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Optimizing Treatment for Her 2 Positive Early Stage Breast Cancer Patients. Sunil Verma MD, MSEd, FRCPC Medical Oncologist Chair, Breast Medical Oncology Sunnybrook Odette Cancer Centre Associate Professor, University of Toronto. Outline. Overview of Adjuvant EBC Her 2 Positive Trials - PowerPoint PPT Presentation
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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