Products

Date: 2012-02-08

Type of information: Granting of a Market Authorisation in the EU

Product name: Perjeta®

Compound: pertuzumab

Therapeutic area: Cancer - Oncology

Action mechanism:

• monoclonal antibody. Pertuzumab is a humanized monoclonal antibody. It has been designed specifically to prevent the HER2 receptor from pairing (dimerizing) with other HER receptors (EGFR/HER1, HER3 and HER4), a process that is believed to play a critical role in the growth and formation of several different cancer types. By preventing receptor pairing, pertuzumab is thought to block cell signaling, which may inhibit cancer cell growth or lead to the death of the cancer cell. Binding of pertuzumab to HER2 may also signal the body’s immune system to destroy the cancer cells.
• The mechanisms of action of pertuzumab and Herceptin® are believed to complement each other, as both bind to the HER2 receptor but on different regions. The goal of combining pertuzumab with Herceptin® and chemotherapy is to determine if the combination may provide a more comprehensive blockade of HER signaling pathways.

Company: Genentech, a member of the Roche Group (USA - Switzerland)

Disease:

• use in combination with trastuzumab and docetaxel in adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer, who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease

Latest news:

• • On March 5, 2013, Roche announced that the European Medicines Agency (EMA) has approved Perjeta® (pertuzumab) for patients with previously untreated HER2-positive metastatic breast cancer (mBC). Perjeta® is approved in combination with Herceptin® (trastuzumab) and docetaxel in adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer, who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease.
• The European approval comes after the Phase III CLEOPATRA trial showed that the combination of Perjeta®, Herceptin® and chemotherapy provided patients with a median of 6.1 months longer without their disease worsening or death (progression-free survival, PFS) and provided a 34 percent reduction in the risk of death (overall survival) compared to Herceptin® and chemotherapy alone. Perjeta® is now approved in the EU, the US, and Switzerland for the treatment of people with HER2-positive mBC who have not received prior therapy for their metastatic disease. Further country approvals are anticipated during 2013.
• • On 13 December 2012, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for Perjeta®, 420 mg, concentrate for solution for infusion intended for use in combination with trastuzumab and docetaxel in adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer, who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease. The most common side effects are were diarrhoea, alopecia, leucopenia and (febrile) neutropenia. A pharmacovigilance plan for Perjeta® will be implemented as part of the marketing authorisation. It is proposed that Perjeta® be prescribed by physicians experienced in the administration of anticancer agents.
• • On June 8, 2012, the FDA has approved pertuzumab injection (Perjeta®) 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. 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 ? 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 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 intravenous (IV) infusion at an initial dose of 840 mg, followed by 420 mg every three weeks thereafter. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal. All but two patients were female (99.8%), and the median age was 54 years. Forty-eight percent of patients were hormone receptor positive, and 47% received prior adjuvant or neoadjuvant chemotherapy. Forty-five percent of hormone receptor positive patients received prior adjuvant hormonal therapy. Eleven percent of patients received prior adjuvant or neoadjuvant trastuzumab. A statistically significant 6.1 month improvement in median progression-free survival (PFS) was observed in patients receiving pertuzumab compared to those receiving placebo [HR 0.62 (95% CI: 0.51, 0.75), p< 0.0001, log-rank test]. The median PFS was 18.5 and 12.4 months for patients on the pertuzumab and placebo arms, respectively. At the time of PFS analysis, a planned interim analysis for overall survival (OS) was performed [HR 0.64 (95% 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.
• The most common (> 30%) adverse reactions observed in patients receiving pertuzumab in combination with trastuzumab and docetaxel neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common (> 2%) 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.were diarrhea, alopecia,
• 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 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, thereafter, 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
• • On May 25, 2012, Chugai Pharmaceutical, a member of Roche Group, announced  that it has filed a new drug application to the Japanese Ministry of Health, Labour and Welfare (MHLW), for humanized HER dimerization inhibitory monoclonal antibody “pertuzumab” for the treatment of “HER2-positive metastatic or recurrent breast cancer.” Chugai filed an application for approval with the MHLW based on the results from a multinational phase III clinical trial (CLEOPATRA trial, including Japanese patients) and a domestic phase I clinical trial.
• • On February 8, 2012, Roche and Genentech have announced that the FDA has accepted the company’s Biologics License Application for pertuzumab and granted Priority Review. The FDA confirmed the action date is June 8, 2012. Roche has also submitted a Marketing Authorization Application to the European Medicines Agency (EMA) for pertuzumab for people with previously untreated HER2-positive metastatic breast cancer (mBC). The pertuzumab application is also based on results from the pivotal Phase III CLEOPATRA study. The study demonstrated a 6.1 month improvement in median progression-free survival (PFS) for people who received a pertuzumab-based regimen (pertuzumab combined with Herceptin® and docetaxel chemotherapy) compared to those who received Herceptin and chemotherapy alone (median PFS 18.5 vs. 12.4 months). People who received the combination also experienced a 38 percent reduction in the risk of their disease worsening or death (HR=0.62, p-value less than 0.0001, according to independent review).
• Adverse events (AEs) were consistent with those seen in previous studies of pertuzumab and Herceptin, either in combination or alone. Rates of Grade 3 or higher AEs with more than 2 percent difference between arms were observed for neutropenia (low white blood cell count), febrile neutropenia (fever plus low white blood cell count) and diarrhea with 48.9 percent, 13.8 percent and 7.9 percent in the pertuzumab, Herceptin® and chemotherapy arm compared with 45.8 percent, 7.6 percent and 5.0 percent in the Herceptin plus chemotherapy arm, respectively. The pertuzumab-based regimen was not associated with a higher incidence of cardiac AEs or left ventricular dysfunction compared with Herceptin® and chemotherapy. Left ventricular dysfunction occurred in 8.3 percent of people in the Herceptin® and chemotherapy arm and 4.4 percent of people in the pertuzumab, Herceptin® and chemotherapy arm. well tolerated.

Patents:

Submission of marketing authorization application USA :

Submission of marketing authorization application UE:

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization: 2012-06-08

UE authorization: 2013-03-04

Favourable opinion UE: 2012-12-13

Favourable opinion USA:

Orphan status USA:

Orphan status UE:

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

Is general: Yes