Pertuzumab (Perjeta)

Pertuzumab (Perjeta), manufactured by Genentech, is a human epidermal growth factor receptor 2 HER2/neu receptor antagonist recently FDA approved for use in combination with trastuzumab (Herceptin) and docetaxel (Taxotere) for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Pertuzumab, a recombinant humanized monoclonal antibody, targets the extracellular dimerization domain of HER2, as well as other HER family members, including EGFR, HER3, and HER4.^1,2

The HER2 protein is involved in normal cell growth; however, overexpression of the HER2/ neu protein is observed in 20% to 30% of human breast cancers and correlates with more aggressive tumors and a poorer prognosis. Pertuzumab works by targeting a different part of the HER2 protein than trastuzumab, resulting in further reduction in growth and survival of HER2- positive breast cancer cells. Therefore, the mechanisms of action of pertuzumab and trastuzumab are believed to complement each other since both bind to different regions of the HER2 receptor.^2,3

Pharmacokinetics

Pertuzumab exhibits linear pharmacokinetics at a dose range of 2 to 25 mg/kg. Based on a population PK analysis of 481 patients, the median clearance (CL) of pertuzumab was 0.24 L/day and the median half-life was 18 days. Following the FDA-approved dosing regimen, steady-state concentration of pertuzumab was reached after the first maintenance dose. The population PK analysis suggests no PK differences based on age, gender, and ethnicity (Japanese versus nonJapanese). Baseline serum albumin level and lean body weight as covariates only exerted a minor influence on PK parameters. Therefore, no dose adjustments based on body weight or baseline albumin level are needed.^1,2

Dosing

The initial dose of pertuzumab is 840 mg administered as a 60-minute intravenous (IV) infusion, followed every 3 weeks by a 420-mg IV infusion administered over 30 to 60 minutes. When administered with pertuzumab, the recommended initial dose of trastuzumab is 8 mg/kg administered as a 90-minute IV infusion, followed every 3 weeks by a 6-mg/kg IV infusion administered over 30 to 90 minutes. The recommended initial dose of docetaxel when administered with pertuzumab is 75 mg/m2 as an IV infusion. The dose may be escalated to 100 mg/m2 every 3 weeks if the initial dose is well tolerated.^1,2

For delayed or missed doses, if the time between infusions is less than 6 weeks, the 420 mg dose of pertuzumab should be administered. If the time between infusions is 6 weeks or more, the initial dose of 840 mg pertuzumab should be readministered followed every 3 weeks by a 420-mg dose. Pertuzumab should be withheld or discontinued if trastuzumab treatment is withheld or discontinued. If docetaxel is discontinued, treatment with pertuzumab and trastuzumab may continue. Dose reductions are not recommended for pertuzumab.^1,2

Clinical Efficacy

FDA approval of pertuzumab was based on a randomized, double-blind, placebo-controlled, multicenter trial in patients with HER2-positive metastatic breast cancer.^4,5 A total of 808 patients were randomly allocated (1:1) to receive pertuzumab in combination with trastuzumab and docetaxel (n = 402) or placebo in combination with trastuzumab and docetaxel (n = 406). Pertuzumab was given by IV infusion at an initial dose of 840 mg, followed by 420 mg every 3 weeks thereafter. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal.

The median age of patients in the study was 54 years. Almost half of patients (48%) were hormone receptor positive, and had received prior adjuvant or neoadjuvant chemotherapy (47%). Eleven percent of patients received prior adjuvant or neoadjuvant trastuzumab.

The median progression-free survival (PFS) was 18.5 and 12.4 months for patients on the pertuzumab and placebo arms, respectively. The 6.1 month improvement in median PFS observed in patients receiving pertuzumab compared with those receiving placebo was shown to be statistically significant [hazard ratio 0.62 (95% conference interval: 0.51, 0.75), p <0.0001]. The authors concluded that the combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects.^4,5

Medication Safety

Decreases in left ventricular ejection fraction (LVEF) have been reported with HER2 inhibitors, including pertuzumab; however, the rate of cardiotoxicity has not been increased compared with placebo in studies of pertuzumab/trastuzumab/ docetaxel. Patients who received prior anthracycline therapy or chest irradiation may be at an increased risk for cardiotoxicity, and LVEF should be evaluated prior to initiation of pertuzumab as well as at regular intervals during treatment (eg, every 3 months). Pertuzumab and trastuzumab treatment should be withheld for at least 3 weeks for a drop in LVEF to less than 40% or LVEF of 40% to 45% with a 10% or greater absolute decrease below pretreatment values. Pertuzumab may be resumed if the LVEF has recovered to greater than 45% or to 40% to 45% associated with less than a 10% absolute decrease below pretreatment values.^1,2

HER2 Testing

Detection of HER2 protein overexpression is necessary for selection of patients appropriate for pertuzumab treatment, as thus far these are the only patients who have been studied and shown benefit with pertuzumab. Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized; improper assay performance can lead to unreliable results.

Product Availability and Cost Considerations

Pertuzumab is available as 420- mg, single-use vials containing preservative-free solution. Vials should be kept refrigerated and protected from light. Each vial must be diluted in 250 mL of 0.9% sodium chloride and administered immediately once prepared. Dextrose should not be used to prepare pertuzumab. If the diluted infusion is not used immediately it can be stored for up to 24 hours if refrigerated.

The Average Wholesale Price of pertuzumab (Perjeta) is $4890 per 420-mg vial. Health care professionals can access more information about pertuzumab, including complete prescribing information at www.perjeta .com.

Ashley N. Lewis, PharmD, BCPS, is a drug information specialist at University of North Carolina Hospitals (UNCH). She completed her pharmacy training at Virginia Commonwealth University and went on to complete a general pharmacy practice residency followed by a drug information specialty residency at the Medical University of South Carolina. She is currently the pharmacy and therapeutics secretary at UNCH, and manages the day-to-day operations of the Drug Information Center and serves as a clinical assistant professor at the UNC Eshelman School of Pharmacy

References:

1. Perjeta package insert. Genentech, Inc. South San Francisco, CA. 6/12. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=17f85d17-ab71-4f5b-9fe3-0b8c822f69ff

2. Pertuzumab. In: DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically.

3. Mittendorf E, Storrer C, Shriver C, et al. Investigating the combination of trastuzumab and HER2/neu peptide vaccines for the treatment of breast cancer. Ann Surg Oncol. 2006;13(8):1085-98.

4. Baselga J, Cortes J, Kim S, et al. Petuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Eng J Med. 2012;366:109-19.

5. U.S. Food and Drug Administration. Drug Approvals and Databases. Pertuzumab [Internet]. FDA; [cited 2012 June 22]. Available from: http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm307592.htm?utm_campaign=Google2&utm_source=fdaSearch&utm_medium=website&utm_term=pertuzumab&utm_content=1