Top Banner
Adjuvant therapy of HER2 positive early breast cancer The Evidences Antonio Frassoldati Oncologia Clinica - Ferrara
27

Adjuvant therapy of HER2 positive early breast cancer The Evidences

Feb 24, 2016

Download

Documents

Adjuvant therapy of HER2 positive early breast cancer The Evidences. Antonio Frassoldati Oncologia Clinica - Ferrara. Evidences on adjuvant trastuzumab are based on randomized trials in over 14,000 women . S= sequential; C= concomitant - PowerPoint PPT Presentation
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Page 1: Adjuvant therapy of HER2 positive early breast cancer The Evidences

Adjuvant therapy of HER2 positive early breast cancer The Evidences

Antonio Frassoldati

Oncologia Clinica - Ferrara

Page 2: Adjuvant therapy of HER2 positive early breast cancer The Evidences

Evidences on adjuvant trastuzumab are based on randomized trials in over 14,000

women

Trial Pt. N. Trastuz. Duration Median FU Published results

B31/N9831 3351 C+S 1 y 48 mos Y

N9831 3046 S or C+S 1 y 72 mos Y*

HERA 5090 S 1 or 2 y 48 mos Y

BCIRG006 3222 C+S 1 y 65 mos Y

FinHER 232 C 3 m 62 mos Y

PACS-04 528 S 1y 47 mos Y

S= sequential; C= concomitant

* Early release after second interim analysis (arm A, B) and first interim analysis (arm B,C)

Page 3: Adjuvant therapy of HER2 positive early breast cancer The Evidences

Main trial designs of adjuvant Trastuzumab

NSABP B-31Node positive

N9831 Node pos/neg HR

Paclitaxel q3w x 4

Paclitaxel x 4, H qw x 52 AC q3w x 4

H qw x 52

Paclitaxel qw x 12

Paclitaxel qw x 12

Paclitaxel qw x 12, H qw x 52

AC q3w x 4

BCIRG 006 Node pos/neg HR

Docetaxel q3w x 4AC q3w x 4

AC q3w x 4H qw x 12, q3w† x 14

Docetaxel q3w x 4

Carboplatin + Docetaxel q3w† x 6H qw x 18, q3w x 12

HERA Chemotherapy (any) Node pos/neg HR Chemotherapy (any) H qw x 52

Chemotherapy (any) H qw x 104

Page 4: Adjuvant therapy of HER2 positive early breast cancer The Evidences

Main research questions in trials of adjuvant trastuzumab

• Does trastuzumab reduce the rate of recurrence (and death)? (All)

• Does the schedule of trastuzumab administration matter? (N9831, BCIRG006)

• Does the duration of trastuzumab matter? (HERA)

• Does the chemotherapy regimen influence the activity and safety of trastuzumab? (BCIRG006)

Page 5: Adjuvant therapy of HER2 positive early breast cancer The Evidences

Cross-comparison among the trials of adjuvant trastuzuamb

Trial Pt. N. Primary endpoint

Crossover

B31/N9831 3351 DFS 15%

N9831 3046 DFS Y

HERA° 5090 DFS 52%

BCIRG006 3222 DFS 2.1%

FinHER 232 DFS N

PACS04 528 DFS N

° Pts in HERA trial were randomized after the end of adjuvant therapy

Page 6: Adjuvant therapy of HER2 positive early breast cancer The Evidences

B31/N9831Efficacy results

Perez, JCO 2011

Rel

apse

HR 0.52 (0.45-0.60)

Page 7: Adjuvant therapy of HER2 positive early breast cancer The Evidences

B31/N9831Efficacy results

Perez, JCO 2011

Dea

th

HR 0.61 (0.50-0.75)

Page 8: Adjuvant therapy of HER2 positive early breast cancer The Evidences

No. of deathsH 1 year vs. observation

0 1 2Favourstrastuzumab

Favours notrastuzumab

HR

OS benefit

29 vs. 37p=0.26

20051

1 year(0%)

59 vs. 90p=0.0115

182 vs. 213p=0.1087

Median follow-up (% follow-up time

after selective crossover)

20062

2 years(4.1%)

20083

4 years(30.9%)

20051

1 year (0%)

Median follow-up (% follow-up time

after selective crossover)

20062

2 years (4.3%)

20083

4 years (33.8%)

No. of DFS eventsH 1 year vs. observation

127 vs. 220p<0.0001

218 vs. 321p<0.0001

369 vs. 458p<0.0001

0 1 2Favourstrastuzumab

Favours notrastuzumab

HR

DFS benefit

1. Piccart-Gebhart et al 2005; 2. Smith et al 2007; 3. Gianni et al 2011

HERA: DFS and overall survival over time

Page 9: Adjuvant therapy of HER2 positive early breast cancer The Evidences

HERA - Observation patients by status on 16 May 2005

1698 patients originally randomised to observation

1354 patients alive and disease free 16 May 2005

344 patients DFS event or lost to follow-up

198 alive post DFS event

469 patients remained on observation

344 patients ineligible for

crossover

Gianni, Lancet Oncol 2011

885 patients crossed over to

trastuzumab

Page 10: Adjuvant therapy of HER2 positive early breast cancer The Evidences

HERA - DFS (landmark analysis): selective crossover and no crossover

100

80

60

40

20

00

Months from randomisation

No. at risk

Patients alive and disease free (%)

Selective crossover*No crossover

6 12 18 24 30 36 42 48

885 885 884 878 870 851 822 690 480469 468 455 438 408 388 358 302 232

HR 0.68 (0.51-0.90)

p=0.0077

Gianni, Lancet Oncol 2011* Median time to start trastuzumab: 22.8 mos (4.5-52.7)

Page 11: Adjuvant therapy of HER2 positive early breast cancer The Evidences

N9831Efficacy results

Sequ

entia

l vs

Con

com

itant

+ s

eque

ntia

l

Perez, JCO 2011

Page 12: Adjuvant therapy of HER2 positive early breast cancer The Evidences

BCIRG006Efficacy results

Slamon, NEJM 2011

DFS HR

AC-TH vs AC-T 0.64

TCH vs AC-T 0.75

Page 13: Adjuvant therapy of HER2 positive early breast cancer The Evidences

FinHEREfficacy results

Joensuu, JCO 2009

Page 14: Adjuvant therapy of HER2 positive early breast cancer The Evidences

Efficacy of adjuvant trastuzuambon Survival

Trial HR Median FU

B31/N9831 0.61 48 mos

N9831AC-T vs AC-T-H

AC-T-H vs AC-TH-H0.880.78

72 mos

HERA° 0.85 48 mos

BCIRG006AC-T vs AC-TH-H

AC-T vs TCH0.630.77

65 mos

FinHER 0.55 62 mos

° ITT, not adjusted for selective crossover

Page 15: Adjuvant therapy of HER2 positive early breast cancer The Evidences

Efficacy in subgroupsER and Nodal status

Slamon, NEJM 2011

AC-TH-H

TCH

Page 16: Adjuvant therapy of HER2 positive early breast cancer The Evidences

Time-dependent Hazard Rate for recurrence by hormone receptor status

ER positive

ER negative

Untch, Ann Oncol 2008HERA trial

Page 17: Adjuvant therapy of HER2 positive early breast cancer The Evidences

Efficacy in subgroupsSmall tumors

Gonzalez-Angulo, JCO 2009

MD

AC

C

965 pT1a-b N0

Hazard Ratio for recurrence 5.3

97.2%

86.4%

Page 18: Adjuvant therapy of HER2 positive early breast cancer The Evidences

Efficacy in subgroupsSmall tumors

Slamon, NEJM 2011

BC

IRG

006

Page 19: Adjuvant therapy of HER2 positive early breast cancer The Evidences

Efficacy in subgroupsTopo2A status

Slamon, NEJM 2011

With Topo2A coamplification

Without Topo2A coamplification

Page 20: Adjuvant therapy of HER2 positive early breast cancer The Evidences

Cardiac safety

Trial Not starting trastuzuamb

Trastuz. Discontin.

Cardiac dysfunction°

CHF

B31/N9831 4.3% 17.3% 17.3%320/1845

3.8%

N9831 (C+S) 2.8% 19% 9.1% 87/949

2.2%

HERA -- 5.2% 3.7% 0.8%

BCIRG006 AC-TH 2.1% n.r. AC-TH 18.6% TCH 9.4%

AC-TH 2.0% TCH 0.4%

FinHER -- 4-7% of doses

3.9%* 0.9% *

° >10 points relative reduction in LVEF *after CT

Page 21: Adjuvant therapy of HER2 positive early breast cancer The Evidences

0.00

Suter et al 2007aMedian follow-up 12 months; DFS, disease-free survival

Obs; any cardiac end point

H; any cardiac end point

Obs; DFS eventsH; DFS events

6 12 18 24Monthsa

0.05

0.10

0.15

0.20

0.25Pr

obab

ility

No. at riskObservationTrastuzumab

1693 1106 784 455 2261693 1139 861 520 260

0

HERA: risk-benefit ratio with adjuvant trastuzumaba

Page 22: Adjuvant therapy of HER2 positive early breast cancer The Evidences

Cardiac outcomes after any type of cardiac endpoint

No acute recoveryAcute recovery

Trastuzumab patients who have any type of CE (n=73)

Trastuzumab patients who reached acuterecovery after any type of CE (n=59)

Trastuzumab patients who had a furtherLVEF drop to <50% (n=59)

19.2%

80.8%

Further LVEF drop to <50%No further LVEF drop to <50%

71.2%

28.8%

Progressive diseaseFavorable outcome

35.3%

64.7%

Page 23: Adjuvant therapy of HER2 positive early breast cancer The Evidences

Duration of Trastuzumab

Trial Duration in months

CT regimen No. of pts

HERA (BIG) 12 vs. 24 Center’s choice

3,387

PHARE (France) 6 vs. 12 Center’s choice

3,400

PERSEPHONE (UK) 6 vs. 12 Center’s choice

4,000

SHORTER (Italy) 3 vs.12 A+T vs. T+FEC

1,500

SOLD (Finland & BCG)

3 vs 12 T+FEC 3,000

Page 24: Adjuvant therapy of HER2 positive early breast cancer The Evidences

Adjuvant HER2- directed Therapy

Questions to be solved:

– Indication for the better regimen for combination with trastuzumab (Anthracycline/taxane or docetaxel/carboplatin)

– Role of shorter trastuzumab regimens– Treatment of triple-positive tumor migth avoid

chemotherapy, particularly on small tumors (T1a,b N0)– Prediction of response to individual HER2-directed agents– Role of dual HER2 inhibition

Page 25: Adjuvant therapy of HER2 positive early breast cancer The Evidences

Double inhibition of HER2

Page 26: Adjuvant therapy of HER2 positive early breast cancer The Evidences

Trastuzumab clearly changed the prognosis of HER2

breast cancer patients.

Several new ways for further

improvements can now to be explored

HER2 street

Page 27: Adjuvant therapy of HER2 positive early breast cancer The Evidences