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Review
. 2013 Mar;8(1):49-55.
doi: 10.1159/000346837.

HER2 Dimerization Inhibitor Pertuzumab - Mode of Action and Clinical Data in Breast Cancer

Nadia Harbeck  1 , Matthias W Beckmann  2 , Achim Rody  3 , Andreas Schneeweiss  4 , Volkmar Müller  5 , Tanja Fehm  6 , Norbert Marschner  7 , Oleg Gluz  8 , Iris Schrader  9 , Georg Heinrich  10 , Michael Untch  11 , Christian Jackisch  12
Affiliations
Review

HER2 Dimerization Inhibitor Pertuzumab - Mode of Action and Clinical Data in Breast Cancer

Nadia Harbeck et al. Breast Care (Basel). 2013 Mar.

Abstract
in English, German

The humanized monoclonal antibody pertuzumab prevents the dimerization of HER2 with other HER receptors, in particular the pairing of the most potent signaling heterodimer HER2/HER3, thus providing a potent strategy for dual HER2 inhibition. It binds to the extracellular domain of HER2 at a different epitope than trastuzumab. Pertuzumab and trastuzumab act in a complementary fashion and provide a more complete blockade of HER2-mediated signal transduction than either agent alone. Phase II studies demonstrated that pertuzumab was generally well tolerated as a single agent or in combination with trastuzumab and/or cytotoxic agents, and implied an improved clinical efficacy of the combination of pertuzumab and trastuzumab in early and advanced HER2-positive breast cancer. Results of the pivotal phase III study CLEOPATRA in patients with HER2-positive metastatic breast cancer demonstrated that the addition of pertuzumab to first-line combination therapy with docetaxel and trastuzumab significantly prolonged progression-free and overall survival without increasing cardiac toxicity. Currently, the combination of both antibodies is being explored in the palliative setting as well as in the treatment of early HER2-positive breast cancer. Dual HER2 inhibition with the HER2 dimerization inhibitor pertuzumab and trastuzumab may change clinical practice in HER2-positive first-line metastatic breast cancer treatment.

Der humanisierte monoklonale Antikörper Pertuzumab verhindert die Dimerisierung von HER2 mit anderen HER-Rezeptoren, insbesondere die Bildung des im Hinblick auf Signaltransduktionskaskaden potentesten Heterodimers HER2-HER3 und ermöglicht damit eine grundlegend andere Strategie der dualen HER2-Inhibition. Pertuzumab bindet an die extrazelluläre Domäne von HER2, aber einem anderen Epitop als Trastuzumab. Pertuzumab und Trastuzumab erreichen zusammen eine vollständigere Blockade der HER2-vermittelten Signaltransduktion als jede Substanz alleine. Phase-II-Studien konnten zeigen, dass Pertuzumab alleine oder in Kombination gut verträglich ist. Sie legten auch eine verbesserte klinische Wirksamkeit der Kombination von Pertuzumab und Trastuzumab bei primärem und fortgeschrittenem HER2-positiven Brustkrebs nahe. Die Ergebnisse der Phase-III-Studie CLEOPATRA bei Patientinnen mit metastasiertem HER2-positivem Mammakarzinom zeigten, dass die zusätzliche Gabe von Pertuzumab zu einer Erstlinien-Kombinationstherapie mit Docetaxel und Trastuzumab das progressionsfreie Überleben und das Gesamtüberleben signifikant verlängerte ohne Steigerung der kardialen Toxizität. Derzeit wird die Kombination aus beiden Antikörpern in der palliativen Situation und in der Behandlung des frühen HER2-positiven Mammakarzinoms untersucht. Die duale HER2-Inhibition mit Trastuzumab und dem HER2 Dimerisationsinhibitor Pertuzumab könnte die klinische Praxis für die Erstlinientherapie beim metastasierten HER2-positiven Mammakarzinom und möglicherweise auch in früheren Stadien verändern.

Keywords: Breast cancer, metastatic; Dual inhibition; HER2-positive; Pertuzumab; Trastuzumab.

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Figures

Fig. 1
Fig. 1
Complementary mechanisms of action of pertuzumab and trastuzumab. Adapted from Baselga J et al. [40] ADCC = antibody-dependent cell-mediated cytotoxicity; ECD = extracellular domain.
Fig. 2
Fig. 2
CLEOPATRA: Study design. Adapted from Baselga J et al. [40]. MBC = metastatic breast cancer; PD = progressive disease.
Fig. 3
Fig. 3
Independently and investigator-assessed progression-free survival. Adapted from Baselga J et al. [39, 40].
Fig. 4
Fig. 4
CLEOPATRA: Predefined interim analysis of overall survival (n=165 events). Adapted from Baselga J et al. [39, 40]. D = docetaxel; OS = overall survival; Pla = placebo; Ptz = pertuzumab; T = trastuzumab.
Fig. 5
Fig. 5
APHINITY: Study design. Trastuzumab loading dose at first cycle 8 mg/kg, dose of 6 mg/kg 3-weekly in subsequent cycles. Pertuzumab loading dose of 840 mg i.V., dose of 420 mg i.v. 3-weekly in subsequent cycles. Placebo i.v. 3 weekly. A limited number of standard anthracycline or non-anthracycline (TCH) regimens are allowed.
See this image and copyright information in PMC

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