Women with HER2-positive metastatic breast cancer have been given a double-edged sword, with the Food and Drug Administration granting approval to pertuzumab on Friday, June 8, as a first-line therapy.*

The addition of pertuzumab (Perjeta), a new HER2 blocker, to a standard chemotherapy combination of trastuzumab (Herceptin) and docetaxel (Taxotere) has been shown to extend progression-free survival in these patients. Overall survival data are not yet available.

Pertuzumab is a humanized monoclonal antibody, manufactured through biotechnology methods by Genentech, a subsidiary of Roche. It also blocks other HER family members, including EGFR, HER3, and HER4, and is believed to complement HER2 inhibition by trastuzumab, also made by Genentech and Roche.

The approval rides largely on the results of the CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) trial. Dual HER2 blockade boosted median progression-free survival from 12.4 months in a control group treated with only the standard combination to 18.5 months in a group treated with standard therapy plus-pertuzumab. This is a statistically significant difference that corresponds to a 38% reduction in the risk for progression or death and an increase of 6.1 months in median progression-free survival. These results were published in the New England Journal of Medicine (2012;366:109-19).

For the double-blind phase III trial, 808 patients aged 18 years and older with centrally confirmed HER2-positive metastatic or locally recurrent, unresectable breast cancer were randomized either to a control group that received placebo plus trastuzumab and docetaxel or to the pertuzumab group, which received pertuzumab plus trastuzumab and docetaxel.

Preliminary data from the CLEOPATRA trial were presented at the annual San Antonio Breast Cancer Symposium in early December 2011. For expert commentary on the trial, see our video report.

Supply, Cost Could Be Concerns

In their announcements of pertuzumab approval, Genentech, maker of the drug, and the FDA disclosed that production issues could affect the long-term supply of the drug.

"We expect to meet demand for Perjeta following today\'s FDA approval. We recently identified a cell growth issue that might affect our future supply of the medicine," said Patrick Y. Yang, Ph.D., head, Pharma Global Technical Operations. "We take this very seriously and are working with the FDA to ensure a consistent manufacturing process that maintains drug supply for the people who need it."

With the approval, Genentech has agreed to postmarketing commitments related to the manufacturing process for Perjeta. These include FDA review of data from the next several productions of the medicine.

The FDA limited its approval to drug product that has not been affected by production issues, according to Dr. Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research.

"Given the need for additional treatments for metastatic breast cancer, we made the decision to approve this drug today and not to delay its availability to patients pending resolution of the production issues relating to future supply," she said in the FDA announcement.

"Genentech is currently developing a plan to mitigate the effect on patients of any potential shortage of Perjeta."

An added concern is the high cost of dual HER2 inhibition at a time when oncologists are under pressure to contain costs. According to the New York Times, Genentech is putting the wholesale cost of pertuzumab at $5,900/month, which added to the typical $4,500/month costs of trastuzumab, would drive the cost of 18 months of treatment to $187,000.

Boxed Warning Put on Label

Pertuzumab is indicated in combination with trastuzumab and docetaxel for "patients with HER2-positive metastatic breast cancer who have not received prior anti–HER2 therapy or chemotherapy for metastatic disease."

The FDA announced that pertuzumab would have a boxed warning on its label. This is to alert clinicians and patients to the potential risk of death or severe effects to a fetus. "Pregnancy status must be verified prior to the start of Perjeta treatment," it said; patients should be advised "of these risks and need for effective contraception prior to starting pertuzumab."

According to the agency, the most common side effects observed with use of pertuzumab in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral sensory neuropathy.

Although left ventricular dysfunction was observed, the FDA said the combination of pertuzumab with standard therapy "was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction or decreases in left ventricular ejection fraction, compared with placebo in combination with trastuzumab and docetaxel.

The FDA recommended that pertuzumab be started at an initial dose of 840 mg administered as a 60-minute IV infusion, followed every 3 weeks, thereafter, by 420 mg administered as a 30- to 60-minute IV infusion. It also recommended that when trastuzumab is used with pertuzumab, trastuzumab should be started at 8 mg/kg administered as a 90-minute IV infusion, followed every 3 weeks by a dose of 6 mg/kg administered IV over 30 to 90 minutes. When docetaxel is given with pertuzumab, the recommended starting docetaxel dose is 75 mg/m² administered as an IV infusion. If well tolerated, docetaxel may be escalated to 100 mg/m² every 3 weeks.

* This story was updated on 11/30/2012.

FDA Approves Pertuzumab for Metastatic HER2+ Breast Cancer