Compound Name:PertuzumabMolecular Target:HER2Molecular Structure:Humanized IgG1? monoclonal antibody, glycosylatedLicensed Indication:HER2 overexpressing breast cancer, in combination with trastuzumab and docetaxelManufacturer and/or Distributor:GenentechInitial FDA Approval:2012Summary:Pertuzumab (Perjeta), a recombinant humanized IgG1k monoclonal antibody, targeted at the extracellular dimerization domain (Subdomain II) of the human epidermal growth factor receptor 2 protein (HER2, also known as Neu, c-erbB2, CD340 or p185). HER2 is an oncogenic transmembrane receptor protein, which is overexpressed about 25% of breast cancers (Ben Y. Durkee, et al., 2015). In fact, HER2 also dimerizes with the other members of the HER family, such as HER1, HER3, and HER4 (Joseph J. Maly & Erin R. Macrae, 2013). Mechanistically, Pertuzumab binds to the HER2 extracellular domain to prevent ligand-dependent, hetero-dimerization of HER2 with HER3 receptor. As shown in Figure 1, this hetero-dimerization in turn blocks the intracellular signaling of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways to inhibit survival, proliferation and growth of HER2 positive tumor cells. Indirectly, pertuzumab mediates tumor cell killing by antibody dependent cellular cytotoxicity (ADCC) and thus induces apoptosis of tumor cells. Pertuzumab is usually administered by intravenous infusion every three weeks. Significant safety concerns with pertuzumab include infusion reactions, left ventricular dysfunction, and embryo-fetal toxicity such as mucosal inflammation, diarrhea, alopecia, neutropenia, nausea, fatigue and peripheral edema (Sandra M. Swain et al., 2014). Pertuzumab was approved by the FDA in June, 2012, on the basis of a single clinical trial (CLEOPATRA) and based on pCR as the endpoint (Joensuu, H., 2017). The approval stipulates use with trastuzumab and docetaxel in breast cancer patients whose tumors are HER2 positive, metastatic, and not previously treated with anti-HER2 therapy or with chemotherapy for metastatic disease. The addition of pertuzumab to the two-drug regimen increased the progression free survival by almost 50% (12.4 mo to 18.5 mo). In 2013, the FDA granted accelerated approval to pertuzumab in the neoadjuvant setting based on the efficacy and safety data provided by two neoadjuvant trials, NeoSphere and TRYPHAENA. The final prespecified overall survival analysis in the phase III CLEOPATRA study showed a significant 15.7-month increase in median overall survival over 50 months of follow-up with the addition of pertuzumab to trastuzumab and docetaxel in the first-line treatment of women with HER2-positive metastatic breast cancer. Significant safety concerns with pertuzumab include infusion reactions, left ventricular dysfunction, and embryo-fetal toxicity.References

Package Insert:

1. Joensuu H, Escalating and de-escalating treatment in HER2-positive early breast cancer. Cancer Treatment Reviews 52 (2017) 1 – 11.

2. Maly, J. J. and Macrae ER. Pertuzumab in combination with Trastuzumab and chemotherapy treatment of HER2-positive metastatic breast cancer: safety, efficacy, and progression free survival. Breast Cancer: Basic and Clinical Research 2014:8, 81-88

3. Singh JC., Jhaveri K. and Esteva FJ.  HER2-positive advanced breast cancer: optimizing patient outcomes and opportunities for drug development. British Journal of Cancer. 2014 June; 111, 1888-1898.

4. Durkee BY., Qian Y., Pollom EL., et al. Cost-effectiveness of Pertuzumab in human epidermal growth factor receptor 2 – positive metastatic breast cancer. Journal of Clinical Oncology. 2015 September 8; 33, 1-12.

5. Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12; 366(2):109-119.

6. Keating GM. Pertuzumab: in the first-line treatment of HER2-positive metastatic breast cancer. Drugs. 2012 Feb 12; 72(3):353-360.

7. Arteaga CL, Sliwkowski MX, Osborne CK, Perez EA, Puglisi F, Gianni L. Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol. 2012 Jan; 9(1):16-32.

8. Press MF, Bernstein L, Thomas PA, Meisner LF, Zhou JY, Ma Y, et al. HER-2/neu gene amplification characterized by fluorescence in situ hybridization: poor prognosis in node-negative breast carcinomas. J Clin Oncol. 1997 Aug; 15(8):2894-2904.

9. Pegram M, Slamon D. Biological rationale for HER2/neu (c-erbB2) as a target for monoclonal antibody therapy. Semin Oncol. 2000 Oct; 27(5 Suppl 9):13-19.

10. Kawajiri H1, Takashima T, Kashiwagi S, Noda S, Onoda N, Hirakawa K. Pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer. Expert Rev Anticancer Ther. 2015 Jan; 15(1):17-26.

11. Swain SM, Baselga J, Kim S-B, Ro J, Semiglazov V et al. Pertuzumab, Trastuzumab, and Docetaxel in HER2-Positive Metastatic Breast Cancer. N Engl J Med 2015; 372:724-734.