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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, 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

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Optimizing Treatment for Her 2 Positive Early Stage Breast Cancer Patients

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  1. 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

  2. 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

  3. 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

  4. Four pivotal trials in over 12000 patients established trastuzumab as the standard of care for HER2-positive EBC HERA (ex-USA)1 BCIRG 006 (global)2 Observation FISHN = 3222 IHC/FISHN = 5102 1 year 1 year 2 years 1 year NCCTG N9831 (USA)3 NSABP B-31 (USA)3 IHC/FISHN = 2101 IHC/FISHN = 1944 1 year 1 year 1 year Doxorubicin + cyclophosphamide Docetaxel + carboplatin Docetaxel Trastuzumab Paclitaxel Chemotherapy+/- radiotherapy 1. Gianni L, et al.Lancet Oncol 2011; 12:236244;2. Slamon D, et al.N Engl J Med 2011; 365:12731283; 3. Perez EA, et al.J Clin Oncol 2011; 29:33663373. IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation.

  5. US approval:HER2-positive MBC1 EU/US approval:HER2-positive EBC3 1998 2000 2006 EU approval:HER2-positive MBC2 Her 2 EBCAdjuvant Trastuzumab Trials Timeline EMA approval: concurrent trastuzumab+ chemotherapy in EBC4 2010 2013 2012 2011 HERA 2-yearresults published5 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; 344:783792;2. Marty M, et al. J Clin Oncol 2005; 23:42654274; 3. Piccart-Gebhart MJ, et al. N Engl J Med 2005; 353:16591672;4. Perez EA, et al. J Clin Oncol 2011; 29:44914497;5. Goldhirsch A, et al. Lancet 2013 [Epub ahead of print].

  6. 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.

  7. The survival benefit is maintained irrespective of hormone receptor status HERA 1 year vs. obs: 1 year follow-up1 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 HERA 1 year vs. obs: 2 years’follow-up2 NCCTG N9831/NSABP B-314 years’ follow-up4 NCCTG N9831/NSABP B-3110 years’ follow-up5 HR * OS ER, oestrogen receptor; obs, observation; OS, overall survival; PgR, progesterone receptor. 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. Goldhirsch A, et al. Lancet 2013 [Epub ahead of print]; 4. Perez EA, et al.J Clin Oncol 2011; 29:33663373; 5. Romond EH, et al. SABCS 2012 (Abstract S5-5; oral presentation).

  8. NCCTG N9831/NSABP B-31: Cumulative incidence of distant recurrence as a first event ER- and PgR-negative ER- and/or PgR-positive 25 22.3% AC→T 21.5% AC→T 20 Δ = 9.6% Δ = 9.6% 15 12.7% 11.9% Cumulative incidence (%) 10 AC→TH AC→TH N events N events 5 AC→T 1105 216 AC→T 911 175 1110 124 917 103 AC→TH AC→TH 0 0 2 4 6 8 10 0 2 4 6 8 10 Years from randomisation Romond EH, et al. SABCS 2012 (Abstract S5-5; oral presentation).

  9. 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 Cardiac events: NYHA class III/IV or severe symptomatic congestive heart failure or cardiac death Adjuvantstudies: N9831 ACTH (n = 570)1 N9831 ACTH (n = 710)1 Cumulative incidence (%) BCIRG 006 ACTH (n = 1068)2 3.3% HERA CTH (n = 1682)3,6,7 2.8% 2.0% BCIRG 006 TCH (n = 1056)2 0.8% 0.4% Time (years) 1. Perez EA, et al.J Clin Oncol 2008; 26:12311238. 2. Slamon D, et al.N Engl J Med 2011; 365:12731283; 3. Procter M, et al.J Clin Oncol 2010; 28:34223428;4. Gianni L, et al.Lancet Oncol 2011; 12:236244;5. Perez EA, et al.J Clin Oncol 2011; 29:33663373;6. Suter TM, et al.J Clin Oncol 2007; 25:38593865; 7. Goldhirsch A, et al. Lancet 2013 [Epub ahead of print]. NYHA, New York Heart Association.

  10. 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

  11. Several ongoing trials are investigating the optimal duration of trastuzumab in EBC Reported Ongoing Trastuzumab for <1 year vs.trastuzumab for 1 year Trastuzumab for 2 years vs. trastuzumab for 1 year 6 months 9 weeks 1 year(standard of care) 2 years HERA 1 year vs. observation7–9 PHARE6 months vs. 1 year1 SOLD49 weeks vs. 1 year HERA 2 years vs. 1 year6 NCCTG N983110 HORG6 months vs. 1 year2 SHORT-HER9 weeks vs. 1 year5 NSABP B3110 PERSEPHONE6 months vs. 1 year3 FinHer9 weeks vs. chemo BCIRG 00611 Trastuzumab for 1 year remains the standard of care in EBC, as recommended by international guidelines12–14 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; 369:2936; 9. Gianni L, et al. Lancet Oncol 2011; 12:236244;10. Perez EA, et al. J Clin Oncol 2011; 29:3366–3373; 11. Slamon D, et al.N Engl J Med 2011; 365:12731283; 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].

  12. FinHer: No statistically significant improvement in DDFS or OS with 9 weeks of trastuzumab vs. chemotherapy alone 95.7% 90.4% 100 100 91.3% DDFS OS 83.3% 90.5% 80 80 82.3% 77.6% 73.0% 60 60 DDFS (%) 40 40 Trastuzumab 9 weeks + chemotherapy Trastuzumab 9 weeks + chemotherapy Chemotherapy Chemotherapy 20 20 0 0 OS (%) 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 Years from randomisation Years from randomisation Joensuu H, et al. J Clin Oncol 2009;27:5685–5692. CI, confidence interval; DDFs, distant disease-free survival.

  13. HERA: Trastuzumab for 2 years was as efficacious as the standard 1 year of treatment, with no additional benefit 97.4% 100 100 92.6% 89.1% 86.4% DFS1 OS2 96.5% 81.6% 91.4% 75.8% 80 80 87.6% 86.7% 81.0% 76.0% Trastuzumab 2 years Trastuzumab 1 year 60 60 Trastuzumab 2 years Trastuzumab 1 year DFS (%) 40 40 20 20 0 0 OS (%) 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 Years from randomisation Years from randomisation 1. Goldhirsch A, et al. Lancet 2013 [Epub ahead of print]; 2. Goldhirsch A, et al. SABCS 2012 (Abstract S5-2; oral presentation).

  14. PHARE: Non-inferiority of 6 months vs. 1 year of trastuzumab was not demonstrated 100 100 DFS OS 80 80 Trastuzumab 6 months Trastuzumab 1 year 60 60 Trastuzumab 6 months Trastuzumab 1 year DFS (%) 40 40 0 12 24 36 48 60 Months from randomisation 20 20 0 0 OS (%) HR (95% CI): 1.46 (1.06, 2.01) (above the prespecifiednon-inferiority CI of 1.15) 0 12 24 36 48 60 Months from randomisation Pivot X, et al. Lancet Oncol 2013;14:741–748.

  15. 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

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

  17. Trastuzumab in < 1cm, N+BCIRG 006

  18. 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

  19. 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

  20. 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.

  21. BCIRG 006DFS

  22. BCIRG 006DFS by Nodal Positivity

  23. 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)

  24. 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

  25. 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 (TL) 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

  26. Slide 5 Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

  27. Distribution of the Stratification Factors by Treatment Arm Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

  28. Distribution of patient characteristics by Treatment Arm Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

  29. ALTTO vs. Neo-ALTTO

  30. DISEASE-FREE SURVIVAL (DFS) ANALYSIS Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

  31. DFS BY Hormone Receptor Status Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

  32. OVERALL SURVIVAL (OS) ANALYSIS Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

  33. PROPORTION OF PATIENTS RECEIVING ≥ 85% OF THE PLANNED DOSE OF ANTI-HER2 DRUGS Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

  34. MAIN DIFFERENCES IN AEs BY TREATMENT ARM Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

  35. 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

  36. 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

  37. Future Questions in EBC • Which is the best combination of targeted agents? • Lapatinib and Trastuzumab • Pertuzumab and Trastuzumab • ?T-DM1 and Pertuzumab • Do we need to offer patients one year of Herceptin or one year of combined blockade? • ? Role of anti-HER2 agents in HER2 1+ or 2+ patients

  38. 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?

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