[Jackie07]

Hopefully Pertuzumab will be approved soon:

Pertuzumab
Pertuzumab (OmnitargTM; Genentech/Roche, South San Francisco, CA) is a humanised monoclonal antibody that targets the extracellular domain of HER-2. However, the structure and function analysis demonstrated that pertuzumab binds to a quite distinct site of the HER-2 extracellular part from that of trastuzumab and is considered to serve as a HERs dimerisation inhibitor [23]. Receptor dimerisation can occur between two different EGFR family members (heterodimerisation) or between two symmetric EGFR receptors (homodimerisation). The intercellular tyrosine kinase of one receptor can only be phosphorylated and activated through dimerisation. This mechanism is quite important for HER-2/HER-3 dimers as the HER-3 receptor which lacked active tyrosine kinase domain and disabled to form the homodimers. Different investigations suggested that HER-2/HER-3 can act as an oncogenic unit, which initiates activation of the PI3K/Akt signal pathway to enhance tumour progression [24]. Pertuzumab is designed to bind to the junction part of HER-2 extracellular domain and thereby ultimately block the formation of HER-2 related homo- and hetero-dimerisation as well as their downstream signal transduction. The good tolerance and antitumour activity of pertuzumab has been identified in several completed phase I and phase II studies [25]. Pertuzumab showed a compensating anti-HER-2 efficacy after use in trastuzumab refractory metastatic breast cancer patients, which meant that it could partially reverse trastuzumab resistance [26]. A recently published phase II trial reported a 24.2% objective response rate and 50% clinical benefit rate in the regimen consisting of pertuzumab plus trastuzumab in advanced breast cancer patients with HER-2 overexpression and patients whose disease progresses aftertrastuzumab-based therapy. The promising results strongly demonstrate a synergistic efficacy of the two combined antibodies [27]. Two randomised phase III studies with pertuzumab that can increase knowledge of it are currently ongoing. The CLinical Evaluation of PErtuzumab and TRAstuzumab, sponsored by a Genentech (CLEOPATRA) study aims to compare the efficacy and safety of docetaxel plus trastuzumab with or without the combination of pertuzumab in previously untreated breast cancer patients. The neoadjuvant treatment with herceptin and pertuzumab, sponsored by a Hoffmann-LaRoche (NEOSPHERE) study recruits patients with locally advanced, inflammatory, or early-stage HER-2 positive breast cancer to evaluate the complete pathological response rate of the combination of trastuzumab, pertuzumab, and docetaxel. The first clinical data shows that pertuzumab and trastuzumab plus docetaxel given in a neoadjuvant setting prior to surgery significantly improved the pathological complete response rate as compared with trastuzumab plus docetaxel (San Antonio Breast Cancer Symposium, SABCS 2010).