1. 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

2. 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:
Perez et al, J Clin Oncol. 2011;29:
Piccart-Gebhart et al, N Engl J Med. 2005;353:
Smith et al, Lancet. 2007;369:29-36.
Joensuu et al, N Engl J Med. 2006;354:
Slamon et al, N Engl J Med. 2011;365:

3. 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.

4. NeoALLTO – Effect of dual HER2 blockade: Study design
Lapatinib 1000 mg + trastuzumab 4 mg/kg  2 mg/kg (n=152)
Lapatinib 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:

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

6. 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.

7. NeoSphere – Neoadjuvant pertuzumab + trastuzumab: Pathologic CR
pCR (%) *
*p= vs trastuzumab + 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 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

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