Pertuzumab: A Review of Its Use for First-Line Combination Treatment of HER2-Positive Metastatic Breast Cancer
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Pertuzumab (Perjeta®) is a humanized anti-HER2 monoclonal antibody that binds to the extracellular dimerization subdomain of the HER2 receptor and reduces HER2 intracellular signalling by preventing HER2 from forming heterodimers with other HER receptors. Inhibition of HER2 signalling results in a reduction of tumour cell proliferation, invasiveness and survival. Pertuzumab and trastuzumab bind to different sites on the HER2 receptor and have complementary antitumour activities; they act synergistically in inhibiting the growth of HER2-overexpressing breast cancer cell lines in vitro. The efficacy of intravenous pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) in combination with trastuzumab plus docetaxel in the first-line treatment of HER2-positive metastatic breast cancer was demonstrated in the randomized, double-blind, placebo-controlled, multinational, phase III CLEOPATRA trial. Pertuzumab in combination with trastuzumab and docetaxel significantly increased independently assessed median progression-free survival (primary endpoint), objective response rate and overall survival compared with placebo in combination with trastuzumab and docetaxel. Pertuzumab had an acceptable tolerability profile when added to trastuzumab and docetaxel in the pivotal CLEOPATRA trial. Thus, pertuzumab is a valuable addition to the growing list of anti-HER2 targeted therapies for breast cancer.
KeywordsDocetaxel Trastuzumab Human Epidermal Growth Factor Receptor Febrile Neutropenia Pertuzumab
The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the author on the basis of scientific and editorial merit.
- 6.European Medicines Agency. Herceptin (trastuzumab): summary of product characteristics. 2010. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000278/WC500074922.pdf. Accessed 8 Aug 2013.
- 7.Genentech Inc. Herceptin (trastuzumab): US prescribing information. 2010. http://www.gene.com/download/pdf/herceptin_prescribing.pdf. Accessed 8 Aug 2013.
- 9.European Medicines Agency. Perjeta (pertuzumab): summary of product characteristics. 2013. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002547/WC500140980.pdf. Accessed 8 Aug 2013.
- 10.US FDA. Perjeta (pertuzumab): US prescribing information. 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125409lbl.pdf. Accessed 8 Aug 2013.
- 18.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.Google Scholar
- 19.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;38(Suppl. 7):S149.Google Scholar
- 20.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;44(2nd ed):150.Google Scholar
- 24.Cortes J, Baselga J, Fumoleau P, et al. Pertuzumab and trastuzumab: exploratory biomarker correlations with clinical benefit in patients with metastatic HER2-positive breast cancer [abstract no. 1066]. J Clin Oncol. 2010;28(15 Suppl. 1).Google Scholar
- 25.Cortes J, Fumoleau P, Bianchi GV, et al. Pertuzumab monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab: activity and tolerability in patients with advanced human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2012;30(14):1594–600.PubMedCrossRefGoogle Scholar
- 26.Garg A, Li J, Clark E, et al. Exposure-response (E-R) analysis of pertuzumab (PTZ) in patients with HER2-positive (HER2+) metastatic breast cancer (MBC): effect on QTc prolongation and other ECG parameters [abstract no. PI-78]. Clin Pharmacol Ther. 2013;93(Suppl. 1):S42.Google Scholar
- 30.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;28(7):1131–7.PubMedCrossRefGoogle Scholar
- 31.Cortes J, Swain S, Kudaba I, et al. Pharmacokinetics (Pk) of pertuzumab (P) with trastuzumab (T) and docetaxel (D) in HER2-positive first-line metastatic breast cancer (MBC): results from the phase III trial CLEOPATRA [abstract no. 344P]. 37th Congress of the European Society for Medical Oncology, 28 Sep-2 Oct 2012, Vienna.Google Scholar
- 34.US FDA. Center for Drug Evaluation and Research medical review of pertuzumab. 2012. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/125409Orig1s000MedR.pdf. Accessed 8 Aug 2013.
- 36.Cortes J, Baselga J, Im YH, et al. Health-related quality-of-life assessment in CLEOPATRA, a phase III study combining pertuzumab with trastuzumab and docetaxel in metastatic breast cancer. Ann Oncol. 2013. doi: 10.1093/annonc/mdt274.
- 38.Baselga J, Cortes J, Im S-A, et al. Adverse events with pertuzumab and trastuzumab: evolution during treatment with and without docetaxel in CLEOPATRA [abstract no. 597]. J Clin Oncol. 2012;30(15 Suppl. 1).Google Scholar
- 40.National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: breast cancer (version 2.2013). 2013. http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed 15 Jul 2013.
- 41.Miles D, Peretz-Yablonski T, Ciruelos E, et al. Pertuzumab in combination with trastuzumab and a taxane for the first-line treatment of patients with HER2-positive advanced breast cancer: a single arm phase IIIb study (PERUSE) [abstract no. 409TiP]. 37th Congress of the European Society for Medical Oncology, 27 Sep-1 Oct 2012, Vienna.Google Scholar
- 42.ClinicalTrials.gov (pertuzumab AND breast cancer). 2013. http://clinicaltrials.gov/ct2/results/displayOpt?flds=a&flds=b&flds=f&flds=g&flds=k&flds=l&flds=r&flds=o&submit_fld_opt=on&term=pertuzumab+AND+breast&show_flds=Y. Accessed 8 Aug 2013.
- 43.Gianni L, Pienkowski T, Im Y-H, 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;13(1):25–32.PubMedCrossRefGoogle Scholar
- 44.Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013. doi: 10.1093/annonc/mdt182.Google Scholar
- 45.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]. J Clin Oncol. 2011;29(15 Suppl. 1).Google Scholar
- 46.Hoffman-La Roche. A study of trastuzumab emtansine (T-DM1) plus pertuzumab/pertuzumab placebo versus trastuzumab [Herceptin] plus a taxane in patients with metastatic breast cancer (MARIANNE) [ClinicalTrials.gov identifier NCT01120184]. US National Institutes of Health, ClincialTrials.gov [online]. 2013. http://clinicaltrials.gov/ct2/show/NCT01120184?term=NCT01120184&rank=1. Accessed 8 Aug 2013.
- 47.von Minckwitz 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;71(24 Suppl. 3):602S.Google Scholar
- 48.Hoffman-La Roche. A study of pertuzumab in addition to chemotherapy and Herceptin (trastuzumab) as adjuvant therapy in patients with HER2-positive primary breast cancer. [ClinicalTrials.gov identifier NCT01358877]. US National Institutes of Health, ClincialTrials.gov [online]. 2013. http://clinicaltrials.gov/ct2/show/NCT01358877?term=NCT01358877&rank=1. Accessed 8 Aug 2013.
- 49.Hoffman-La Roche. A study of pertuzumab in combination with trastuzumab plus an aromatase inhibitor in patients with hormone receptor-positive, metastatic HER2-positive breast cancer. [ClinicalTrials.gov identifier NCT01491737]. US National Institutes of Health, ClincialTrials.gov [online]. 2013. http://clinicaltrials.gov/ct2/show/NCT01491737?term=NCT01491737&rank=1. Accessed 8 Aug 2013.
- 50.Hoffman-La Roche. A study of pertuzumab in combination with Herceptin (trastuzumab) and vinorelbine in first line in patients with metastatic or locally advanced HER2-positive breast cancer. 2013. http://clinicaltrials.gov/ct2/show/NCT01565083?term=pertuzumab+AND+breast&rank=16&submit_fld_opt=. Accessed 8 Aug 2013.
- 51.Andersson M, Lopez-Vega JM, Del Mastro L, et al. Pertuzumab and trastuzumab in combination with vinorelbine for first-line treatment of patients with HER2-positive locally advanced or metastatic breast cancer (LABC/MBC): a single-arm, two-cohort, phase II study (VELVET) [abstract no. 408TiP]. Ann Oncol. 2012;23(Suppl. 9):ix142.Google Scholar
- 52.Genentech. An observational study of pregnancy and pregnancy outcomes in women with breast cancer treated with Herceptin or Perjeta in combination with Herceptin during pregnancy or within 6 months prior to conception (MotHER). [ClinicalTrials.gov identifier NCT00833963]. US National Institutes of Health, ClincialTrials.gov [online]. 2012. http://clinicaltrials.gov/ct2/show/NCT00833963?term=NCT00833963&rank=1. Accessed 8 Aug 2013.