Pertuzumab: The New Kid on “HER” Block

Approximately 20% of all breast cancers are caused by the oncogenic human epidermal growth factor receptor 2 (HER2) and although trastuzumab has led to significant improvements in treating HER2-positive breast cancers, many patients develop resistance to trastuzumab and relapse. Trastuzumab works by attaching to the subdomain IV of the HER2 receptor and exerts its antitumor effects by blocking HER2 signalling (by preventing HER2 cleavage), and stimulating antibody-dependent, cell-mediated cytotoxicity (an immune response).

Pertuzumab is a new humanized monoclonal antibody that attaches to the extra cellular domain (subdomain II) of HER2 and prevents HER2 from dimerizing with other HER receptors (such as HER3). Like trastuzumab, pertuzumab stimulates an antibody-dependent, cell-mediated response but because pertuzumab and trastuzumab bind to different regions of HER2, they have complementary mechanisms of action and combining both drugs leads to stronger HER2 inhibition and greater antitumor activity than either agent alone.

In this clinical trial, combining pertuzumab and trastuzumab with docetaxel resulted in an objective response rate of 80.2%, compared with 69.3% in the control group (trastuzumab and docetaxel alone). Furthermore, the median progression-free survival rate for the pertuzumab group was 21.6 mths compared, with 12.6 mths for the control group. While it is too early to determine the benefits in regards to overall survival, the interim results indicate a significantly higher survival rate for patients treated with pertuzumab, trastuzumab and docetaxel. See Fig 1 below. I like this approach because it addresses the issue of tumor heterogeneity (variation) and shows the benefits of using multiple drugs with different mechanisms for the same molecular target.

FIG 1: Overall survival rate of patients treated with Pertuzumab (red) compared with control (blue). See Baselga et al., (2011).

Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer.



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