1. Metastatic HER2-Positive Breast Cancer: Treatment Selection and Sequencing in the First Line and Beyond
Moderator:
Joseph Gligorov, MD, PhD
Head, Cancer Coordination Center HUEP
University Cancer Institute
Sorbonne University
Paris, France
Panelist:
Carlos H. Barrios, MD
Professor of Internal Medicine;
Director, Oncology Research Unit
Pontifícia Universidade Católica
Porto Alegre, Brazil
Panelist:
Javier Cortés, MD, PhD
Head, Breast Cancer Program
Department of Oncology
Vall d'Hebron University Hospital Barcelona, Spain
David W. Miles, MD
Consultant Medical Oncologist
Mount Vernon Cancer Centre
London, United Kingdom

2. This Program Will Review:
Recent clinical trial data on the management of HER2+ advanced and MBC
Challenges of integrating HER2-targeting agents into clinical practice
Selecting a first-line treatment
Sequencing treatments in second line and beyond
Knowing how to proceed when evidence is unclear
Balancing treatment efficacy with patient quality of life
HER2 = human epidermal growth factor 2; MBC = metastatic breast cancer

3. Historical Context: Targeting HER2
First demonstration of clinical benefit with HER2 targeting: the addition of trastuzumab to chemotherapy*
Chemotherapy + Trastuzumab
(n=236)
Chemotherapy Alone (n=234)
P value
Median time to disease progression
7.4 months
4.6 months
HR=0.51
P<.001
Median TTF
6.9 months
4.5 months
HR=0.58
Median OS
25.1 months
20.3 months
HR=0.80
P=.046
*Either anthracycline + cyclophosphamide or paclitaxel
HR = hazard ratio; OS = overall survival; TTF= time to treatment failure
Slamon DJ, et al. N Engl J Med. 2001;344(11):

4. Historical Context: Targeting HER2 (cont)
Paclitaxel + Trastuzumab
(n=92)
Paclitaxel Alone (n=96)
P value
Median time to disease progression
6.9 months
3.0 months
HR=0.38
P<.001
Median TTF
5.8 months
2.9 months
HR=0.46
Median OS
22.1 months
18.4 months
HR=0.80
P=.17
Slamon DJ, et al. N Engl J Med. 2001;344(11):

5. Trastuzumab binds to subdomain IV and inhibits downstream signalling
Pertuzumab and Trastuzumab: Mechanisms of Action
Pertuzumab binds to a specific domain II and inhibits ligand-activated dimerization
Trastuzumab binds to subdomain IV and inhibits downstream signalling
HER2
HER1-4
Cell membrane
The combined regimen of pertuzumab and trastuzumab offers the potential for a more comprehensive HER blockade
Franklin MC, et al. Cancer Cell. 2004;5(4): 5

6. Phase 2 Study: Pertuzumab + Trastuzumab in Patients Progressing on Trastuzumab
Pertuzumab + Trastuzumab[a]
(n=66)
Pertuzumab Alone[c] (n=29)
Pertuzumab  Pertuzumab + Trastuzumab[c]
(n=17)
Objective response rate
24.2%
3.4%
17.6%
Clinical benefit rate*
50%
10.3%
41.2%
*Defined as complete response, partial response, and stable disease ≥ 6 months
a. Baselga J, et al. J Clin Oncol. 2010;28(7):
b. Cortes J, et al. J Clin Oncol. 2012;30(14):

7. CLEOPATRA: Trastuzumab + Docetaxel + Pertuzumab or Placebo
RANDOMIZE
Trastuzumab + pertuzumab until progressive disease
808 patients with centrally confirmed HER2+ MBC
≥ 6 cycles of docetaxel recommended
1:1
Trastuzumab + placebo until progressive disease
≥ 6 cycles of docetaxel recommended
Study dosing every 3 weeks
Pertuzumab/Placebo: 840 mg loading dose, 420 mg maintenance
Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance
Docetaxel: 75 mg/m2, escalating to 100 mg/m2 if tolerated
Baselga J, et al. N Engl J Med. 2012;366(2):

8. CLEOPATRA: Updated Survival Results
Pertuzumab + Trastuzumab + Docetaxel
(n=402)
Placebo + Trastuzumab + Docetaxel
(n=406)
P value
Median PFS
18.7 months
12.4 months
HR=0.68
P<.0001
Improvement: 6.3 months
Median OS
56.5 months
40.8 months
P<.0002
Improvement: 15.7 months
PFS = progression-free survival
Swain SJ, et al. ESMO Abstract 350O_PR.

9. CLEOPATRA: Adverse Events
Pertuzumab + Trastuzumab + Docetaxel
(n=408)
Placebo + Trastuzumab + Docetaxel
(n=396)
Grade 3/4 hematologic AEs
Leukopenia
12.3%
14.9%
Neutropenia
49.0%
46.2%
Febrile neutropenia
13.7%
7.6%
Diarrhea (grade 3/4)
9.3%
5.1%
LVEF decline to < 50% and by ≥ 10% points from baseline
6.1%
7.4%
AE = adverse event; LVEF = left ventricular ejection fraction
Swain SJ, et al. ESMO Abstract 350O_PR.

10. PERUSE: Pertuzumab + Trastuzumab + Investigator’s Choice of Taxane
Select Grade 3/4 AEs (Initial Results)
Bachelot T, et al. ASCO Abstract 548.

11. VELVET: Pertuzumab + Trastuzumab + Vinorelbine Selected AEs (Interim Analysis)
VELVET[a]
HERNATA[b]
Diarrhea
49.1%
11.6%
Alopecia
23.6% NR
Neutropenia (grade 3/4)
41.5%
Febrile neutropenia
5.7%
10.8%
Leukopenia (grade 3/4)
8.5% 21
a. Perez E, et al. SABCS Abstract P
b. Andersson M, et al. J Clin Oncol. 2011;29(3):

12. MARIANNE: T-DM1 + Pertuzumab or Placebo vs Trastuzumab + Taxane
Arm A
RANDOMIZE
Trastuzumab + taxane until progressive disease
1092 patients with HER2+ MBC
Arm B
1:1:1
T-DM1 + pertuzumab until progressive disease
Arm C
T-DM1 + placebo until progressive disease
Primary endpoint: PFS (independent assessment)
T-DM1 = trastuzumab emtansine
Ellis PA, et al. ASCO Abstract TPS102.

13. First-Line Treatment: Applying Trial Data to Clinical Practice
Patients on HER2-blocking regimens have better outcomes than ever before
Dual blockade with trastuzumab + pertuzumab is the standard of care -- maximal blockade of HER2 is clearly critical
Choice of chemotherapy may not be as important for treatment outcomes; choice of chemotherapy arm is important to minimize side effects
More research will help determine whether some populations might do well with dual HER2 blockade only, without chemotherapy

14. The Benefits of Continued HER2 Blockade Beyond Progression
Trastuzumab + Capecitabine vs Capecitabine[a]
Lapatinib + Capecitabine vs
Capecitabine[b,c]
Median TTP
8.2 vs 5.6 months
HR=0.69; P=.0338
6.2 vs 4.3 months
HR=0.57; P<.001
Median OS
25.5 vs 20.4 months
HR=0.76; P=.257
75.0 vs 64.7 weeks
HR=0.87; P=.206
TTP = time to progression
a. Von Minckwitz G, et al. J Clin Oncol. 2009;27(12):
b. Cameron D, et al. Breast Cancer Res Treat. 2008;112(3):
c. Cameron D, et al. Oncologist. 2010;15(9):

15. T-DM1: Antibody Drug Conjugate
HER2
HER2
Cell membrane
Intracellular emtansine release  inhibition of microtubule polymerization
LoRusso PM, et al. Clin Cancer Res. 2011;17(20): 15

16. EMILIA: T-DM1 vs Lapatinib + Capecitabine
991 patients previously treated with trastuzumab and a taxane
T-DM1
Lapatinib + Capecitabine
P value
Median PFS
9.4 months
6.4 month
HR=.65
P<.0001
Median OS
30.9 months
25.1 months
HR=.682
P=.0006
12-month survival rate
85.2%
78.4%
24-month survival rate
64.7%
51.8%
Verma S, et al. N Engl J Med. 2012;367(19):

17. EGF104900: Trastuzumab + Lapatinib
296 patients previously treated with trastuzumab and a taxane randomly assigned (1:1) to lapatinib ± trastuzumab
Lapatinib
Lapatinib + Trastuzumab
P value
Median PFS
8.1 weeks
11.1 weeks
HR=0.74
P=.011
Median OS
9.5 months
14.0 months
P=.026
12-month survival rate
80%
56%
24-month survival rate
70%
41%
Blackwell K, et al. J Clin Oncol. 2012;30(21):

18. BOLERO-3: Trastuzumab + the mTOR Inhibitor Everolimus
PI3K/Akt/mTOR pathway is upregulated in trastuzumab resistant HER2+ MBC
Everolimus is an mTORC1 inhibitor that downregulates activity of the pathway
Design
569 patients previously treated with trastuzumab + taxane
Treated with trastuzumab + vinorelbine + everolimus or placebo
Outcomes
PFS: vs 5.78 months; HR=0.78; P=.0067
ORR: 41% vs 37%; P=.2108
ORR = overall response rate
Andre F, et al. Lancet Oncol. 2014;15(6):

19. TH3RESA: T-DM1 in Heavily Pretreated MBC
600 patients previously treated with ≥ 2 prior therapies (trastuzumab, lapatinib, taxane) randomly assigned (2:1) to T-DM1 or treatment of physician’s choice*
T-DM1
Physician’s choice
P value
ORR
31.3%
8.6%
P<.0001
Median PFS
6.2 months
3.3 months
HR=0.528
Median OS (interim analysis) NE
14.9 months
HR=0.552
P=.0034
*Single-agent chemotherapy, hormonal therapy, or HER2-directed therapy, or a combination of a HER2-directed therapy with a chemotherapy, hormonal therapy, or other HER2-directed therapy.
NE = not estimable
Krop IE, et al. Lancet Oncol ;15(7):

20. Second-Line and Beyond: Applying Trial Data to Clinical Practice
Continued blockade of HER2 is clearly beneficial
T-DM1 is the standard of care for second-line treatment; there are no patient populations not likely to benefit
More research is needed to define the optimal treatment regimen in different patient populations
Role for pertuzumab if not given in the first line
Sequence of treatments beyond first line
Using toxicity to drive treatment selection

21. Conclusions
Multiple available treatments significantly prolong OS in patients with HER2+ MBC
Standard of care at all stages: continued HER2+ blockade
First-line: trastuzumab + pertuzumab (CLEOPATRA)
Second-line: T-DM1 (EMILIA)
Ongoing research will help define the best use of each agent in each line of therapy
With appropriate use of these drugs, HER2+ MBC is beginning to turn into a chronic disease with very good quality of life

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