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Anti-HER2 Therapies: When More Is More

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Anti-HER2 Therapies: When More Is More Perspective Anti-HER2 therapies: When more is more Monica Arnedos1, Britta Weigelt2, Jorge S. Reis-Filho3 1Department of Medical Oncology and INSERM Unit U981, Institut Gustave Roussy, Villejuif 94805, France; 2Signal Transduction Laboratory, Cancer Research UK London Research Institute, WC2A 3LY, UK; 3Molecular Pathology Team, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK Corresponding to: Jorge S. Reis-Filho, MD, PhD, FRCPath. Molecular Pathology Team, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK. Tel: +442071535529; Fax: +442071535533. Email: [email protected]. Submitted Mar 08, 2012. Accepted for publication Apr 05, 2012. DOI: 10.3978/j.issn.2218-676X.2012.03.07 Scan to your mobile device or view this article at: http://tcr.thepbpc.org/article/view/373/722 Human epidermal growth factor receptor 2 (HER2) is a Trastuzumab is a humanised monoclonal antibody (mAb) member of the epidermal growth factor receptor (EGFR) that binds to the extracellular, juxtamembrane portion family of receptor tyrosine kinases (RTKs), which includes of the HER2 receptor and suppresses HER2 signalling EGFR (HER1), c-erbB2 (HER2), c-erbB3 (HER3), activity, resulting in inhibition of downstream signalling and c-erbB4 (HER4) (1). These four receptors share an pathways, cell cycle arrest and a reduction in angiogenesis. extracellular domain in N-terminal position corresponding As a result of antibody binding to the HER2 extracellular to the ligand binding site, a transmembrane domain, and domain, Trastuzumab also leads to antibody-dependent an intracellular domain in C-terminal position having cell-mediated cytotoxicity (ADCC), and prevents HER2 tyrosine kinase (TK) activity, except for HER3, whose receptor extracellular domain cleavage, leading to tumour kinase domain is inactive. Apart for HER2, for which no cell stasis and/or death (7-9). In patients with advanced ligand has been identified, for other members of the HER HER2-amplified breast cancer, Trastuzumab has shown family, ligands bind to the receptor leading to homo- or antitumour activity (10,11) and improves overall survival hetero-dimerisation, and self-activation of tyrosine residues (OS) when given in combination with chemotherapy in in the C terminal domain, and transduction of signal via the the first-line setting (12,13). It has, however, become clear Ras/Raf/MEK/ERK and the PI3K/AKT/mTOR pathways that a subset of patients with HER2-positive disease fails to (2,3) involved in cell survival, migration, apoptosis and benefit from Trastuzumab treatment, either due to primary proliferation. (also known as de novo) resistance, or the acquisition of Approximately 10-15% of early breast cancers overexpress resistance during the course of treatment (secondary HER2 and/or harbour HER2 gene amplification (2,3). resistance) (14). HER2 protein overexpression has been shown to be Pertuzumab is a humanised monoclonal antibody that underpinned by HER2 gene amplification in >90% of binds to a distinct epitope of HER2 (domain II), preventing cases (4). Importantly, HER2 overexpression and gene HER2 from dimerisation with other ligand-activated HER2 amplification have been shown to constitute drivers of receptors, mostly HER3 (15). As a single agent Pertuzumab breast cancer in in vitro and in vivo models (5,6), and are was assessed in HER2-negative breast cancer advanced independent prognostic factors (2). A number of therapeutic patients showing only modest activity (16). approaches have been developed against HER2, including Given that Pertuzumab and Trastuzumab bind to Trastuzumab (Herceptin™, Roche-Genentech, CA, USA), different HER2 epitopes and have complementary Pertuzumab (Omnitarg™, Roche-Genentech, CA, USA) mechanisms of action (15), preclinical studies have shown a and Lapatinib (Tykerb™/Tyverb™, GlaxoSmithKline, UK), synergistic effect when these two agents were administered which have either been incorporated into clinical practice together (17,18). In a phase 2 study in the advanced setting or are being tested in the context of clinical trials (Tables 1, 2). a benefit was observed for the Trastuzumab-Pertuzumab © Pioneer Bioscience Publishing Company. All rights reserved. www.theTCR.org Transl Cancer Res 2012;1(1):49-54 50 Arnedos et al. Anti-HER2 therapies Table 1 Published clinical trials including targeted agents in development to reverse or prevent Trastuzumab resistance Phase Compound Target Treatment arms Stage n patients Primary endpoint Trial ID II Pertuzumab HER2 Pertuzumab+trastuzumab Advanced 66 ORR NCT00301899 II Pertuzumab HER2 Trastuzumab+docetaxel neoadjuvant 417 pCR NCT00545688 vs. trastuzumab+ docetaxel+ pertuzumab vs. Trastuzumab+pertuzumab vs. docetaxel+pertuzumab III Pertuzumab HER2 Trastuzumab+docetaxel vs. advanced 1st 808 PFS NCT00567190 Trastuzumab+docetaxel+ line pertuzumab II T-DM1 HER2 T-DM1 advanced 112 ORR NCT00509769 II Neratinib HER2/ Neratinib advanced 136 PFS NCT00300781 EGFR II Afatinib HER2/ Afatinib advanced 41 ORR NCT00431067 EGFR Abbreviations: ORR, Overall Response Rate; pCR, pathological complete response; PFS, progression-free survival combination in patients who had failed Trastuzumab (19). the benefit was observed in both Trastuzumab pre- In early breast cancer, the results of the Neoadjuvant treated and Trastuzumab-naive patients suggests that Study of Pertuzumab and Herceptin in an Early Regimen Trastuzumab-resistant HER2-positive breast cancers may Evaluation (NEOSPHERE; NCT00545688) have shown still depend on HER2 signalling. The observed clinical a markedly higher pathological complete response rate benefit of Pertuzumab is likely to stem from the different with the triple therapy of docetaxel, Trastuzumab and mechanisms of action of Trastuzumab and Pertuzumab. Pertuzumab compared to docetaxel with either one of the Unlike Trastuzumab, Pertuzumab-mediated blockade of anti-HER2 therapies alone (20). However, the true clinical the epitope II, involved in heterodimer formation, prevents significance of pathological complete response, or lack of, in the formation of HER2-HER3 heterodimers, which are oestrogen receptor-positive HER2-positive breast cancers the most potent in activating the PI3K pathway (22). This remains to be fully established. mechanisms of action would add to the previously described The recently published Clinical Evaluation of mechanism of Trastuzumab benefit, which are not solely Pertuzumab and Trastuzumab study (CLEOPATRA; linked to a direct HER2 inhibition (9). Importantly, no NCT00567190) (21) has provided direct evidence significant increase in toxicity, especially in terms of cardiac to demonstrate that the addition of Pertuzumab to events, was observed with the combination of the two Trastuzumab plus docetaxel improved progression-free monoclonal antibodies compared to Trastuzumab alone and survival (PFS) by 6.1 months (18.5 vs. 12.4 months for no significant differences in treatment exposure to docetaxel Pertuzumab arm vs. control, respectively; HR, 0.62; 95% occurred between the two treatment groups. This is of CI, 0.51-0.75; P<0.001). This benefit was observed in all crucial importance, given that one of the main challenges pre-defined subgroups based on previous neoadjuvant in combinatorial therapies where one of the agents is a or adjuvant treatment (chemotherapy+/-Trastuzumab), targeted agent, is the fact that full dose chemotherapy geographic region, age, race, visceral involvement, treatment cannot be delivered due to compounded toxicity hormone receptor status and if HER2-positivity had been [e.g., Sunitinib in combination to docetaxel (23)]. determined by immunohistochemistry or fluorescence in In addition to the direct inhibition of HER2, alternative situ hybridisation. There was a non-significant trend in approaches for targeting the overexpression of this benefit in overall survival (P=0.05), although the analysis transmembrane receptor have emerged. Trastuzumab- was performed after only 43% of the pre-specified total maytansine (DM1) (T-DM1, Roche-Genentech, CA, USA) number of events requested for the final analysis. These is an immunoconjugate agent that combines Trastuzumab results are therefore consistent with those observed in with DM1, an antimicrotubule cytotoxic agent. A phase the previously described phase II studies. The fact that II study (NCT00509769) has now shown significant © Pioneer Bioscience Publishing Company. All rights reserved. www.theTCR.org Transl Cancer Res 2012;1(1):49-54 Translational Cancer Research, Vol 1, No 1 June 2012 51 Table 2 Unpublished or still recruiting clinical trials with novel anti-HER2 therapies or targeted agents to reverse or prevent Trastuzumab resistance Phase Compound Target Treatment arms Stage Status trial Trial ID Ib/II BEZ235 PI3K/mTORC Trastuzumab+BEZ235 advanced not open yet NCT01471847 Ib/II BKM120 PI3K Trastuzumab+BKM120 advanced recruiting NCT01132664 XL147 PI3K XL147+trastuzumab vs. advanced recruiting NCT01042925 Ib/II paclitaxel+trastuzumab GDC-0941 PI3K GDC-0941+T-DM1 vs. advanced recruiting NCT00928330 Ib GDC-0941+trastuzumab T-DM1+pertuzumab vs. recruiting NCT01120184 T-DM1/ HER2 advanced III pertuzumab+placebo vs. Pertuzumab trastuzumab+taxane T-DM1 HER2 T-DM1 vs. lapatininb+ advanced recruiting NCT00829166 III capecitabine T-DM1/ HER2 T-DM1+paclitaxel+/- advanced recruiting NCT00951665 Ib Pertuzumab pertuzumab T-DM1 HER2 T-DM1 vs. trastuzumab+ advanced recruitment NCT00679341 II docetaxel completed II Pertuzumab HER2
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