Optimizing Treatment for Her 2 Positive Early Stage Breast Cancer Patients Sunil Verma MD, MSEd,...
Transcript of Optimizing Treatment for Her 2 Positive Early Stage Breast Cancer Patients Sunil Verma MD, MSEd,...
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
US approval:HER2-positive MBC1
20102000
EU approval:HER2-positive MBC2
EU approval:HER2-positive MBC2
2011
EMA approval: concurrent
trastuzumab+ chemotherapy in
EBC4
EMA approval: concurrent
trastuzumab+ chemotherapy in
EBC4
2006
EU/US approval:HER2-positive EBC3
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)
Cu
mu
lati
ve in
cid
ence
(%
)
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.
DD
FS (%
)
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) 0.094
Chemo 116 21
Patients Events
HR(9 weeks vs. none) 95% CI p value
9 weeks 115 22 0.65 (0.38, 1.12) 0.12
Chemo 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 value
2 years 1553 196 1.05 (0.86, 1.28) 0.63
1 year 1552 186
Patients EventsHR
(2 vs. 1 year) 95% CI p value
2 years 1553 367 0.99 (0.84, 1.14) 0.86
1 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) 0.03
1 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) 0.29
1 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