1. Management of HER2 Over-Expressed Breast Cancer in the Adjuvant, Neoadjuvant, and Metastatic settings
Christy A Russell, MD
Keck School of Medicine
University of Southern California

2. Metastatic Breast Cancer

3. Chemotherapy Plus Trastuzumab in Metastatic Disease
Slamon et al
n = 469
Marty et al
n = 186
Treatment Arms
AC or T* vs
AC or T→H†
Docetaxel
Docetaxel →H†
Time to Disease Progression (mos)
4.6
7.4
P value
6.1
11.7
< 0.001
0.0001
Response Rate
32%
50%
34%
61%
0.0002
Median Overall Survival (mos) 20 25
0.046 23 31
0.0325
*T = paclitaxel; †H = trastuzumab.
Hudis CA. N Engl J Med. 2007;357:36-51; Slamon DJ, et al. N Engl J Med. 2001;344: ; Marty M, et al. J Clin Oncol. 2005;23:

4. Anti-HER2 Targeted Therapy: Pertuzumab

5. Pertuzumab-HER2 Complex Trastuzumab-HER2 Complex
Pertuzumab and Trastuzumab Bind to Distinct Extracellular HER2 Epitopes
Pertuzumab-HER2 Complex
Trastuzumab-HER2 Complex
Pertuzumab
Dimerization domain I I II II
III
III
Trastuzumab IV IV
ADCC, antibody-dependent cell-mediated cytotoxicity.
Like trastuzumab, pertuzumab was among the first-line anti-HER2 antibodies tested preclinically in vitro and in vivo that showed that antibodies against the HER2 extracellular domain could growth-inhibit these tumors preclinically. Although they are both HER2-targeting agents, pertuzumab and trastuzumab have some distinct differences, listed here. The most important difference is that pertuzumab binds to a different epitope in the HER2 extracellular domain that inhibits the HER2 dimerization with other HER family receptors. In particular, pertuzumab more strongly inhibits the most effective signaling dimerization partner complex, HER2 plus HER3.
Inhibits HER2 dimerization with other HER family receptors (particularly HER3)
Activates ADCC
Inhibits multiple HER-mediated signaling pathways
Activates ADCC
Inhibits HER-mediated signaling pathways
Prevents HER2 domain cleavage
Hubbard SR. Cancer Cell. 2005;7:

6. Trastuzumab and Pertuzumab Bind to Different Regions on HER2 and May Have Synergistic Activity
Subdomain IV of HER2
Dimerization domain of HER2
Trastuzumab does not inhibit HER2 dimerization, thus blocking HER2:HER3
Trastuzumab prevents HER2 receptor shedding
Trastuzumab blocks HER2 signaling and flags cells for destruction by the immune system
Pertuzumab inhibits HER2 from forming dimer pairs
Flags cells for destruction by the immune system
Pertuzumab does not prevent HER2 receptor shedding 6

7. CLEOPATRA Study Design
Docetaxel (≥ 6 cycles recommended)
Centrally confirmed HER2-positive locally recurrent, unresectable or MBC
≤ 1 hormonal regimen for MBC
Prior (neo)adjuvant systemic Rx, including trastuzumab and/or taxane allowed if followed by DFS ≥ 12 mos
Baseline LVEF ≥ 50%; no CHF or LVEF < 50% during or after previous trastuzumab
N = 406
Trastuzumab
Placebo R
1:1
Docetaxel (≥ 6 cycles recommended)
Trastuzumab
N = 402
Pertuzumab
Primary endpoint: Independently assessed PFS
Baselga J, et al. N Engl J Med. 2012;366:

8. CLEOPATRA: PFS Assessed at an IRF
100
Pertuzumab (median: 18.5 mos) Control (median: 12.4 mos) 90 80 70 60
PFS (%) 50 40
HR: 0.62 (95% CI: ; P < .001) 30 20 10 5 10 15 20 25 30 35 40
Mos
Pts at Risk, n Pertuzumab Control
139 93
83 42
32 17
10 7
0 0
0 0
Baselga J, et al. N Engl J Med. 2012;366:

9. Adding Pertuzumab to Trastuzumab and Chemotherapy

10. Trastuzumab + Docetaxel + Pertuzumab Trastuzumab + Docetaxel + Placebo
CLEOPATRA: Safety
Adverse Events, %
Trastuzumab + Docetaxel + Pertuzumab
(n = 407)
Trastuzumab + Docetaxel + Placebo
(n = 397)
All Grades
Grade 3/4
Diarrhea
66.8
7.9
46.3
5.0
Alopecia
60.9 NR
60.5
Neutropenia
52.8
48.9
49.6
45.8
Nausea
42.3
41.6
Fatigue
37.6
2.2
36.8
3.3
Rash
33.7
24.2
Decreased appetite
29.2
26.4
Mucosal inflammation
27.8
19.9
Asthenia
26.0
2.5
30.2
1.5
Peripheral edema
23.1
30.0
Constipation
15.0
24.9
Febrile neutropenia
13.8
7.6
Dry skin
10.6
4.3
Leukopenia
12.3
14.6
Baselga J, et al. N Engl J Med. 2012;366:

11. NCCN: First-line Treatment of HER2+ MBC With No Previous Trastuzumab Exposure
Preferred regimens
Docetaxel + trastuzumab + pertuzumab (category 1)
Paclitaxel + trastuzumab + pertuzumab
Other regimens
Trastuzumab with:
Paclitaxel ± carboplatin
Docetaxel
Vinorelbine
Capecitabine
NCCN. Clinical practice guidelines in oncology: breast cancer. V

12. NCCN: Treatment of HER2+ MBC Beyond First Line With Previous Trastuzumab Exposure
Preferred agents
Ado-trastuzumab emtansine (T-DM1)
Other agents
Lapatinib + capecitabine
Trastuzumab + capecitabine
Trastuzumab + lapatinib (without cytotoxic therapy)
Trastuzumab + other agents
NCCN. Clinical practice guidelines in oncology: breast cancer. V

13. Second-line and Further Therapy TDM-1

14. Trastuzumab/Emtansine: Novel Antibody–Drug Conjugate
Monoclonal antibody: trastuzumab
Target expression: HER2
Trastuzumab
Highly potent cytotoxic agent
Cytotoxic agent: emtansine (DM1)
MCC
DM1
Systemically stable
Linker: SMCC
T-DM1 Average drug:antibody ratio ≅ 3.5:1

15. EMILIA Phase III Study: T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC
Stratified by world region, number of previous chemotherapy regimens for MBC or unresectable locally advanced breast cancer, presence of visceral disease
T-DM1 3.6 mg/kg by IV every 3 wks (n = 495)
Patients with HER2-positive locally advanced or MBC* (N = 980) PD
Capecitabine 1000 mg/m2 orally twice daily on Days 1-14, every 3 wks + Lapatinib 1250 mg/day orally continuously (n = 496)
*All pts received previous
taxane and trastuzumab
Primary endpoint: PFS by IRF, OS, safety
Secondary endpoints: QoL (FACT B), DOR, PFS by investigator assessment
Verma S, et al. NEJM 2012;367:

16. T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC (EMILIA): PFS
Median, Mos
Events, n
1.0
Capecitabine/lapatinib T-DM1
304
265
0.8
Stratified HR: (95% CI: ; P < .0001)
0.6
Proportion Progression Free
0.4
T-DM1
Capecitabine/ lapatinib
0.2 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Mos
Verma S, et al. NEJM 2012;367:

17. OS: Second Interim Analysis
Median No. of Mos
No. of Events
100
85.2% (95% CI: )
Lapatinib-capecitabine T-DM1
Stratified HR: 0.68 (95% CI: ; P < .001) 80
64.7% (95% CI: )
Efficacy stopping boundary P = or HR: 0.73 60
78.4% (95% CI: )
T-DM1
OS (%) 40
51.8% (95% CI: )
Lapatinib-capecitabine 20 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Pts at Risk, n Lapatinib- capecitabine T-DM1
Mos
63 86
45 62
27 38
17 28
7 13
4 5
Data cutoff July 31, 2012; median follow-up: 18.6 mos.
Verma S, et al. N Engl J Med. 2012;367:

18. T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC (EMILIA): Adverse Events
Capecitabine + Lapatinib
(n = 488)
All Grades
Grades ≥ 3
Nonhematologic
Diarrhea
23.3
1.6
79.7
20.7
Hand-foot syndrome
1.2
58.0
16.4
Vomiting
19.0
0.8
29.3
4.5
Hypokalemia
8.6
2.2
4.1
Fatigue
35.1
2.4
27.9
3.5
Nausea
39.2
44.7
2.5
Mucosal inflammation
6.7
0.2
19.1
2.3
Increased AST
22.4
4.3
9.4
Increased ALT
16.9
2.9
8.8
1.4
Hematologic
Neutropenia
5.9
2.0
Febrile neutropenia
1.0
Anemia
10.4
2.7
8.0
Thrombocytopenia
28.0
12.8
Verma S, et al. NEJM 2012;367:

19. Ongoing Clinical Trials for Metastatic Breast Cancer

20. Phase III MARIANNE Study: T-DM1 ± Pertuzumab in HER2+ MBCPD
Trastuzumab + Taxane
(n = 364)
Patients with HER2+, previously untreated MBC
(N = 1092)
T-DM1 + Pertuzumab
(n = 364)
T-DM1 + Placebo
(n = 364)
Primary endpoints: PFS as assessed by IRF, AEs
Superiority design with a noninferiority analyses
Interim futility analysis: option to drop experimental arm
Secondary endpoints: OS, TTF by IRF, ORR, CBR, DOR
ClinicalTrials.gov. NCT 20

21. Phase III Trial of Everolimus in Combination With Trastuzumab and Paclitaxel as Frontline Therapy for HER2+ MBC (BOLERO-1)
RANDOMIZATION
HER+ MBC
No prior anthracycline/taxane-based chemotherapy in the metastatic setting
(N = 719)
Everolim us 10 mg PO +
Paclitaxel 80 mg/m2 qwk d 1, 8, 15
+ Trastuzu mab 2 mg/kg d 1, 8, 15, 22
Placebo +
Primary Endpoint: PFS
Available at:

22. Other Trials With Completed or Ongoing Accrual in MBC
T-DM1 vs investigator’s choice (TH3RESA)
Addition of pertuzumab to vinorelbine and trastuzumab (VELVET)

23. Neoadjuvant Therapy

24. Trastuzumab + Lapatinib Trials

25. pCR Rates (breast and LN) with Trastuzumab (H) and/or Lapatinib (L)
Study/Neoadjuvant Regimen
Total pCR
Trastuzumab
Lapatinib
H + L
NeoALTTO1
(6 week H and/or L (WP) x 12 plus H and/or L)
N=455
27.6%
20.0%
46.8%
NSABP B-412
(AC x 4  WP x 12 plus H and/or L)
N=519
49.4%
47.4%
60.2%
CALGB
(WP x 16 plus H and/or L)
N=299
43%
29%
52%
CHER-LOB4
(WP x 12  FEC x 4 plus H and or L throughout
N=121
25%
26.3%
46.7%
WP=weekly paclitaxel; AC=doxorubicin/cyclophosphamide; FEC=5-FU, epirubicin, cyclophosphamide
Baselga J, et al. Lancet 2012;18: Robidoux, et al Lancet Oncol; pub online Oct 4, 2013
3. Carey, et al. ASCO 2013, abst Guarneri, et al. JCO 2012;31.

32. CALGB Schema
Carey L, et al ASCO 2013 Abstr # 500

33. Breast pCR Rate by HR Status
HR+ (N=173) HR- (N=123)
Carey L, et al ASCO 2013 Abstr # 500

34. pCR Rate by Arm and Subtype
Basal-like
(N=11)
HER2-E
(N=52)
Lum-A
(N=51)
Lum-B
(N=35)
Carey L, et al ASCO 2013 Abstr # 500

35. Neoadjuvant Trastuzumab + Pertuzumab Trials

36. NeoSphere: study design
TH (n=107) docetaxel + trastuzumab S U R G E Y
FEC q3w x 3
trastuzumab q3w cycles 5–17
trastuzumab q3w cycles 5–21
Patients with operable or locally advanced /inflammatory* HER2-positive BC
Chemo-naïve & primary tumors >2cm (N=417)
THP (n=107) docetaxel + trastuzumab + pertuzumab
HP (n=107) trastuzumab + pertuzumab
docetaxel q3w x 4→FEC q3w x 3
trastuzumab q3w cycles 5–17
TP (n=96) docetaxel + pertuzumab
Study dosing: q3w x 4
BC, breast cancer; FEC, 5-fluorouracil, epirubicin and cyclophosphamide *Locally advanced=T2–3, N2–3, M0 or T4a–c, any N, M0; operable=T2–3, N0–1, M0; inflammatory = T4d, any N, M0 H, trastuzumab; P, pertuzumab; T, docetaxel 3

37. NeoSphere pCR rates: ITT population summary50
p = 0.003 40
pCR, %  95% CI
45.8 30 20
29.0
24.0 10
16.8
H, trastuzumab; P, pertuzumab; T, docetaxel TH
THP HP TP

38. NeoSphere: pCR and Hormone Receptors Status
Gianni L, et al. Cancer Res. 2010;70 (24 Suppl): Abstract [S3-2].

39. NeoSphere Trial: pCR in Breast and Nodes
HR+
HR- n
%pCR
Trastuzumab + docetaxel 50
12% 57
29.8%
Trastuzumab + docetaxel + pertuzumab
22%
54.4%
Trastuzumab + pertuzumab 51 2% 55
20%
Docetaxel + pertuzumab 46
8.7%
26%

40. TRYPHAENA Study: TCH + pertuzumab
225 patients with locally advanced, operable, or inflammatory breast cancer (T2-T4d)
Trial was designed to assess cardiac safety
Schneeweiss, et al. Ann Oncol 2013;24

41. TRYPHAENA pCR Neoadjuvant Regimen HR+ HR- %pCR TCH + Pertuzumab (76)
47.5%
81.1%
FEC (75)
P + T + Docetaxel
45.7%
62.5%
Pertuzumab + Trastuzumab
41.0%
73.5%
FEC (72)
Docetaxel
Schneeweiss, et al. Ann Oncol 2013;24

42. FDA Approval in Neoadjuvant Setting
Pertuzumab is indicated for use in combination with trastuzumab and docetaxel for the neoadjuvant treatment of patients with HER2+, locally advanced, inflammatory, or early stage breast cancer (either >2 cm or node positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pCR rate. No data are available demonstrating improvement in EFS or OS.
Limitations of Use:
The safety of pertuzumab as part of a doxorubicin-containing regimen has not been established.
The safety of pertuzumab administered for > 6 cycles for early breast cancer has not been established.

43. Adjuvant HER-2 Targeted Therapy

44. NCCTG N9831 Trial Incorporating Trastuzumab in Adjuvant Therapy
Group A AC T R A N D O M I Z E
Group B
HER2 positive (FISH+ or IHC 3+) AC T H
Group C
n=3,505 AC T H
= AC (doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4)
= T (paclitaxel 80 mg/m2/wk × 12)
= H (trastuzumab 4 mg/kg loading dose + 2 mg/kg/wk × 51)

45. NSABP B-31 Trial Incorporating Trastuzumab in Adjuvant Therapy
Group 1 AC T R A N D O M I Z E
Node positive
HER2 positive (FISH+ or IHC 3+)
Group 2
N=2,006 AC T H
= AC (doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4)
= T (paclitaxel 175 mg/m2 q3w × 4 or 80 mg/m2/wk × 12)
= H (trastuzumab 4 mg/kg loading dose + 2 mg/kg/wk × 51)

46. Joint Analysis of HER2+ Adjuvant Trials 2 Arms of N9831 + B-31
Control Group (n=1,979): AC  T AC T
N9831 Group A AC T
B-31 Group 1
Trastuzumab Group (n=1,989): AC  T+H AC T
N9831 Group C H AC T
B-31 Group 2 H
= AC (doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4)
= T (paclitaxel 80 mg/m2/wk × 12)
= T (paclitaxel 175 mg/m2 q3w × 4 or 80 mg/m2/wk × 12)
= H (trastuzumab 4 mg/kg loading dose + 2 mg/kg/wk × 51)

47. Kaplan-Meier estimates of (A) event-free survival and (B) overall survival.
HR 0.52
P < .001
HR 0.61
Perez E A et al. JCO 2011;29:
©2011 by American Society of Clinical Oncology

48. Events Per Year From Randomization
Perez E A et al. JCO 2011;29:
©2011 by American Society of Clinical Oncology

49. Breast Cancer International Research Group (BCIRG) 006 Trial: Treatment SchemaD O M I Z E
AC T (n=1073)
SURGERY
HER2-positive tumor (FISH+);
node-positive or high-risk node-negative disease
AC TH (n=1074)
52 weeks
TCH (n=1075)
52 weeks
Endpoints
1°: Disease-free survival (DFS)
2°: Overall survival, toxicity, pathologic and molecular markers
= H = Trastuzumab 4 mg/kg loading dose
= H = Trastuzumab 2 mg/kg qw
= H = Trastuzumab 6 mg/kg q3w
= AC = doxorubicin/cyclophosphamide 60/600 mg/m2 q3w
= T = docetaxel 100 mg/m2 q3w
= TC = docetaxel 75 mg/m2/carboplatin target AUC 6 mg/mL· min
Radiation therapy and/or hormonal therapy may be given after completion of chemotherapy if indicated
Slamon et al. NEJM 2011;365.
Herceptin® (trastuzumab) PI. March 2009.

50. Disease-Free Survival Among all Study Patients
DFS
AC-TH vs AC-T
HR .64 p<0.001
TCH vs AC-T
HR .75 p=0.04 OS
AC-TH vs AC-T
HR .63 p<0.001
TCH vs AC-T
HR .77 p=0.04

51. Overall Survival
Overall Survival

52. Trials to be Reported

53. ALTTO Trial Design
Trastuzumab 8 mg/kg IV (loading dose)*  6 mg/kg every 3 wks for 1 yr 
Paclitaxel 80 mg/m2 IV once wkly x 12
Women with centrally determined HER2-positive
invasive breast cancer
(N = 8381 accrued)
Surgery, adjuvant anthracycline-based therapy for 4 cycles;
LVEF ≥ 50
6-week wash-out
Trastuzumab 4 mg/kg IV (loading dose)  2 mg/kg once wkly x 11 
Paclitaxel 80 mg/m2 IV once wkly x 12
Lapatinib
1500 mg orally once daily x 34 wks
Lapatinib 1500 mg/kg orally once daily x 51 wks 
Paclitaxel 80 mg/m2 IV once wkly x 12
(This arm closed in 9/2011 due to inferiority)
*For concomitant dosing with paclitaxel, trastuzumab will be given on a weekly schedule (4 mg/kg IV loading dose followed by 2 mg/kg IV weekly). Trastuzumab will revert to the 3-weekly schedule (6 mg/kg without loading dose).
Trastuzumab 8 mg/kg (loading dose)  6 mg/kg every 3 wks for 1 yr
Lapatinib 1000 mg orally once daily x 51 wks 
Paclitaxel 80 mg/m2 IV once wkly x 12

54. APHINITY Chemotherapy + trastuzumab and pertuzumab
S U R G E R Y R A N D O M I Z T F O L W U P 10 Y R S
Chemotherapy + trastuzumab and pertuzumab
Anthracycline or non-anthracycline–based chemotherapy allowed
N = 3806
N = 3806
Central confirmation
of HER2 status
Chemotherapy + trastuzumab and placebo
Anthracycline or non-anthracycline–based chemotherapy allowed
Randomization within 7 wks of surgery
Start treatment within 1 wk
Anti-HER2 therapy for a total of 1 yr (52 wks)
Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy
ClinicalTrials.gov Identifier: NCT

55. Conclusions
Trastuzumab in addition to chemotherapy remains the standard for all “high-risk” HER-2+ early breast cancer.
Controversies exist regarding the following:
Use of anthracyclines
Definition of “high-risk”
Role of additional biologic agents to trastuzumab

56. “Low-Risk” HER2+ Breast Cancer

57. Background
The three randomized adjuvant trials of HER2+ early breast cancer included limited patients with stage I disease, and virtually no patients with tumors < 1 cm.
Many patients with stage I, HER2+ EBC will have a sufficiently high risk of recurrence to justify administration of adjuvant therapy, but they will likely derive a smaller absolute benefit.
The development of regimens with lower degrees of toxicity is important for this population.
Tolaney SM, et al. Cancer Res 2013;73:Abst S1-04.

58. [TITLE]
Presented By Ines Maria Vaz Duarte Luis, MD at 2013 ASCO Annual Meeting

59. [TITLE]
Presented By Ines Maria Vaz Duarte Luis, MD at 2013 ASCO Annual Meeting

60. Treatment of T1a/b N0 Tumors: NCCN
Luis IV, et al ASCO 2013 Abstr # 1006

61. [TITLE]
Presented By Ines Maria Vaz Duarte Luis, MD at 2013 ASCO Annual Meeting

62. APT Trial
Tolaney SM, et. Cancer Res 2013;73:Abst S1-04.

68. Conclusions
Metastatic breast cancer: The landscape of drug choices has changed with the addition of pertuzumab in the front-line and TDM-1 in the second-line.
Neoadjuvant therapy: The landscape has changed with the approval of pertuzumab in the neoadjuvant setting.
Adjuvant therapy:
We await adjuvant trial data on anti-HER2 doublets
Identify “low-risk” patients for alternative trastuzumab + chemotherapy regimens.