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Harold Burstein, MD Assistant Professor of Medicine Dana-Farber Cancer Institute Boston , MA

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.

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Harold Burstein, MD Assistant Professor of Medicine Dana-Farber Cancer Institute Boston , MA

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  1. 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

  2. Studies of adjuvant trastuzumab therapy: Summary • 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 ClinOncol. 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

  3. 1 year of adjuvant trastuzumab appears optimal: Results from PHARE and HERA • PHARE1 • 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. Goldhirschet al, Ann Oncol. 2012; 23(Suppl9):ixe2#LBA6_PR.

  4. NeoALLTO– Effect of dual HER2 blockade: Study design Lapatinib 1000 mg + trastuzumab4 mg/kg  2 mg/kg(n=152) Lapatinib1500 mg (n=154) HER2 + ≥2 cm Primary endpoint:pCR R 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.

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

  6. NeoSphere – Neoadjuvant pertuzumab + trastuzumab: Study design Trastuzumab + pertuzumab + docetaxel(n=107) Trastuzumab + pertuzumab (n=107) Primary endpoint:pCR HER2 + ≥2 cm R 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.

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

  8. APHINITY: Combined HER2 inhibition with trastuzumab + pertuzumab – Study Design Anthracycline based chemotherapy Non-anthracycline based chemotherapy 6 cycles 6 cycles FOLLOW UP 10 YEARS FOLLOW UP 10 YEARS A A T T 3.4 cycles 3.4 cycles 3.4 cycles 3.4 cycles TC TC Arm 1 Arm 1 Trastuzumab* 6 mg/kg 3-weekly Trastuzumab* 6 mg/kg 3-weekly SURGERY SURGERY • Pertuzumab** 420 mg IV 3-weekly* Pertuzumab** 420 mg IV 3-weekly* Central confirmation of HER2 status Central confirmation of HER2 status R R Arm 2 Arm 2 Trastuzumab* 6 mg/kg 3-weekly 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 3-4 cycles of anthracycline containing chemotherapy 6 cycles of docetaxel + capecitabine KEY Trastuzumab A TC *Site personnel, patients, study management teams and sponsor will be blinded as to treatment assignment 3-4 cycles of taxane containing chemotherapy Pertuzumab Placebo T * Trastuzumab must be given at a 8mg/kg loading dose at the trastuzumab cycle** Pertuzumabmustbe 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

  9. 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

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