Sunil Verma MD, MSEd, FRCPC Medical Oncologist

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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 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 HERA (ex-USA)1 BCIRG 006 (global)2 Observation IHC/FISH N = 5102 FISH N = 3222 1 year 1 year 2 years 1 year NCCTG N9831 (USA)3 NSABP B-31 (USA)3 References Gianni L, Dafni U, Gelber RD, et al. Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236244. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011; 365:12731283. Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:33663373. IHC/FISH N = 2101 IHC/FISH N = 1944 1 year 1 year 1 year Chemotherapy +/- radiotherapy Doxorubicin + cyclophosphamide Docetaxel + carboplatin Docetaxel Trastuzumab Paclitaxel 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.

Her 2 EBC Adjuvant Trastuzumab Trials Timeline 1998 US approval: HER2-positive MBC1 2006 EU/US approval: HER2-positive EBC3 EMA approval: concurrent trastuzumab + chemotherapy in EBC4 2000 EU approval: HER2-positive MBC2 2010 2011 2012 2013 References Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344:783792. Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol 2005; 23:42654274. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353:16591672. Perez EA, Suman VJ, Davidson NE, et al. Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol 2011; 29:44914497. Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 2013 [Epub ahead of print]. HERA 2-year results published5 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]. BC, breast cancer; EBC, early breast cancer; EMA, European Medicines Agency; MBC, metastatic breast cancer.

DFS and OS benefits demonstrated during long-term follow-up in the the four pivotal clinical trials of trastuzumab for 1 year DFS OS Study Follow-up (years) N HR p value HERA1–4 CT+/–RTH vs. CT+/–RT 1 3387 0.54 < 0.0001 0.76 0.26 2 3401 0.64 0.66 0.0115 4 0.85 0.1087 8 0.0005 NCCTG N9831/ NSABP B-315–7 ACTHH vs. ACT 3351 0.48 – 4045 0.52 < 0.001 0.61 8.4 4046 0.60 0.63 BCIRG 0068 ACTHH vs. ACT 5.5 3222 TCH vs. ACT 0.75 0.04 0.77 References Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353:16591672. Smith I, Procter M, Gelber RD, et al. HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007; 369:2936. Gianni L, Dafni U, Gelber RD, et al; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236244. Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 2013 [Epub ahead of print]. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353:16731684. Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:33663373. Romond EH, Suman VJ, Jeong J-H, et al. Trastuzumab plus Adjuvant Chemotherapy for HER2-positive Breast Cancer: Final Planned Joint Analysis of Overall Survival from NSABP B-31 and NCCTG N9831. Cancer Res 2012; 72 (Suppl 3): Abstract S5-5 (and associated oral presentation). Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011; 365:12731283. 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. CT, chemotherapy; DFS, disease-free survival; H, trastuzumab; HR, hazard ratio; OS, overall survival; RT, radiotherapy; T, taxane.

The survival benefit is maintained irrespective of hormone receptor status 1 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) 126 vs. 190 0.63 (0.50, 0.78) 12 vs. 12 0.77 (0.34, 1.74) 26 vs. 39 0.82 (0.50, 1.34) 46 vs. 61 0.63 (0.43, 0.93) ER- and PgR-negative 1.00 ER- 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)* 0.65 0.61 HERA 1 year vs. obs: 1 year follow-up1 0.0 0.5 1.0 1.5 2.0 HERA 1 year vs. obs: 2 years’ follow-up2 0.0 0.5 1.0 1.5 2.0 NCCTG N9831/ NSABP B-31 4 years’ follow-up4 0.0 0.5 1.0 1.5 2.0 References Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353:16591672. Smith I, Procter M, Gelber RD, et al. HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007; 369:2936. Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 2013 [Epub ahead of print]. Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:33663373. Romond EH, VJ Suman VJ, Jeong J-H, et al. Trastuzumab plus adjuvant chemotherapy for HER2-positive breast cancer: Final planned joint analysis of overall survival (OS) from NSABP B-31 and NCCTG N9831. Cancer Research 2012; 72 (15 December suppl): Abstract S5-5 (and associated oral presentation). NCCTG N9831/ NSABP B-31 10 years’ follow-up5 0.0 0.5 1.0 1.5 2.0 HR 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). * OS ER, oestrogen receptor; obs, observation; OS, overall survival; PgR, progesterone receptor.

NCCTG N9831/NSABP B-31: Cumulative incidence of distant recurrence as a first event ER- and/or PgR-positive ER- and PgR-negative 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 Reference Romond EH, VJ Suman VJ, Jeong J-H, et al. Trastuzumab plus adjuvant chemotherapy for HER2-positive breast cancer: Final planned joint analysis of overall survival (OS) from NSABP B-31 and NCCTG N9831. Cancer Research 2012; 72 (15 December suppl): Abstract S5-5 (and associated oral presentation). 5 N events N events AC→T 1105 216 AC→T 911 175 AC→TH 1110 124 AC→TH 917 103 2 4 6 8 10 2 4 6 8 10 Years from randomisation Romond EH, et al. SABCS 2012 (Abstract S5-5; oral presentation).

Cumulative incidence (%) 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 Time (years) Cumulative incidence (%) 3.3% 0.8% 0.4% 2.8% 2.0% N9831 ACTH (n = 570)1 BCIRG 006 ACTH (n = 1068)2 BCIRG 006 TCH (n = 1056)2 N9831 ACTH (n = 710)1 HERA CTH (n = 1682)3,6,7 Adjuvant studies: Cardiac events: NYHA class III/IV or severe symptomatic congestive heart failure or cardiac death References Perez EA, Suman VJ, Davidson NE, et al. Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 Adjuvant Breast Cancer Trial. J Clin Oncol 2008; 26:12311238. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011; 365:12731283. Procter M, Suter TM, de Azambuja E, et al. Longer-term assessment of trastuzumab-related cardiac adverse events in the Herceptin Adjuvant (HERA) Trial. J Clin Oncol 2010; 28:34223428. Gianni L, Dafni U, Gelber RD, et al. Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236244. Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:33663373. Suter TM, Procter M, van Veldhuisen DJ, et al. Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial. J Clin Oncol 2007; 25:38593865. Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 2013 [Epub ahead of print]. 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.

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 Reported Ongoing Trastuzumab for <1 year vs. trastuzumab for 1 year Trastuzumab for 2 years vs. trastuzumab for 1 year 6 months 9 weeks 2 years 1 year (standard of care) HERA 1 year vs. observation7–9 PHARE 6 months vs. 1 year1 SOLD4 9 weeks vs. 1 year HERA 2 years vs. 1 year6 NCCTG N983110 HORG 6 months vs. 1 year2 SHORT-HER 9 weeks vs. 1 year5 References Pivot X, Romieu G, Debled M, et al. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol 2013; 14:741–748. ClinicalTrials.gov. Six vs 12 months of trastuzumab with docetaxel following FEC as adjuvant treatment in N+ breast cancer. Available at: http://clinicaltrials.gov/ct2/show/NCT00615602 (Accessed July 2013). Earl HM, Cameron DA, Miles D, et al. PERSEPHONE: Duration of trastuzumab with chemotherapy in women with HER2-positive early breast cancer—six versus twelve months. J Clin Oncol 2013; 31 (20 May suppl): Abstract TPS667. ClinicalTrials.gov. The synergism or long duration (SOLD) study. Available at: http://clinicaltrials.gov/ct2/show/NCT00593697 (Accessed July 2013). ClinicalTrials.gov. combination chemotherapy and trastuzumab in treating women with stage I, Stage II, or Stage III HER2-Positive Breast Cancer. Available at: http://clinicaltrials.gov/ct2/show/NCT00629278 (Accessed July 2013). Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 2013 [Epub ahead of print]. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353:1659–1672. Smith I, Procter M, Gelber RD, et al; HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007; 369:2936. Gianni L, Dafni U, Gelber RD, et al; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236244. Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:3366–3373. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011; 365:12731283. NCCN Clinical Practice Guidelines in Oncology. Breast Cancer V1.2013. Available at http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf (Accessed 27 August 2013). Senkus E, Kyriakides S, Penault-Llorca F, et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013 [Epub ahead of print]. Goldhirsch A, Winer EP, Coates AS, et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol 2013 [Epub ahead of print]. NSABP B3110 PERSEPHONE 6 months vs. 1 year3 FinHer 9 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].

Years from randomisation Years from randomisation FinHer: No statistically significant improvement in DDFS or OS with 9 weeks of trastuzumab vs. chemotherapy alone DDFS OS 100 80 60 40 20 1 2 3 4 5 6 7 OS (%) Years from randomisation 95.7% 90.5% 82.3% 91.3% DDFS (%) Years from randomisation 90.4% 77.6% 73.0% 83.3% 100 80 60 40 20 1 2 3 4 5 6 7 Chemotherapy Trastuzumab 9 weeks + chemotherapy Reference Joensuu H, Bono P, Kataja V, et al. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer Trial. J Clin Oncol 2013; 27:5685–5692. 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 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 CI, confidence interval; DDFs, distant disease-free survival. Joensuu H, et al. J Clin Oncol 2009;27:5685–5692.

Years from randomisation Years from randomisation HERA: Trastuzumab for 2 years was as efficacious as the standard 1 year of treatment, with no additional benefit DFS1 OS2 100 80 60 40 20 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 year Trastuzumab 2 years DFS (%) Years from randomisation 89.1% 86.7% 81.0% 81.6% 75.8% 76.0% 100 80 60 40 20 1 2 3 4 5 6 7 8 9 Trastuzumab 1 year Trastuzumab 2 years References Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 2013 [Epub ahead of print]. Goldhirsch A, Piccart-Gebhart MJ, Procter M, et al. HERA TRIAL: 2 Years Versus 1 Year of Trastuzumab after Adjuvant Chemotherapy in Women with HER2-Positive Early Breast Cancer at 8 Years of Median Follow Up. 35th Annual San Antonio Breast Cancer Symposium 2012 (abstract S5-2 and associated oral presentation). Patients Events HR (2 vs. 1 year) 95% CI p value 2 years 1553 367 0.99 (0.84, 1.14) 0.86 1 year 1552 Patients Events HR (2 vs. 1 year) 95% CI p value 2 years 1553 196 1.05 (0.86, 1.28) 0.63 1 year 1552 186 1. Goldhirsch A, et al. Lancet 2013 [Epub ahead of print]; 2. Goldhirsch A, et al. SABCS 2012 (Abstract S5-2; oral presentation).

Months from randomisation Months from randomisation PHARE: Non-inferiority of 6 months vs. 1 year of trastuzumab was not demonstrated DFS OS 100 80 60 40 20 12 24 36 48 Months from randomisation OS (%) Months from randomisation Trastuzumab 1 year Trastuzumab 6 months 100 80 60 40 20 48 36 24 12 Trastuzumab 1 year Trastuzumab 6 months DFS (%) Reference Pivot X, Romieu G, Debled M, et al. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol 2013; 14:741–748. 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 66 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 175 HR (95% CI): 1.46 (1.06, 2.01) (above the prespecified non-inferiority CI of 1.15) Pivot X, et al. Lancet Oncol 2013;14:741–748.

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, N0 French 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 DFS OS Study Follow-up (years) N HR p value HERA1–4 CT+/–RTH vs. CT+/–RT 1 3387 0.54 < 0.0001 0.76 0.26 2 3401 0.64 0.66 0.0115 4 0.85 0.1087 8 0.0005 NCCTG N9831/ NSABP B-315–7 ACTHH vs. ACT 3351 0.48 – 4045 0.52 < 0.001 0.61 8.4 4046 0.60 0.63 BCIRG 0068 ACTHH vs. ACT 5.5 3222 TCH vs. ACT 0.75 0.04 0.77 References Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353:16591672. Smith I, Procter M, Gelber RD, et al. HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007; 369:2936. Gianni L, Dafni U, Gelber RD, et al; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236244. Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 2013 [Epub ahead of print]. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353:16731684. Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:33663373. Romond EH, Suman VJ, Jeong J-H, et al. Trastuzumab plus Adjuvant Chemotherapy for HER2-positive Breast Cancer: Final Planned Joint Analysis of Overall Survival from NSABP B-31 and NCCTG N9831. Cancer Res 2012; 72 (Suppl 3): Abstract S5-5 (and associated oral presentation). Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011; 365:12731283. 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. CT, chemotherapy; DFS, disease-free survival; H, trastuzumab; HR, hazard ratio; OS, overall survival; RT, radiotherapy; T, taxane.

BCIRG 006 DFS

BCIRG 006 DFS 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

Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting 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

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

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 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

Improving the outcome of EBC patients A 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