The document discusses neoadjuvant and adjuvant therapies for HER2-positive breast cancer. It summarizes several clinical trials evaluating combinations of trastuzumab, pertuzumab, docetaxel, and other chemotherapies in the neoadjuvant and adjuvant settings. Combinations including dual HER2 blockade with trastuzumab and pertuzumab were found to significantly improve pathological complete response rates compared to other regimens. Ongoing studies continue exploring new targeted agents and combinations to further improve outcomes for patients with high-risk HER2-positive breast cancer.

1. FLASCO Spring Session
April 1, 2017
Orlando, FL
Anti-HER2 Therapies in Breast Cancer: Adjuvant and Neoadjuvant.
Michel Velez, MD
No relevant financial relationships in the past twelve months by presenter or spouse/partner
The speaker will directly disclosure the use of products for which are not labeled (e.g.,
off label use) or if the product is still investigational.

2. Neoadjuvant trials – HER2/neu +

3. T-DM1 and Pertuzumab Mechanisms of Action

4. Study Schema
TH q 3w x 4
(n = 107)
Surgery
THP q 3w x 4
(n = 107)
HP q 3w x 4
(n = 107)
TP q 3w x 4
(n = 96)
H q 3w x 13
+
FEC q 3w x 3
H q 3w x 13
+
FEC q 3w x 3
H q 3w x 17
+
FEC q 3w x 3
H q 3w x 13
+
T q3w x 4
FEC q 3w x 3
T = Docetaxel, H = Trastuzumab, P = Pertuzumab
F = 5-fluorouracil, E = Epirubicin, C = Cyclophosphamide
SurgerySurgerySurgery
R
Gianni L et al. Proc SABCS 2010;Abstract S3-2.

5. Efficacy Results by Breast
and Lymph Nodal Status
TH
(n = 107)
THP
(n = 107)
HP
(n = 107)
TP
(n = 96)
pCR in breast 29.0% 45.8% 16.8% 24.0%
pCR in breast and node negative
at surgery
21.5% 39.3% 11.2% 17.7%
pCR in breast and node positive at
surgery
7.5% 6.5% 5.6% 6.3%
The differences between the THP arm and other arms for pCR were
statistically significant, with all the p-values being <0.05.
Gianni L et al. Proc SABCS 2010;Abstract S3-2.

6. Efficacy Results by ER/PR Status
TH THP HP TP
pCR (ER- or PR-positive) 22.0% 26.0% 5.9% 17.4%
pCR (ER- and PR-negative) 36.8% 63.2% 29.1% 30.0%
Gianni L et al. Proc SABCS 2010;Abstract S3-2.

7. Safety Results
Gianni L et al. Proc SABCS 2010;Abstract S3-2.
TH
(n = 107)
THP
(n = 107)
HP
(n = 108)
TP
(n = 94)
Grade 3-4 neutropenia 57.0% 44.9% 0.9% 55.3%
Febrile neutropenia 7.5% 8.4% 0.0% 7.4%
Grade 3-4 diarrhea 3.7% 5.6% 0.0% 4.3%
Grade 3-4 rash 1.9% 1.9% 0.0% 1.1%
Grade 3-4 increased ALT 2.8% 0.0% 0.0% 1.1%
Serious adverse events 16.8% 10.3% 3.7% 17.0%
Any changes in left ventricular ejection fraction did not appear clinically meaningful and were similar among all
the four arms.

10. Tryphaena

11. ADAPT HER2+/HR-: Design

12. ADAPT HER2+/HR+: <br />Endpoints

13. ADAPT HER2+/HR-: <br />Baseline characteristics

14. ADAPT HER2+/HR+: pCR (no <br />invasive tumor in breast and nodes)

15. KRISTINE Study Design

16. Primary Endpoint: pCR (ypT0/is, ypN0)

17. pCR by Central ER/PR Receptor Status

18. Maintenance of HRQoL and Physical Function

19. I-SPY 2 TRIAL Schema:<br />Her2+ Patients

20. pCR Probability Distributions by Signature<br />

21. Slide 7

24. APHINITY: CT and Trastuzumab ±
Pertuzumab in HER2+ BC
Chemotherapy (6-8 cycles)*
Trastuzumab (1 yr)
Pertuzumab 840 mg in cycle 1, then
420 mg q3w
Chemotherapy (6-8 cycles)*
Trastuzumab (1 yr)
Placebo
Patients with resected HER2+
primary
breast cancer
(planned N = 4800)
10-yr follow-
up
Randomization within 7 wks of surgery
*Anthracycline or nonanthracycline. Radiotherapy and/or endocrine therapy may be started after completion of adjuvant chemotherapy.
ClinicalTrials.gov. NCT01358877.
Primary endpoint: invasive DFS
Secondary endpoints: invasive DFS, including second non-breast cancer, DFS, OS, RFI, distant RFI, safety, QoL

25. • Low-molecular-weight, irreversible, pan-
HER inhibitor (ErB 1,2,4
• Interferes with ligand-induced
dimerization of HER receptors
• Disrupts previously formed receptor
dimers
Mechanism of Action Of Neratinib

26. ExteNET : Final study design
Chan et al, SABCS 2015

27. 3-year iDFS analysis : Centrally confirmed HER 2+ &
According to Hormone receptor status
Chan et al, SABCS 2015

28. CLEOPATRA: Study Design
CLinical Evaluation Of Pertuzumab And TRAstuzumab study
 Randomization stratified by geographic region and previous treatment status (neo/adjuvant chemotherapy
received or not)
 Study dosing q3w:
– 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
Patients with
HER2-positive MBC
centrally confirmed
(n = 808)
Placebo + Trastuzumab
(n = 406)
1:1
(n = 402)
Docetaxel*
≥6 cycles recommended
PD
Pertuzumab + Trastuzumab
Docetaxel*
≥6 cycles recommended
PD
*<6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at
investigator discretion.
Baselga J, et al. N Engl J Med. 2012;366:109-119

29. Cleopatra OS
Swain , SM et al. ESMO 2014

30. Cleopatra PFS

31. Select Adverse Events (Grade ≥ 3), % Pertuzumab
(n = 407)
Placebo
(n = 397)
Neutropenia 48.9 45.8
Febrile neutropenia 13.8 7.6
Leukopenia 12.3 14.6
Diarrhea 7.9 5.0
Peripheral neuropathy 2.7 1.8
Left ventricular systolic dysfunction 1.2 2.8
Baselga J, et al. N Engl J Med. 2012;366:109-119.
Trastuzumab and Docetaxel ± Pertuzumab in HER2+ MBC
(CLEOPATRA): Safety

32. Conclusions
• Neoadjuvant systemic therapy in Her2neu positive Breast Cancer is a safe
and effective strategy with various regimens available including dual
Her2neu blockade
• PCR improves outcomes especially in adverse breast cancer histology such
as Her2neu positive disease
• TDM-1 with Pertuzumab is not indicated for the treatment of Her2neu
positive breast cancer in the neoadjuvant setting but provides an attractive
strategy where tolerance may be an issue
• New therapies continue to emerge in an aim to continue to improve
outcomes in patients with high risk Her2nue positive breast cancer
(Residual disease after neoadjuvant therapy)
• First line treatment of Her2neu positive must include
Trastuzumab/Pertuzumab/Taxane combination unless tolerance is an issue.
• Trastuzumab and Pertuzumab can be safely continued until PD