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Cancer Drug Information

  • Updated: 10/01/2013

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FDA Approval for Pertuzumab

Brand name: Perjeta®

Full prescribing information is available, including a Boxed Warning for embryo-fetal toxicity, clinical trial information, safety, dosing, and use in specific populations.

Neoadjuvant Treatment of HER2-positive Breast Cancer

On September 30, 2013, the Food and Drug Administration (FDA) granted accelerated approval to pertuzumab injection (Perjeta®, made by Genentech, Inc.) for use in combination with trastuzumab and docetaxel for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory or early-stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer.

The approval of pertuzumab for neoadjuvant treatment of breast cancer is based on a randomized, multicenter, open-label trial in patients with HER2-positive, operable, locally advanced or inflammatory breast cancer (T2-4d). Breast tumor samples were required to show HER2 overexpression (IHC 3+ or FISH amplification ratio  of at least 2.0 determined by a central laboratory). The trial enrolled 417 patients who were randomly assigned to receive 1 of 4 neoadjuvant regimens prior to surgery as follows: trastuzumab plus docetaxel; pertuzumab plus trastuzumab and docetaxel; pertuzumab plus trastuzumab; or pertuzumab plus docetaxel.

Pertuzumab, trastuzumab, and docetaxel were administered preoperatively by intravenous infusion (IV) every 3 weeks for a total of 4 cycles. Following surgery all patients received 3 cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) IV every 3 weeks and trastuzumab was administered IV every 3 weeks to complete 1 year of therapy. The trial’s primary endpoint was pathologic complete response (pCR) rate defined as the absence of invasive cancer in the breast (ypT0/is). The FDA-preferred definition of pCR is the absence of invasive cancer in the breast and lymph nodes (ypT0/is ypN0).

Patient demographics were well balanced. Seven percent had inflammatory breast cancer, 32 percent had locally advanced cancer, and 70 percent had clinically node-positive breast cancer. Forty-seven percent of patients had hormone receptor-positive disease.

The pCR (ypT0/is ypN0) rates were 39.3 percent in patients who received pertuzumab plus trastuzumab and docetaxel and 21.5 percent in patients who received trastuzumab plus docetaxel. This difference of 17.8 percent was statistically significant (adjusted p-value = 0.0063, Cochran-Mantel-Haenszel test).  The pCR rates and magnitude of improvement with the addition of pertuzumab were lower in the subgroup of patients with hormone receptor-positive tumors compared to patients with hormone receptor-negative tumors.

The most common adverse reactions (more than 30 percent) with pertuzumab in combination with trastuzumab and docetaxel were alopecia, diarrhea, nausea and neutropenia. The most common (more than 2 percent) NCI – CTCAE (version 3) grade 3 – 4 adverse reactions were neutropenia, febrile neutropenia, leukopenia, and diarrhea. Other significant adverse reactions reported with pertuzumab include left ventricular dysfunction, infusion-related reactions, hypersensitivity reactions, and anaphylaxis. 

This approval is supported by an additional randomized phase II study conducted in 225 patients with HER2-positive, locally advanced, operable or inflammatory (T2-4d) breast cancer designed primarily to assess cardiac safety when FEC or carboplatin is incorporated into the preoperative regimen.

Pertuzumab is approved with a BOXED WARNING regarding cardiomyopathy and embryo-fetal toxicity. The cardiomyopathy warning is based on an increased rate of left ventricular ejection fraction (LVEF) decline observed in the neoadjuvant trials. Cardiac function should be evaluated prior to and during treatment with pertuzumab. The embryo-fetal toxicity warning is based on observations of oligohydramnios, delayed renal development and embryo-fetal death in animal studies.  Patients should be advised of these risks and the need for effective contraception prior to starting pertuzumab. 

The recommended dose and schedule of pertuzumab is an initial dose of 840 mg administered IV as a 60‑minute infusion followed every 3 weeks by 420 mg administered IV as a 30- to 60-minute infusion. Pertuzumab should be administered every 3 weeks for 3 to 6 cycles as part of one of the following treatment regimens for early breast cancer:

  • Four preoperative cycles of pertuzumab in combination with trastuzumab and docetaxel, followed by 3 postoperative cycles of FEC;
  • Three preoperative cycles of FEC alone, followed by 3 preoperative cycles of pertuzumab in combination with docetaxel and trastuzumab; or
  • Six preoperative cycles of pertuzumab in combination with docetaxel, carboplatin and trastuzumab (TCH).

Following surgery, patients should continue to receive trastuzumab to complete 1 year of treatment.  There is insufficient evidence to recommend continued use of pertuzumab for greater than 6 cycles for early breast cancer. There is insufficient evidence to recommend concomitant administration of an anthracycline with pertuzumab, and there are no safety data to support sequential use of doxorubicin with pertuzumab.

Pertuzumab, originally approved in June 2012, is a recombinant humanized monoclonal antibody that targets the extracellular dimerization domain (Subdomain II) of HER2, and thereby blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3, and HER4. 

This accelerated approval is based on demonstration of an improvement in pCR rate. No data are available demonstrating improvement in event-free survival or overall survival. Continued approval for this indication is contingent upon demonstration of improvement in disease-free survival in the confirmatory trial.

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Neoadjuvant Treatment of HER2-positive Breast Cancer

HER2-positive Metastatic Breast Cancer

On June 8, 2012, Food and Drug Administration approved pertuzumab injection (Perjeta, made by Genentech, Inc.) for use in combination with trastuzumab and docetaxel 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 is a recombinant humanized monoclonal antibody that targets the extracellular dimerization domain (subdomain II) of HER2 and thereby blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3, and HER4. 

The approval is based on a randomized double-blind placebo-controlled multicenter trial in patients with HER2-positive metastatic breast cancer. Breast tumor specimens were required to show HER2 overexpression, defined as 3+ IHC or FISH amplification ratio more than 2.0 using FDA-approved tests at a central laboratory. Patients with prior adjuvant or neoadjuvant therapy were required to have a disease-free interval of greater than 12 months before trial enrollment. 

The trial enrolled 808 patients who were randomly assigned (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 intravenous (IV) infusion at an initial dose of 840 mg, followed by 420 mg every three weeks. Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent. 

All but two patients were female (99.8 percent), and the median age was 54 years. Forty-eight percent of patients were hormone receptor positive, and 47 percent had received prior adjuvant or neoadjuvant chemotherapy. Forty-five percent of hormone receptor-positive patients had received prior adjuvant hormonal therapy. Eleven percent of patients had received prior adjuvant or neoadjuvant trastuzumab. 

A statistically significant 6.1-month improvement in median progression-free survival (PFS) was observed in patients in the pertuzumab group compared with patients in the placebo group [HR 0.62 (95 percent CI: 0.51, 0.75), p< 0.0001, log-rank test]. The median PFS was 18.5 months for patients in the pertuzumab group and 12.4 months for patients in the placebo group. At the time of PFS analysis, a planned interim analysis for overall survival (OS) was performed that showed a trend toward better OS in the pertuzumab group [HR 0.64 (95 percent CI: 0.47, 0.88), p=0.0053]. However, the HR and p-value for the interim analysis of OS did not meet the pre-defined stopping boundary (HR ≤ 0.603, p ≤ 0.0012).

The most common (more than 30 percent) adverse reactions observed in patients who received pertuzumab in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common (more than 2 percent)  NCI – CTCAE (version 3) grade 3 – 4 adverse reactions were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. Other significant adverse reactions reported with pertuzumab include left ventricular dysfunction, infusion-associated reactions, hypersensitivity reactions, and anaphylaxis. Pertuzumab in combination with trastuzumab and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in left ventricular ejection fraction (LVEF) compared with placebo in combination with trastuzumab and docetaxel.

Pertuzumab is being approved with a BOXED WARNING regarding embryo-fetal toxicity and birth defects, based on observations of oligohydramnios, delayed renal development and embryo-fetal death in animal studies. Patients should be advised of these risks and the need for effective contraception prior to starting pertuzumab. 

The recommended dose and schedule of pertuzumab is an initial dose of 840 mg administered as a 60-minute IV infusion, followed every 3 weeks, by 420 mg administered as a 30- to 60-minute IV infusion. When administered with pertuzumab, the recommended initial trastuzumab dose is 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 administered with pertuzumab, the recommended initial docetaxel dose is 75 mg/m2 administered as an IV infusion. The dose may be escalated to 100 mg/m2 administered every 3 weeks if the initial dose is well tolerated.

This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.

The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.

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