Optimizing Treatment for Her 2 Positive Early Stage Breast Cancer Patients

Optimizing Treatment for Her 2 Positive Early Stage Breast Cancer Patients

Sunil Verma MD, MSEd, FRCPCMedical Oncologist

Chair, Breast Medical OncologySunnybrook Odette Cancer Centre

Associate Professor, University of Toronto

Outline

• Overview of Adjuvant EBC Her 2 Positive Trials• Duration of Therapy• < 1cm Node Negative• Role of Non-Anthracycline based chemotherapy• Incorporation of other Anti Her2 Therapies

Outline

• Overview of Adjuvant EBC Her 2 Positive Trials• Duration of Therapy• < 1cm Node Negative• Role of Non-Anthracycline based chemotherapy• Incorporation of other Anti Her2 Therapies

Four pivotal trials in over 12 000 patients established trastuzumab as the standard of care for HER2-positive EBC

IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation.

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.

Docetaxel

NCCTG N9831 (USA)3

BCIRG 006 (global)2

NSABP B-31 (USA)3

IHC/FISHN = 1944

FISHN = 3222

IHC/FISHN = 2101

Docetaxel + carboplatin

Doxorubicin + cyclophosphamide Trastuzumab Paclitaxel

HERA (ex-USA)1

IHC/FISHN = 5102

Observation

1 year

Chemotherapy+/- radiotherapy

2 years

1 year

1 year1 year

1 year

1 year

Her 2 EBCAdjuvant Trastuzumab Trials Timeline

BC, breast cancer; EBC, early breast cancer; EMA, European Medicines Agency; MBC, metastatic breast cancer.

1. Slamon DJ, et al. N Engl J Med 2001; 344:783792;2. Marty M, et al. J Clin Oncol 2005; 23:42654274;

3. Piccart-Gebhart MJ, et al. N Engl J Med 2005; 353:16591672;

4. Perez EA, et al. J Clin Oncol 2011; 29:44914497;5. Goldhirsch A, et al. Lancet 2013 [Epub ahead of print].

1998

US approval:HER2-positive MBC1

20102000

EU approval:HER2-positive MBC2

2011

EMA approval: concurrent

trastuzumab+ chemotherapy in

EBC4

2006

EU/US approval:HER2-positive EBC3

20132012

HERA 2-yearresults published5

DFS and OS benefits demonstrated during long-term follow-up in the the four pivotal clinical trials of trastuzumab for 1 year

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.

DFS OS

StudyFollow-up

(years) 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

Hormone receptor status1 year of

trastuzumab better Observation better DFS events, n DFS HR (95% CI)

ER-negative and PgR-negative 73 vs. 133 0.52 (0.39, 0.69)ER-negative and PgR-positive 7 vs. 8 0.67 (0.24, 1.84)ER-positive and PgR-negative 15 vs. 29 0.63 (0.34, 1.17)ER-positive and PgR-positive 28 vs. 38 0.61 (0.38, 1.00)

ER-negative and PgR-negative 126 vs. 190 0.63 (0.50, 0.78)ER-negative and PgR-positive 12 vs. 12 0.77 (0.34, 1.74)ER-positive and PgR-negative 26 vs. 39 0.82 (0.50, 1.34)ER-positive and PgR-positive 46 vs. 61 0.63 (0.43, 0.93)

ER- and PgR-negative 1.00ER- or PgR-positive 81.6 vs. 69.4 0.66 (0.57, 0.76)

ER- or PgR-positive* 89.4 vs. 77.2 0.57 (0.46, 0.69)*

ER- and PgR-negative 0.65ER- or PgR-positive 0.61

The survival benefit is maintained irrespective of hormone receptor status

* OSER, oestrogen receptor; obs, observation; OS, overall survival; PgR, progesterone receptor.

1. Piccart-Gebhart MJ, et al. N Engl J Med 2005; 353:16591672;2. Smith I, et al. Lancet 2007; 369:2936; 3. Goldhirsch A, et al. Lancet 2013 [Epub ahead of print];

4. Perez EA, et al. J Clin Oncol 2011; 29:33663373; 5. Romond EH, et al. SABCS 2012 (Abstract S5-5; oral presentation).

HERA1 year vs. obs: 1

year follow-up1

NCCTG N9831/NSABP B-31

4 years’ follow-up4

NCCTG N9831/NSABP B-31

10 years’ follow-up5

HERA1 year vs. obs: 2

years’follow-up2

0.0 0.5 1.0 1.5 2.0

0.0 0.5 1.0 1.5 2.0

0.0 0.5 1.0 1.5 2.0

0.0 0.5 1.0 1.5 2.0

HR

NCCTG N9831/NSABP B-31: Cumulative incidence of distant recurrence as a first event

Romond EH, et al. SABCS 2012 (Abstract S5-5; oral presentation).

25

20

15

10

5

0

0 2 4 6 8 10

Cum

ulati

ve in

cide

nce

(%)

Years from randomisation0 2 4 6 8 10

AC→T

22.3%

Δ = 9.6%

12.7%

AC→TH

AC→THAC→T 1105 216

1241110

N events

AC→T 21.5%

Δ = 9.6%

11.9%

AC→TH

N events

911 175103917AC→TH

AC→T

ER- and/or PgR-positive ER- and PgR-negative

Key trials showed a consistent safety and tolerability profile with trastuzumab for 1 year, with a low cumulative incidence of cardiac events after long-term follow-up1–7

NYHA, New York Heart Association.

1. Perez EA, et al. J Clin Oncol 2008; 26:12311238.2. Slamon D, et al. N Engl J Med 2011; 365:12731283;

3. Procter M, et al. J Clin Oncol 2010; 28:34223428;4. Gianni L, et al. Lancet Oncol 2011; 12:236244;

5. Perez EA, et al. J Clin Oncol 2011; 29:33663373;6. Suter TM, et al. J Clin Oncol 2007; 25:38593865;

7. Goldhirsch A, et al. Lancet 2013 [Epub ahead of print].

Time (years)

Cum

ulat

ive

inci

denc

e (%

)

3.3%

0.8%0.4%

2.8% 2.0%

N9831 ACTH (n = 570)1

BCIRG 006 ACTH (n = 1068)2

BCIRG 006 TCH (n = 1056)2

N9831 ACTH (n = 710)1

HERA CTH (n = 1682)3,6,7

Adjuvant studies:Cardiac events: NYHA class III/IV or severe symptomatic congestive heart

failure or cardiac death

Outline

• Overview of Adjuvant EBC Her 2 Positive Trials• Duration of Trastuzumab Therapy• < 1cm Node Negative• Role of Non-Anthracycline based chemotherapy• Incorporation of other Anti Her2 Therapies

Several ongoing trials are investigating the optimal duration of trastuzumab in EBC

1. Pivot X, et al. Lancet Oncol 2013; 14:741–748; 2. http://clinicaltrials.gov/ct2/show/NCT00615602; 3. Earl HM, et al. ASCO 2013 (Abstract TPS667);4. http://clinicaltrials.gov/ct2/show/NCT00593697; 5. http://clinicaltrials.gov/ct2/show/NCT00629278; 6. Goldhirsch A, et al. Lancet 2013 [Epub ahead of print];

7. Piccart-Gebhart MJ, et al. N Engl J Med 2005; 353:1659–1672; 8. Smith I, et al. Lancet 2007; 369:2936; 9. Gianni L, et al. Lancet Oncol 2011; 12:236244;10. Perez EA, et al. J Clin Oncol 2011; 29:3366–3373; 11. Slamon D, et al. N Engl J Med 2011; 365:12731283;

12. NCCN Clinical Practice Guidelines in Oncology; Breast Cancer V1.2013; 13. Senkus E, et al. Ann Oncol 2013 [Epub ahead of print];14. Goldhirsch A, et al. Ann Oncol 2013 [Epub ahead of print].

6 months

Trastuzumab for <1 year vs.trastuzumab for 1 year

PHARE6 months vs. 1 year1

SHORT-HER9 weeks vs. 1 year5

HORG6 months vs. 1 year2

SOLD4

9 weeks vs. 1 year

PERSEPHONE6 months vs. 1 year3

9 weeks

Trastuzumab for 1 year remains the standard of care in EBC, as recommended by international guidelines 12–14

2 years

HERA 2 years vs. 1 year6

Trastuzumab for 2 years vs. trastuzumab

for 1 year

HERA 1 year vs. observation7–9

NCCTG N983110

BCIRG 00611

1 year(standard of care)

NSABP B3110

FinHer9 weeks vs. chemo

Reported

Ongoing

FinHer: No statistically significant improvement in DDFS or OS with 9 weeks of trastuzumab vs. chemotherapy alone

CI, confidence interval; DDFs, distant disease-free survival. Joensuu H, et al. J Clin Oncol 2009;27:5685–5692.

DDFS

(%)

Years from randomisation

90.4%

77.6% 73.0%

83.3%100

80

60

40

20

00 1 2 3 4 5 6 7

Chemotherapy ChemotherapyTrastuzumab 9 weeks + chemotherapy Trastuzumab 9 weeks + chemotherapy

Patients Events

HR(9 weeks vs. none) 95% CI p value

9 weeks 115 12 0.55 (0.27, 1.11) 0.094Chemo 116 21

Patients Events

HR(9 weeks vs. none) 95% CI p value

9 weeks 115 22 0.65 (0.38, 1.12) 0.12Chemo 116 31

100

80

60

40

20

00 1 2 3 4 5 6 7

OS

(%)

Years from randomisation

95.7%

90.5%82.3%

91.3%

DDFS OS

HERA: Trastuzumab for 2 years was as efficacious as the standard 1 year of treatment, with no additional benefit

1. Goldhirsch A, et al. Lancet 2013 [Epub ahead of print];2. Goldhirsch A, et al. SABCS 2012 (Abstract S5-2; oral presentation).

DFS

(%)

Years from randomisation

89.1%

86.7% 81.0%

81.6%75.8%

76.0%

100

80

60

40

20

00 1 2 3 4 5 6 7 8 9

Trastuzumab 1 yearTrastuzumab 2 years

Patients EventsHR

(2 vs. 1 year) 95% CI p value2 years 1553 196 1.05 (0.86, 1.28) 0.631 year 1552 186

Patients EventsHR

(2 vs. 1 year) 95% CI p value2 years 1553 367 0.99 (0.84, 1.14) 0.861 year 1552 367

100

80

60

40

20

00 1 2 3 4 5 6 7 8 9

OS

(%)

Years from randomisation

97.4%

96.5%91.4%

92.6%86.4%

87.6%

Trastuzumab 1 yearTrastuzumab 2 years

DFS1 OS2

Patients Events

HR(6 months vs. 1 year) 95% CI p value

6 months 1690 93 1.46 (1.06, 2.01) 0.031 year 1690 66

PHARE: Non-inferiority of 6 months vs. 1 year of trastuzumab was not demonstrated

Pivot X, et al. Lancet Oncol 2013;14:741–748.

DFS

(%)

100

80

60

40

20

00 12 24 36 48 60

Months from randomisation

Trastuzumab 1 yearTrastuzumab 6 months

Patients Events

HR(6 months vs. 1 year) 95% CI p value

6 months 1690 219 1.28* (1.05, 1.56) 0.291 year 1690 175

OS

(%)

Months from randomisation

Trastuzumab 1 yearTrastuzumab 6 months

100

80

60

40

20

060483624120

HR (95% CI): 1.46 (1.06, 2.01)(above the prespecified non-inferiority CI of 1.15)

DFS OS

Outline

• Overview of Adjuvant EBC Her 2 Positive Trials• Duration of Therapy• < 1cm Node Negative• Role of Non-Anthracycline based chemotherapy• Incorporation of other Anti Her2 Therapies

Trastuzumab in T1a/b, N0French Retrospective Study (n=97)

Trastuzumab in < 1cm, N+BCIRG 006

Summary

• < 1cm node negative patients should be considered for trastuzumab– One has to weigh potential toxicity and absolute

benefit, especially for T1a tumors– Paclitaxel + Trastuzumab may be a very effective

and well tolerated approach for T1 N0 Her 2 positive tumors or for patients not deemed to be suitable for anthracyclines and docetaxel based regimens

Outline

• Overview of Adjuvant EBC Her 2 Positive Trials• Duration of Therapy• < 1cm Node Negative• Role of Non-Anthracycline based chemotherapy• Incorporation of other Anti Her2 Therapies

DFS and OS benefits demonstrated during long-term follow-up in the the four pivotal clinical trials of trastuzumab for 1 year

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.

DFS OS

StudyFollow-up

(years) 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

BCIRG 006DFS

BCIRG 006DFS by Nodal Positivity

Which patients should we considered for a non-anthracycline based anti Her 2 alternative option?

• Patients with cardiac risk factors or underlying cardiac disease

• Patients where the absolute benefit of adjuvant therapy may be low– T1a, T1b tumors

• Older patients (?>70 years of age)

Outline

• Overview of Adjuvant EBC Her 2 Positive Trials• Duration of Therapy• < 1cm Node Negative• Role of Non-Anthracycline based chemotherapy• Incorporation of other Anti Her2 Therapies

First results from the phase III ALTTO trial (BIG 02-06; NCCTG 063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (TL) or their combination (L + T) in the adjuvant treatment of HER2-positive <br />early breast cancer (EBC)

Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

Slide 5

Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

Distribution of the Stratification Factors by Treatment Arm

Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

Distribution of patient characteristics by Treatment Arm

Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

ALTTO vs. Neo-ALTTO

DISEASE-FREE SURVIVAL (DFS) ANALYSIS

Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

DFS BY Hormone Receptor Status

Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

OVERALL SURVIVAL (OS) ANALYSIS

Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

PROPORTION OF PATIENTS RECEIVING ≥ 85% OF THE PLANNED DOSE OF ANTI-HER2 DRUGS

Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

MAIN DIFFERENCES IN AEs BY TREATMENT ARM

Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

Bottom Line

• There is no role for Lapatinib in the adjuvant setting

• Why is ALTTO negative?– The ‘Ceiling Effect’

• OS > 95% in the control arm• low risk patient population• very effective and well-tolerated control arm

– Dose Delivery in the experimental arm– Is it related to MOA for TKI

Outline

• Overview of Adjuvant EBC Her 2 Positive Trials• Duration of Therapy• < 1cm Node Negative• Role of Non-Anthracycline based chemotherapy• Incorporation of other Anti Her2 Therapies • Future Directions and Concluding Remarks

Future Questions in EBC

49

Improving the outcome of EBC patientsA Cost-Effective Approach

• Which patients are ‘cured’ with surgery alone?• Which patients are cured with surgery and traditional

chemotherapy?• Which patients require trastuzumab, only for a short

duration i.e. 9 weeks or 6 months?• Which patients don’t benefit from chemotherapy and

trastuzumab?

Conclusion

• There is continued and maintained benefit with adjuvant trastuzumab

• Duration of Trastuzumab remains to be fully defined– At present one year is standard of treatment

• Identifying the patients who are at a greater risk– Address those who remain at high risk

• The focus needs to be on how we can gain better outcomes with less toxicity– Integration of novel therapies vs. conventional

traditional chemotherapy