1. PERJETA R Premio Galeno 2015 Candidatura ROCHE S.p.A.
420 mg concentrate for solution for infusion
pertuzumab R

2. Perjeta: Therapeutic indications
Metastatic Breast Cancer
Perjeta is indicated for use in combination with trastuzumab and docetaxel in adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer, who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease.
Neoadjuvant Treatment of Breast Cancer
Perjeta is indicated for use in combination with trastuzumab and chemotherapy for the neoadjuvant treatment of adult patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer at high risk of recurrence
Available in Italy from June 2014
Innovation status granted by AIFA
More than 1000 patients treated to date R

3. HER2 overexpression a negative prognostic factor in breast cancer
HER2-positive tumors and high serum HER2 levels correlate with aggressive breast tumor behaviour1
Disease recurrence
Metastasis
Shortened survival
Rapid tumor development
High nuclear grade
Ductal versus lobular status.
HER2 overexpression/HER2 gene amplification occurs in around 18–20% of breast cancers.2 R
Ross JS, Fletcher JA, Linette GP, et al. The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy. Oncologist 2003; 8(4):
Wolff AC, Hammond EH, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med 2007; 131(1):

4. Pertuzumab is the first in a new class of HER2 dimerisation inhibitors
Key HER signalling pathways that mediate cancer cell proliferation and survival are inhibited by pertuzumab blockade of HER2 dimerisation.1–4
In addition, pertuzumab can activate antibody-dependent cellular 5cytotoxicity.5
Pertuzumab
Pertuzumab is the first in a new class of HER2 dimerisation inhibitors
HER1, 3, 4
HER2
Agus DB, Akita RW, Fox WD, et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumour growth. Cancer Cell 2002; 2(2): ; 2:93–95.
Franklin MC, Carey KD, Vajdos FF, et al. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 2004; 5(4):
Scheuer W, Friess T, Burtscher H et al. Strongly enhanced antitumour activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumour models. Cancer Res 2009; 69(24):
Graphical elaboration from text data.
1. Agus DB, et al. Cancer Cell 2002; 2(2): ; 2. Hughes JB, et al. Mol Cancer Ther 2009; 8(7): ; 3. Baselga J. Cancer Cell 2002; 2(2): 93-95; 4. Franklin MC, et al. Cancer Cell 2004; 5(4): ; 5. Scheuer W, et al. Cancer Res 2009; 69(24): R

5. Pertuzumab and trastuzumab bind to different domains on HER2 and have
complementary mechanisms of action
Pertuzumab binds to subdomain II and inhibits ligand-dependent signalling.1
Trastuzumab binds to subdomain IV and inhibits ligand-independent intracellular signalling.2
The pertuzumab–trastuzumab combination offers a more comprehensive HER2 blockade3,4
The same MOA principles apply to pertuzumab–T-DM1 combination.5
Pertuzumab
HER1, 3, 4
HER2
Trastuzumab
Franklin MC, Carey KD, Vajdos FF, et al. Insights into ErbB signalling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 2004; 5(4):
Junttila TT, Akita RW, Parsons K, et al. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC Cancer Cell 2009; 15(5):
Nahta R, Hung MC, Esteva FJ. The Her-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res 2004; 64(7):
Scheuer W, Friess T, Burtscher H, et al. Strongly enhanced antitumour activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumour models. Cancer Res 2009; 69(24):
Fields CT, Crocker LM, Sliwkowski MX & Lewis Phillips GD. Dual targeting of HER2: enhanced anti-tumor efficacy of trastuzumab-DM1 combined with pertuzumab. Proc Am Assoc Cancer Res 2010; 51: abstract 5607.
Graphical elaboration from text data.
1. Franklin MC, et al. Cancer Cell 2004; 5(4): ; 2. Junttila TT, et al. Cancer Cell 2009; 15(5): ; 3. Nahta R, et al. Cancer Res 2004; 64(7): ; 4. Scheuer W, et al. Cancer Res 2009; 69(24): ; 5. Fields C, et al. AACR Abstract 5607. R

6. CLEOPATRA: Phase III trial of trastuzumab plus docetaxel with or without pertuzumab
Placebo + trastuzumab
n = 406
Docetaxel* ≥6 cycles recommended
Patients with HER2-positive MBC centrally confirmed
(N = 808)
1:1 R
Pertuzumab + trastuzumab
n = 402
Docetaxel* ≥6 cycles recommended
*<6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at investigator’s discretion
Randomisation was stratified by geographic region and prior 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
PD, progressive disease; R, randomised.
Baselga J, et al. N Engl J Med 2012; 366(2): (study protocol can be found online with the publication).
*This article is copyrighted by the Massachusetts Medical Society. All rights reserved. It is provided for your personal informational use only. R

7. CLEOPATRA: Patients lived 15
CLEOPATRA: Patients lived 15.7 months longer when treated with P + H + T vs. H + T alone in final OS analysis
Overall survival (%) 10 20 30 40 50 60 70 80 90
100
Time (months)
Δ 15.7 months
PHT: 168 events; median 56.5 months
HT: 221 events; median 40.8 months 1 28
104
226
268
318
371 23 91
179
230
289
350
n at risk
PHT HT
402
406
HR 0.68
95% CI = 0.56, 0.84 p =
Data cut-off: February 2014.
CI, confidence interval; H, trastuzumab; HR, hazard ratio; P, pertuzumab; T, docetaxel.
Adapted from Swain SM, et al. ESMO 2014 (Abstract 350O_PR). R

8. NeoSphere: Phase II study of pertuzumab in the neoadjuvant setting
Neoadjuvant treatment
q3w x 4
Adjuvant treatment
Arm A S U R G E Y
Trastuzumab + docetaxel (n = 107)
Trastuzumab + FEC
Arm B
Pertuzumab + trastuzumab + docetaxel (n = 107)
Trastuzumab + FEC R
N = 417
Arm C
Pertuzumab + trastuzumab (n = 107)
Trastuzumab + [docetaxel  FEC]
Arm D
Pertuzumab + docetaxel (n = 96)
Trastuzumab + FEC
Gianni L, et al. Lancet Oncol 2012; 13(1): (study protocol available with the publication online). R

9. NeoSphere: Pertuzumab and trastuzumab plus docetaxel significantly increased the pCR rate vs. other arms
p =
p =
p = 0.003 50 40 30 20 10 HT
PHT PH PT
Arm A
Arm B
Arm C
Arm D
45.8
pCR, %  95% CI
29.0
24.0
16.8
n = 107
n = 107
n = 107
n = 96
H, trastuzumab; P, pertuzumab; pCR, pathological complete response; T, docetaxel.
Gianni et al. Oral presentation SABCS available at - Last access October 2013; Gianni L, et al. Lancet Oncol 2012; 13(1): R

10. Doing now what patients need next
Grazie dell’attenzione!