cm 68 (16.7)

T1b: > 0.5 to ≤ 1.0 cm 124 (30.5)

T1c: > 1.0 to ≤ 2.0 cm 169 (41.6)

T2: > 2.0 to ≤ 3.0 cm 36 (8.9)

Nodal status

N0 400 (98.5)

N1mic 6 (1.5)

Tolaney S, N Eng J Med 2015;372:134

Taxano e Trastuzumabe “apenas”

Tolaney S, N Eng J Med 2015;372:134

Para tumores T1, N0, Paclitaxel X 12 + Trastuzumab tem alta eficácia

Paclitaxel semanal e Trastuzumabe

Ano Estimativa

3 anos 99,2%

5 anos 98,1%

7 anos 97,5%*

ASCO 2017, abstr #511

*1% de recorrência à distância

Intervalo Livre de Recorrência

6 vs 12 meses

(PHARE vs PERSEPHONE)

6 meses foi não inferior a 12 meses

PHARE DFS e OS

Sequential vs Concomitant

Comparison PHARE vs PERSEPHONE

Parameter PHARE PERSEPHONE

4-DFS in control Around 89% 89.8%

DFS HR 1.08 1.07

Margin required to declare NI 1.15 1.32*

Upper limit of 95% CI for DFS HR 1.25 1.24

Authors’ conclusion of NI Negative Positive

*Not prespecified, but computed on the basis of observed 4-year difference in DFSAnalyses performed by Dr Everardo Saad

Comparison of Buzaid vs Pitt

Adição de Pertuzumabe ao Trastuzumabe

The APHINITY Study Adjuvant Pertuzumab and Herceptin in Initial Therapy

BIG 4-11 / BO25126 / TOC4939g

A randomized comparison of chemotherapy plus trastuzumab

plus placebo versus chemotherapy plus trastuzumab plus

pertuzumab as adjuvant therapy in patients with HER2-positive

early breast cancer

G. von Minckwitz, M. procter, E. de Azambuja, D. Zardavas, M. Benyunes, G.

Viale, T. Suter, A. Arahmani, N. Rouchet, E. Clark, A. Knott, I. Lang, C. levy, D.

Yardley, J. Bines, R. Gelber, M. Piccart, J. Baselga

for the APHINITY Steering Committee and Investigators

APHINITY: Trial Design

APHINITY: Trial Design

Chemotherapy* + trastuzumab

+ pertuzumab

Chemotherapy* + trastuzumab

+ placebo

F

O

L

L

O

W

-

UP

10

Y

E

A

R

SRandomisation and treatment

within 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 adjuvante chemotherapy

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

S

U

R

G

E

R

Y

Central

confirmation

of HER2 status

(n = 4805)

R

APHINITY: Key Eligibility CriteriaAPHINITY: Key Eligibility Criteria

Inclusion criteria

• HER2-positive status confirmed by a central review (IHC 3+ or FISH-/CISH-positive)*

• Node-positive, any tumour size except T0

• Node-negative

• Tumour size > 1 cm

OR

• For tumours > 0.5 and ≤ 1cm, at least 1 of:

• Histological/nuclear grade 3

OR

• ER- and PR-egative

OR

• Age < 35

• Baseline LVEF ≥ 55%

Exclusion criteria

• Prior invasive breast câncer

• Non-operable breast câncer

• Metastatic disease (stage IV)

• Previoues non-reast malignances (except for the following: carcinomain situ of the cervix, carcinomain situ of the colon, melanoma in situ, and basal cell and squamous cell carcinomas of the skin)

• Previous or current anti-cancertherapy or previous radiotherapy for any malignancy

• Cardiac dysfunction or serious medical conditions

*Wolff A et al, J Clin Oncol 2013

APHINITY: Key Eligibility CriteriaAPHINITY: Primary Endpoint: Invasive Disease-Free Survival (IDFS)

Time from randomisation until the date of the first occurrence of one of the following events:

• Ipsilateral invasive breast tumour recurrence

• Ipsilateral local-regional invasive breast câncer recurrence

• Distant recurrence

• Contralateral invasive breast câncer

• Death attributable to any cause including breast câncer, non-breast cancer, or unknown cause

This IDFS definition• Was the FDA’s recommended definition for a trial intended to support a regulatory filing

• Differs from the STEEP definition1 of IDFS since it exclides second primary non-breast

cancers as event

1Hudis CA, J Clin Oncol 2007

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

Inv

asi

ve

dis

ea

se-f

ree

su

rviv

al (

%)

100

80

60

40

20

00 6 12 18 24 30 36 42 48

MonthsNo at Risk

Pertuzumab

Placebo2400

2404

2309

2335

2275

2312

2236

2274

2199

2215

2153

2168

2101

2108

1687

1674

879

866

Pertuzumab, 171 events

Placebo, 210 events

Stratified hazard ratio, 0.81 (95% CI, 0.66-1.00)

p = 0.045

Number needed to treat: 112

Expected: 89.2%

98.6% 96.4% 94.1% 92.3%

98.8%95.7%

93.2% 90.6%

Inv

asi

ve

dis

ea

se-f

ree

su

rviv

al (

%)

100

80

60

40

20

00 6 12 18 24 30 36 42 48

MonthsNo at Risk

Pertuzumab

Placebo1503

1502

1444

1453

1419

1439

1387

1408

1358

1359

1327

1319

1283

1264

912

882

423

405


Placebo, 181 events

Unstratified hazard ratio, 0.77 (95% CI, 0.62-0.96)

p = 0.019


98.1%94.9% 92.0% 89.9%

98.2%93.7%

90.2% 86.7%

APHINITY: Node-positive Subgroup

Inv

asi

ve

dis

ea

se-f

ree

su

rviv

al (

%)

100

80

60

40

20

00 6 12 18 24 30 36 42 48

MonthsNo at Risk

Pertuzumab

Placebo897

902

865

882

856

873

849

866

841

856

826

849

818

844

775

792

456

461


Placebo, 29 events


p = 0.644

99.5% 99.0% 97.5%96.2%

99.7% 99.1% 98.4% 96.7%

APHINITY: Node-negative Subgroup

Inv

asi

ve

dis

ea

se-f

ree

su

rviv

al (

%)

100

80

60

40

20

00 6 12 18 24 30 36 42 48

MonthsNo at Risk

Pertuzumab

Placebo864

858

836

827

821

811

813

793

797

771

774

758

755

730

600

569

314

302


Placebo, 91 events


p = 0.085


98.1% 96.2%92.8%

91.0%97.9%

93.7%91.2% 88.7%

APHINITY: Hormone Receptor-negative Subgroup

Inv

asi

ve

dis

ea

se-f

ree

su

rviv

al (

%)

100

80

60

40

20

00 6 12 18 24 30 36 42 48

MonthsNo at Risk

Pertuzumab

Placebo1536

1546

1473

1508

1454

1501

1423

1481

1402

1444

1379

1410

1346

1378

1087

1105

565

564


Placebo, 119 events


p = 0.277

98.9% 96.5%94.8% 93.0%

99.3% 96.8%94.4%

91.6%

APHINITY: Hormone Receptor-positive Subgroup

APHINITY: Conclusions

The APHINITY study met its primary objective

• Pertuzumab reduced the risk of an IDFS event by 19% compared with placebo (HR 0.81; 95% CI 0.66, 1.00; p = 0.045) at a median follow up of 45.4 months (3 years IDFS of 94.1% with pertuzumab and 93.2% with placebo)

Treatment effect was homogenous throughout all subgroups, however the N+ and HR- negative cohorts appeared to derive most benefit at the current point of time

• with a relative risk reduction of 23% and 24%, respectively and

• a 3-year IDFS absolute increase of 1.8% and 1.6% respectively

Cardiac toxicity was low and not diferente between the two arms

The incidence of diarrhea was increased in the pertuzumab arm and occurred predominantly during chemotherapy and with TCH

Redução de Risco de Morte de 20% (HR 0,80)

Linfonodo Positivo com 50% de Risco de Morte

Linfonodo Negativo com 10% de Risco de Morte

Nº de Pacientes % SG aos 5 anos DiferençaAbsoluta %

Adj. Obs. Adj. Obs.

Nº total 500 500 60 50 10

Nº de mortes 200(0,8 x 250)

250 (300 / 500) (250 / 500) (60 – 50)

Nº de Pacientes % SG aos 5 anos DiferençaAbsoluta %Adj. Obs. Adj. Obs.

Nº total 500 500 92 90 2

Nº de mortes 40(0,8 x 50)

50 (460 / 500) (450 / 500) (92-90)

Take Home Message Neoadjuvância

*Para pacientes muito idosas ou com co-morbidades importantes, considerar T-DM1

neoadjuvante (off label)

Câncer de mama

HER-2 positive*

T > 2 cm ou

N+

TCH+P (favorecido) ou

ACTH +P ou

EC X 3 seguido de Docetaxel X 3 + T + P

Take Home Message Adjuvância

T > 2 cm, N0

T 0,6 a ≤ 2 cm e LN -

T ≤ 0,5 cm e LN -

TH

TCH ou ACTH*

Discutir TH

*Em casos selecionados, considerar TH para pacientes muito idosas ou com

co-morbidades importantes.

Câncer de mama

HER-2 positivo

qqT, LN + TCH+P ou ACTH +P

Thank you

Adjuvância para o Câncer de Mama HER-2 Positivo de Acordo ...

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