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Published in: Drugs 3/2012

01-02-2012 | Adis Drug Profile

Pertuzumab

In the First-Line Treatment of HER2-Positive Metastatic Breast Cancer

Author: Gillian M. Keating

Published in: Drugs | Issue 3/2012

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Abstract

The humanized monoclonal antibody pertuzumab is the first in a new class of drugs, the human epidermal growth factor receptor (HER) dimerization inhibitors. Given that pertuzumab binds to a different epitope of the HER2 extracellular domain than trastuzumab, combination therapy with pertuzumab plus trastuzumab may result in more comprehensive blockade of HER2 signalling than can be achieved with trastuzumab alone.
The efficacy of adding pertuzumab to trastuzumab plus docetaxel for the first-line treatment of HER2-positive metastatic breast cancer was demonstrated in the randomized, double-blind, multinational, phase III CLEOPATRA trial. Both independently assessed progression-free survival (primary endpoint) and investigator-assessed progression-free survival were significantly improved in patients receiving pertuzumab plus trastuzumab and docetaxel compared with those receiving placebo plus trastuzumab and docetaxel.
The prespecified interim analysis of survival revealed a strong trend towards a survival benefit associated with pertuzumab, although this was not considered statistically significant. The objective response rate was higher with pertuzumab than with placebo.
Intravenous pertuzumab had an acceptable tolerability profile when added to trastuzumab and docetaxel in the CLEOPATRA trial.
Literature
1.
go back to reference Agus DB, Akita RW, Fox WD, et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2002 Aug; 2(2): 127–37PubMedCrossRef Agus DB, Akita RW, Fox WD, et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2002 Aug; 2(2): 127–37PubMedCrossRef
2.
go back to reference Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987 Jan 9; 235(4785): 177–82PubMedCrossRef Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987 Jan 9; 235(4785): 177–82PubMedCrossRef
3.
go back to reference Ménard S, Tagliabue E, Campiglio M, et al. Role of HER2 gene overexpression in breast carcinoma. J Cell Physiol 2000 Feb; 182(2): 150–62PubMedCrossRef Ménard S, Tagliabue E, Campiglio M, et al. Role of HER2 gene overexpression in breast carcinoma. J Cell Physiol 2000 Feb; 182(2): 150–62PubMedCrossRef
4.
5.
go back to reference Adams CW, Allison DE, Flagella K, et al. Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab. Cancer Immunol Immunother 2006 Jun; 55(6): 717–27PubMedCrossRef Adams CW, Allison DE, Flagella K, et al. Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab. Cancer Immunol Immunother 2006 Jun; 55(6): 717–27PubMedCrossRef
6.
go back to reference Franklin MC, Carey KD, Vajdos FF, et al. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 2004 Apr; 5(4): 317–28PubMedCrossRef Franklin MC, Carey KD, Vajdos FF, et al. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 2004 Apr; 5(4): 317–28PubMedCrossRef
7.
go back to reference Scheuer W, Friess T, Burtscher H, et al. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res 2009 Dec 15; 69(24): 9330–6PubMedCrossRef Scheuer W, Friess T, Burtscher H, et al. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res 2009 Dec 15; 69(24): 9330–6PubMedCrossRef
9.
go back to reference Albanell J, Baselga J. Unraveling resistance to trastuzumab (Herceptin): insulin-like growth factor-I receptor, a new suspect. J Natl Cancer Inst 2001 Dec 19; 93(24): 1830–2PubMedCrossRef Albanell J, Baselga J. Unraveling resistance to trastuzumab (Herceptin): insulin-like growth factor-I receptor, a new suspect. J Natl Cancer Inst 2001 Dec 19; 93(24): 1830–2PubMedCrossRef
10.
go back to reference Agus DB, Gordon MS, Taylor C, et al. Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer. J Clin Oncol 2005 Apr 10; 23(11): 2534–43PubMedCrossRef Agus DB, Gordon MS, Taylor C, et al. Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer. J Clin Oncol 2005 Apr 10; 23(11): 2534–43PubMedCrossRef
11.
go back to reference Baselga J, Swain SM. CLEOPATRA: a phase III evaluation of pertuzumab and trastuzumab for HER2-positive metastatic breast cancer. Clin Breast Cancer 2010 Dec 1; 10(6): 489–91PubMedCrossRef Baselga J, Swain SM. CLEOPATRA: a phase III evaluation of pertuzumab and trastuzumab for HER2-positive metastatic breast cancer. Clin Breast Cancer 2010 Dec 1; 10(6): 489–91PubMedCrossRef
12.
go back to reference Ng CM, Lum BL, Gimenez V, et al. Rationale for fixed dosing of pertuzumab in cancer patients based on population pharmacokinetic analysis. Pharm Res 2006 Jun; 23(6): 1275–84PubMedCrossRef Ng CM, Lum BL, Gimenez V, et al. Rationale for fixed dosing of pertuzumab in cancer patients based on population pharmacokinetic analysis. Pharm Res 2006 Jun; 23(6): 1275–84PubMedCrossRef
13.
go back to reference Totpal K, Balter I, Akita RW, et al. Targeting ErbB2/HER2’s role as a coreceptor with rhuMAb2C4 inhibits Erb/HER ligand-dependent signaling and poliferation of ovarian tumor cell lines [abstract no. 776]. Proc Am Assoc Cancer Res 2003 Jul; 44: 151 Totpal K, Balter I, Akita RW, et al. Targeting ErbB2/HER2’s role as a coreceptor with rhuMAb2C4 inhibits Erb/HER ligand-dependent signaling and poliferation of ovarian tumor cell lines [abstract no. 776]. Proc Am Assoc Cancer Res 2003 Jul; 44: 151
14.
go back to reference Lewis GD, Lofgren JA, McMurtrey AE, et al. Growth regulation of human breast and ovarian tumor cells by heregulin: evidence for the requirement of ErbB2 as a critical component in mediating heregulin responsiveness. Cancer Res 1996 Mar 15; 56(6): 1457–65PubMed Lewis GD, Lofgren JA, McMurtrey AE, et al. Growth regulation of human breast and ovarian tumor cells by heregulin: evidence for the requirement of ErbB2 as a critical component in mediating heregulin responsiveness. Cancer Res 1996 Mar 15; 56(6): 1457–65PubMed
15.
go back to reference Malik MA, Totpal K, Balter I, et al. Dose-response studies of recombinant humanized monoclonal antibody 2C4 in tumor xenograft models [abstract no. 773]. Proc Am Assoc Cancer Res 2003 Jul; 44: 150 Malik MA, Totpal K, Balter I, et al. Dose-response studies of recombinant humanized monoclonal antibody 2C4 in tumor xenograft models [abstract no. 773]. Proc Am Assoc Cancer Res 2003 Jul; 44: 150
16.
go back to reference Lee-Hoeflich ST, Crocker L, Yao E, et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res 2008 Jul 15; 68(14): 5878–87PubMedCrossRef Lee-Hoeflich ST, Crocker L, Yao E, et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res 2008 Jul 15; 68(14): 5878–87PubMedCrossRef
17.
go back to reference Schaefer G, Fitzpatrick VD, Sliwkowski MX. γ-Heregulin: a novel heregulin isoform that is an autocrine growth factor for the human breast cancer cell line, MDA-MB-175. Oncogene 1997 Sep 18; 15(12): 1385–94PubMedCrossRef Schaefer G, Fitzpatrick VD, Sliwkowski MX. γ-Heregulin: a novel heregulin isoform that is an autocrine growth factor for the human breast cancer cell line, MDA-MB-175. Oncogene 1997 Sep 18; 15(12): 1385–94PubMedCrossRef
18.
go back to reference Mendoza N, Phillips GL, Silva J, et al. Inhibition of ligandmediated HER2 activation in androgen-independent prostate cancer. Cancer Res 2002 Oct 1; 62(19): 5485–8PubMed Mendoza N, Phillips GL, Silva J, et al. Inhibition of ligandmediated HER2 activation in androgen-independent prostate cancer. Cancer Res 2002 Oct 1; 62(19): 5485–8PubMed
19.
go back to reference Liu J, Kern JA. Neuregulin-1 activates the JAK-STAT pathway and regulates lung epithelial cell proliferation. Am J Respir Cell Mol Biol 2002 Sep; 27(3): 306–13PubMedCrossRef Liu J, Kern JA. Neuregulin-1 activates the JAK-STAT pathway and regulates lung epithelial cell proliferation. Am J Respir Cell Mol Biol 2002 Sep; 27(3): 306–13PubMedCrossRef
20.
go back to reference Friess T, Bauer S, Burger AM, et al. In vivo activity of recombinant humanized monoclonal antibody 2C4 in xenografts is independent of tumor type and degree of HER2 overexpression [abstract no. 496]. Eur J Cancer 2002 Nov; 38 Suppl. 7: 149 Friess T, Bauer S, Burger AM, et al. In vivo activity of recombinant humanized monoclonal antibody 2C4 in xenografts is independent of tumor type and degree of HER2 overexpression [abstract no. 496]. Eur J Cancer 2002 Nov; 38 Suppl. 7: 149
21.
go back to reference Bossenmaier B, Hasmann M, Koll H, et al. Presence of HER2/HER3 heterodimers predicts antitumor effects of pertuzumab (Omnitarg) in different human xenograft models [abstract no. 5342]. Proc Am Assoc Cancer Res 2004; 45: 1232 Bossenmaier B, Hasmann M, Koll H, et al. Presence of HER2/HER3 heterodimers predicts antitumor effects of pertuzumab (Omnitarg) in different human xenograft models [abstract no. 5342]. Proc Am Assoc Cancer Res 2004; 45: 1232
22.
go back to reference Mann M, Sheng H, Shao J, et al. Targeting cyclooxygenase 2 and HER-2/neu pathways inhibits colorectal carcinoma growth. Gastroenterology 2001 Jun; 120(7): 1713–9PubMedCrossRef Mann M, Sheng H, Shao J, et al. Targeting cyclooxygenase 2 and HER-2/neu pathways inhibits colorectal carcinoma growth. Gastroenterology 2001 Jun; 120(7): 1713–9PubMedCrossRef
23.
go back to reference Gianni L, Lladó A, Bianchi G, et al. Open-label, phase II, multicenter, randomized study of the efficacy and safety of two dose levels of pertuzumab, a human epidermal growth factor receptor 2 dimerization inhibitor, in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 2010 Mar 1; 28(7): 1131–7PubMedCrossRef Gianni L, Lladó A, Bianchi G, et al. Open-label, phase II, multicenter, randomized study of the efficacy and safety of two dose levels of pertuzumab, a human epidermal growth factor receptor 2 dimerization inhibitor, in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 2010 Mar 1; 28(7): 1131–7PubMedCrossRef
24.
go back to reference Nahta R, Hung M-C, Esteva FJ. The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res 2004 Apr 1; 64(7): 2343–6PubMedCrossRef Nahta R, Hung M-C, Esteva FJ. The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res 2004 Apr 1; 64(7): 2343–6PubMedCrossRef
25.
go back to reference Yamamoto N, Yamada Y, Fujiwara Y, et al. Phase I and pharmacokinetic study of HER2-targeted rhuMAb 2C4 (Pertuzumab, RO4368451) in Japanese patients with solid tumors. Jpn J Clin Oncol 2009; 39(4): 260–6PubMedCrossRef Yamamoto N, Yamada Y, Fujiwara Y, et al. Phase I and pharmacokinetic study of HER2-targeted rhuMAb 2C4 (Pertuzumab, RO4368451) in Japanese patients with solid tumors. Jpn J Clin Oncol 2009; 39(4): 260–6PubMedCrossRef
26.
go back to reference Attard G, Kitzen J, Blagden SP, et al. A phase Ib study of pertuzumab, a recombinant humanised antibody to HER2, and docetaxel in patients with advanced solid tumours. Br J Cancer 2007; 97(10): 1338–43PubMedCrossRef Attard G, Kitzen J, Blagden SP, et al. A phase Ib study of pertuzumab, a recombinant humanised antibody to HER2, and docetaxel in patients with advanced solid tumours. Br J Cancer 2007; 97(10): 1338–43PubMedCrossRef
27.
go back to reference Baselga J, Cortés J, Kim S-B, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012 Jan 12; 366(2): 109–19PubMedCrossRef Baselga J, Cortés J, Kim S-B, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012 Jan 12; 366(2): 109–19PubMedCrossRef
28.
go back to reference Portera CC, Walshe JM, Rosing DR, et al. Cardiac toxicity and efficacy of trastuzumab combined with pertuzumab in patients with trastuzumab-insensitive human epidermal growth factor receptor 2-positive metastatic breast cancer. Clin Cancer Res 2008 May 1; 14(9): 2710–6PubMedCrossRef Portera CC, Walshe JM, Rosing DR, et al. Cardiac toxicity and efficacy of trastuzumab combined with pertuzumab in patients with trastuzumab-insensitive human epidermal growth factor receptor 2-positive metastatic breast cancer. Clin Cancer Res 2008 May 1; 14(9): 2710–6PubMedCrossRef
29.
go back to reference Baselga J, Gelmon KA, Verma S, et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol 2010 Mar 1; 28(7): 1138–44PubMedCrossRef Baselga J, Gelmon KA, Verma S, et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol 2010 Mar 1; 28(7): 1138–44PubMedCrossRef
30.
go back to reference Ellis PA, Barrios CH, Im Y, et al. MARIANNE: a phase III, randomized study of trastuzumab-DM1 (T-DM1) with or without pertuzumab (P) compared with trastuzumab (H) plus taxane for first-line treatment of HER2-positive, progressive, or recurrent locally advanced or metastatic breast cancer (MBC) [abstract no. TPS102]. 47th Annual Meeting of the American Society of Clinical Oncology; 2011 Jun 3–7; Chicago (IL) Ellis PA, Barrios CH, Im Y, et al. MARIANNE: a phase III, randomized study of trastuzumab-DM1 (T-DM1) with or without pertuzumab (P) compared with trastuzumab (H) plus taxane for first-line treatment of HER2-positive, progressive, or recurrent locally advanced or metastatic breast cancer (MBC) [abstract no. TPS102]. 47th Annual Meeting of the American Society of Clinical Oncology; 2011 Jun 3–7; Chicago (IL)
31.
go back to reference Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012 Jan; 13(1): 25–32PubMedCrossRef Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012 Jan; 13(1): 25–32PubMedCrossRef
32.
go back to reference Schneeweiss A, Chia S, Hickish T, et al. Neoadjuvant pertuzumab and trastuzumab concurrent or sequential with an anthracycline-containing or concurrent with an anthracycline-free standard regimen: a randomized phase II study (TRYPHAENA) [abstract no. S5-6]. Cancer Res 2011 Dec 15; 71 (24 Suppl.): 112SCrossRef Schneeweiss A, Chia S, Hickish T, et al. Neoadjuvant pertuzumab and trastuzumab concurrent or sequential with an anthracycline-containing or concurrent with an anthracycline-free standard regimen: a randomized phase II study (TRYPHAENA) [abstract no. S5-6]. Cancer Res 2011 Dec 15; 71 (24 Suppl.): 112SCrossRef
33.
go back to reference von inckwitz G, Baselga J, Bradbury I, et al. Adjuvant pertuzumab and Herceptin in initial therapy of breast cancer: APHINITY [abstract no. OT1-02-04]. Cancer Res 2011 Dec 15; 71 (24 Suppl.): 602SCrossRef von inckwitz G, Baselga J, Bradbury I, et al. Adjuvant pertuzumab and Herceptin in initial therapy of breast cancer: APHINITY [abstract no. OT1-02-04]. Cancer Res 2011 Dec 15; 71 (24 Suppl.): 602SCrossRef
Metadata
Title
Pertuzumab
In the First-Line Treatment of HER2-Positive Metastatic Breast Cancer
Author
Gillian M. Keating
Publication date
01-02-2012
Publisher
Springer International Publishing
Published in
Drugs / Issue 3/2012
Print ISSN: 0012-6667
Electronic ISSN: 1179-1950
DOI
https://doi.org/10.2165/11209000-000000000-00000

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