Pertuzumab Update: The New Kid on “HER” Block

 

Although trastuzumab has led to significant improvements in treating HER2-positive breast cancers, many patients relapse and develop resistance to trastuzumab.

The HER family of growth factor receptors consists of four closely related members that activate receptor tyrosine kinase signalling cascades when paired together. The pairing can form between two different HER members (heterodimerization) or between the same receptors, with the HER2–HER3 heterodimer being the potent signalling pair in driving proliferation of HER2-positive breast cancers. Although HER2 is not directly activated by a ligand, it can bind with any member of the HER family making it a prime candidate for anti-HER therapies (Agus et al., 2002; Hsieh & Moasser, 2007; Lee-Hoeflich et al., 2008).

Trastuzumab works by attaching to the sub-domain IV of the HER2 receptor preventing HER2 cleavage and exerts its anti-tumor effects by blocking HER2 signalling and by stimulating antibody-dependent, cell-mediated cytotoxicity.

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 also stimulates antibody-dependent, cell-mediated responses but since pertuzumab and trastuzumab bind to different regions of the HER2 receptor and inhibit different mechanisms, combining both drugs leads to stronger HER2 inhibition and greater anti-tumor activity than either agent alone.

Results from Clinical Trial:

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 was 18.5 months in the pertuzumab group compared with 12.4 months in the control group (hazard ratio for progression or death = 0.62; 95% confidence interval, 0.51 to 0.75; P<0.001). See Fig 1 below.

While it is too early to determine the benefits in regards to overall survival, the interim results have shown a strong trend in favour of pertuzumab, trastuzumab and docetaxel (Hazard ratio = 0.64; 95% confidence interval, = 0.47 to 0.88; P=0.005. See Fig 2 below.

When used as first-line treatment for HER2-positive metastatic breast cancer, the combination of pertuzumab, trastuzumab and docetaxel significantly prolonged progression-free survival, with no increase in cardiac toxic effects (Baselga et al., 2011).


FIG 1: Progression-free Survival, as Assessed at an Independent Review Facility.
Panel A shows Kaplan–Meier estimates of progression-free survival in the intention-to-treat population, stratified according to prior treatment and region. The median progression-free survival was longer by 6.1 months in the pertuzumab group (pertuzumab, trastuzumab and docetaxel) than in the control group (placebo, trastuzumab and docetaxel). The tick marks indicate the times at which events were recorded.
Panel B shows hazard ratios and 95% confidence intervals for progression-free survival in all prespecified subgroups according to baseline characteristics, without stratification. The hazard ratio for the category of unknown status of estrogen receptor (ER) and progesterone receptor (PgR) was not quantifiable, owing to the small number of patients in the group. FISH denotes fluorescence in situ hybridization, and IHC immunohistochemistry. See Baselga et al., (2011).

 


FIG 2: Overall Survival. Kaplan–Meier estimates of overall survival in patients in the intention-to-treat population are shown. The tick marks indicate the times at which events were recorded. The interim overall survival analysis was performed after 165 events (43% of the pre-specified total number for the final analysis) had occurred: 96 events in the control group (placebo, trastuzumab and docetaxel) and 69 events in the pertuzumab group (pertuzumab, trastuzumab and docetaxel).
Note: The interim analysis of overall survival did not cross the O’Brien–Fleming stopping boundary threshold; therefore, the interim result is not statistically significant and is deemed exploratory. See Baselga et al., (2011).

 

REFERENCES:

Agus et al., (2002). Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell; 2: 127-37.

Baselga et al., (2011). Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer. N Engl J Med. 2011 Dec 7. [Epub ahead of print]

Hsieh & Moasser., (2007). Targeting HER proteins in cancer therapy and the role of the non-target HER3. Br J Cancer; 97: 453-7.

Lee-Hoeflich et al., (2008). A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res; 68: 5878-87.

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LINK TO CLEOPATRA CLINICAL TRIAL TRIAL
A Study to Evaluate Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated Her2-Positive Metastatic Breast Cancer (CLEOPATRA)


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