Assistant Professor of Medicine Dana-Farber Cancer Institute Exploring new and future standards of care in HER2 positive breast cancer: Improving efficacy in the adjuvant / neoadjuvant setting Harold Burstein, MD Assistant Professor of Medicine Dana-Farber Cancer Institute Boston, MA

Studies of adjuvant trastuzumab therapy: Summary NSABP B31 / NCCTG N9831 HERA FinHer BCIRG 006 ACT vs ACT + H ACT vs TCH Patients (n) 4,045 5,081 1,010 3,222 OS HR (95% CI) 0.61 (0.5–0.75) Year 2; 0.66 (0.47–0.91) 0.41 HR 0.63 HR 0.77 P 0.001 <0.0001 ns 0.04 DFS HR (95% CI) 0.52 (0.45–0.60) 0.54 (0.43–0.67) 0.42 (0.21–0.83) 0.64 0.75 <0.001 =0.01 =0.04 Interim analysis of the ALLTO trial (L, T, L+T, or TL) has reported L is inferior to T in this setting; this arm has been discontinued Romand et al, N Engl J Med. 2005;353:1673-84. Perez et al, J Clin Oncol. 2011;29:3366-73. Piccart-Gebhart et al, N Engl J Med. 2005;353:1659-72. Smith et al, Lancet. 2007;369:29-36. Joensuu et al, N Engl J Med. 2006;354:809-20. Slamon et al, N Engl J Med. 2011;365:1273-83. http://www.alttotrials.com/patients.php

1 year of adjuvant trastuzumab appears optimal: Results from PHARE and HERA 3382 patients randomized to 6 or 12 months’ adjuvant trastuzumab, median follow-up 47.2 months DFS 12 vs 6 months’ therapy: HR = 1.28 (95% CI, 1.05–1.56) HERA2 Target DFS events reached in April 2012 (725), 8 years median FU DFS: 2 vs 1 year therapy: HR = 0.99 (95% CI, 0.85–1.14) OS: 2 vs 1 year therapy: HR = 1.05 (95% CI, 0.86–1.28) 1. Pivot et al, Ann Oncol. 2012; 23(Suppl 9):ixe2#LBA5_PR. 2. Goldhirsch et al, Ann Oncol. 2012; 23(Suppl 9):ixe2#LBA6_PR.

NeoALLTO – Effect of dual HER2 blockade: Study design Lapatinib 1000 mg + trastuzumab 4 mg/kg  2 mg/kg (n=152) Lapatinib 1500 mg (n=154) HER2 + ≥2 cm R Primary endpoint: pCR Trastuzumab 4 mg/kg  2 mg/kg (n=149) (6 weeks) Paclitaxel 80 mg/m2/wk (12 weeks) Baselga et al, Lancet. 2012;379:633-40.

NeoALLTO – Effect of dual HER2 blockade: Pathologic CR pCR (%) *** ***p=0.0001 vs trastuzumab alone Baselga et al, Lancet. 2012;379:633-40.

NeoSphere – Neoadjuvant pertuzumab + trastuzumab: Study design Trastuzumab + pertuzumab + docetaxel (n=107) Trastuzumab + pertuzumab (n=107) HER2 + ≥2 cm R Primary endpoint: pCR Pertuzumab + docetaxel (n=96) Trastuzumab + docetaxel (n=107) Docetaxel 75 mg/m2 q3w Trastuzumab 8 mg/kg  6 mg/kg Pertuzumab 840 mg/kg  420 mg/kg (4 cycles) Gianni et al, Lancet Oncol. 2012;13:25-32.

NeoSphere – Neoadjuvant pertuzumab + trastuzumab: Pathologic CR pCR (%) * *p=0.0141 vs trastuzumab + docetaxel Gianni et al, Lancet Oncol. 2012;13:25-32.

APHINITY: Combined HER2 inhibition with trastuzumab + pertuzumab – Study Design Anthracycline based chemotherapy Non-anthracycline based chemotherapy A T 3.4 cycles FOLLOW UP 10 YEARS TC 6 cycles FOLLOW UP 10 YEARS Arm 1 Trastuzumab* 6 mg/kg 3-weekly Arm 1 Trastuzumab* 6 mg/kg 3-weekly SURGERY SURGERY Central confirmation of HER2 status Pertuzumab** 420 mg IV 3-weekly* Central confirmation of HER2 status Pertuzumab** 420 mg IV 3-weekly* R R A T 3.4 cycles TC 6 cycles Arm 2 Trastuzumab* 6 mg/kg 3-weekly Arm 2 Trastuzumab* 6 mg/kg 3-weekly Placebo IV 3-weekly* Placebo IV 3-weekly* Anti-HER2 therapy for a total of 1 year (52 weeks) Anti-HER2 therapy for a total of 1 year (52 weeks) Randomization within 7 weeks of surgery Start treatment within 1 week Randomization within 7 weeks of surgery Start treatment within 1 week Radiotherapy and/or endocrine therapy may be started after the end of adjuvant chemotherapy and in accordance with the protocol recommendations Radiotherapy and/or endocrine therapy may be started after the end of adjuvant chemotherapy and in accordance with the protocol recommendations KEY A 3-4 cycles of anthracycline containing chemotherapy Trastuzumab TC 6 cycles of docetaxel + capecitabine 3-4 cycles of taxane containing chemotherapy *Site personnel, patients, study management teams and sponsor will be blinded as to treatment assignment T Pertuzumab Placebo * Trastuzumab must be given at a 8mg/kg loading dose at the trastuzumab cycle ** Pertuzumab mus tbe given at a 40 mg loading dose at the first pertuzumab cycle http://www.ibcsg.org/Public/Health_Professionals/Open_Trials/IBCSG_39-11/Pages/IBCSG39-11BIG4-11_APHINITY.aspx

Summary Adjuvant trastuzumab has been demonstrated to improve DFS and OS in patients with early stage HER2 positive breast cancer 1 year therapy appears to be optimal Dual HER2 inhibition with lapatinib and trastuzumab in the neoadjuvant setting is superior to trastuzumab or lapatinib alone The combination of the dimerization inhibitor pertuzumab and trastuzumab has promising activity in the neoadjuvant setting when combined with docetaxel The APHINITY trial is addressing the role of pertuzumab in the adjuvant setting