Date: 2014-09-28
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the 2014 Congress of the European Society for Medical Oncology (ESMO)
Company: Roche (Switzerland)
Product: Perjeta® (pertuzumab)
Action
mechanism: monoclonal antibody. Perjeta® is a personalized medicine that targets the HER2 receptor, a protein found in high quantities on the outside of cancer cells in HER2-positive cancers. Perjeta® is designed specifically to prevent the HER2 receptor from pairing (or “dimerizing”) with other HER receptors (EGFR/HER1, HER3 and HER4) on the surface of cells, a process that is believed to play a role in tumor growth and survival. Binding of Perjeta® to HER2 may also signal the body’s immune system to destroy the cancer cells. The mechanisms of action of Perjeta® and Herceptin® are believed to complement each other, as both bind to the HER2 receptor, but to different places. The combination of Perjeta®, Herceptin® and docetaxel chemotherapy is thought to provide a more comprehensive blockade of HER signaling pathways. A companion diagnostic test is used to determine if a person is HER2-positive and whether treatment with Perjeta® and Herceptin® is appropriate.
Disease: previously untreated HER2-positive metastatic breast cancer (mBC)
Therapeutic area: Cancer - Oncology
Country:
Trial
details: CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab) is an international, Phase III, randomized, double-blind, placebo-controlled study. The study evaluated the efficacy and safety profile of Perjeta combined with Herceptin and docetaxel chemotherapy compared to Herceptin and docetaxel chemotherapy plus placebo in 808 people with previously untreated HER2-positive mBC or with HER2-positive mBC that had come back after prior therapy in the adjuvant or neoadjuvant setting. The primary endpoint of the study was progression-free survival (PFS) as assessed by an independent review committee. Secondary endpoints were overall survival, PFS by investigator assessment, safety profile, overall response rate (ORR), duration of response and time to symptom progression. PFS and safety data from CLEOPATRA were presented at SABCS 2011 and simultaneously published in the New England Journal of Medicine.
Latest
news: * On September 28, 2014, Roche announced final survival results from the Phase III CLEOPATRA study, which showed that adding Perjeta® (pertuzumab) to Herceptin® (trastuzumab) and docetaxel chemotherapy extended the lives (overall survival; OS) of people with previously untreated HER2-positive metastatic breast cancer (mBC) by 15.7 months compared to Herceptin® and chemotherapy (median OS: 56.5 vs. 40.8 months). No new safety signals were observed in the study. These data will be presented today in the Presidential Symposium at the European Society for Medical Oncology (ESMO) 2014 congress in Madrid, Spain. At the time of the analysis, median OS had not yet been reached for people receiving the Perjeta® regimen as more than half of these people continued to survive. The results to be presented are from the final pre-specified OS analysis after a median follow-up of 50 months; median OS has now been reached for people receiving the Perjeta regimen. These data will be submitted to the regulatory authorities around the world for inclusion in the prescribing information for Perjeta®. The safety profile of Perjeta® in this analysis was consistent with that observed previously in the CLEOPATRA study, including Perjeta®’s long-term cardiac safety. No new safety signals were observed, and the OS results of this final analysis were consistent across patient subgroups. Perjeta® in combination with Herceptin® and docetaxel chemotherapy is approved in the United States and the EU for people with previously untreated HER2-positive mBC. The Perjeta® regimen has also been granted accelerated approval as a neoadjuvant treatment (use before surgery) for HER2-positive early breast cancer (eBC) by the FDA. An application to update the Marketing Authorisation to include this indication has also recently been submitted to the European Medicines Agency. * On December 7, 2012, Roche and Genentech have announced updated survival results from the Phase III CLEOPATRA study, which showed that the combination of Perjeta®(pertuzumab), Herceptin® (trastuzumab) and docetaxel chemotherapy significantly extended the lives (overall survival) of people with previously untreated HER2-positive metastatic breast cancer (mBC), compared to Herceptin, chemotherapy and placebo. Results showed that the risk of death was reduced by 34 percent for people who received Perjeta, Herceptin and chemotherapy, compared to those who received Herceptin® and chemotherapy (HR=0.66; p=0.0008). At the time of the analysis, median overall survival had not yet been reached in people receiving the Perjeta® combination, as more than half of these people continued to survive. Median overall survival was more than three years (37.6 months) for people who received Herceptin® and chemotherapy. Based on these data, people receiving Herceptin® and chemotherapy in CLEOPATRA have been offered the option to receive Perjeta®. No new safety signals were observed in the study. In June 2012, the FDA approved Perjeta® in combination with Herceptin® and docetaxel chemotherapy for the treatment of people with HER2-positive mBC who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease, based on the results of the CLEOPATRA study. * On June 22, 2012, Roche has announced that people with HER-2 positive metastatic breast cancer (mBC) lived significantly longer (overall survival) when treated with the combination of Perjeta® (pertuzumab), Herceptin® (trastuzumab) and docetaxel chemotherapy, compared to Herceptin and docetaxel chemotherapy alone in the Phase III CLEOPATRA study. These data will be submitted for presentation at an upcoming medical meeting.
Updates to previously reported OS, PFS and safety profile data from the CLEOPATRA study have also been presented. These data showed:
The risk of death was reduced by 32 percent for people who received the Perjeta® regimen compared to those who received Herceptin and chemotherapy (HR=0.68, 95 percent CI 0.56-0.84; p=0.0002).
People who received the Perjeta® regimen had a 32 percent reduction in the risk of their disease worsening or death (PFS; HR=0.68, 95 percent CI 0.58-0.80) compared to people who received Herceptin and chemotherapy.
With longer follow-up, the median PFS improvement of more than six months was maintained (median PFS of 18.7 months for people who received Perjeta®, Herceptin® and chemotherapy compared to 12.4 months for those who received Herceptin and chemotherapy).
The most common adverse events (AEs, rate greater than 25 percent or greater than 5 percent difference between study groups) seen with the Perjeta regimen were diarrhoea, rash, mucosal inflammation, headache, upper respiratory tract infection, itching, low white blood cell count with fever, dry skin and muscle spasms.
The most common Grade 3-4 AEs (rate greater than 10 percent) were low white blood cell count, low white blood cell count with fever and a decrease in a certain type of white blood cells. The safety profile of Perjeta® in this analysis was consistent with that observed previously in the CLEOPATRA study, including Perjeta’s long-term cardiac safety. No new safety signals were observed, and the OS results of this final analysis were consistent across patient subgroups.
This analysis of overall survival in the CLEOPATRA study crossed the pre-specified boundary showing that the combination of Perjeta®, Herceptin® and docetaxel chemotherapy significantly improved overall survival in people with HER2-positive mBC, compared with Herceptin® and chemotherapy. Overall survival is a secondary endpoint of the CLEOPATRA study.
The final progression free survival (PFS, the primary endpoint) and safety profile data from the CLEOPATRA study were published in December 2011 in the New England Journal of Medicine and demonstrated that people who received Perjeta® in combination with Herceptin® and docetaxel chemotherapy had a statistically significant 38 percent reduction in the risk of their disease worsening or death (progression-free survival; PFS, HR=0.62, p-value=<0.0001) compared to people who received Herceptin® and chemotherapy plus placebo (Baselga J, Cortes J, Sung-Bae K, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med.2012; 366:109–119). The median PFS improved by 6.1 months from 12.4 months for people who received Herceptin® and chemotherapy plus placebo to 18.5 months for those who received Perjeta®, Herceptin® and chemotherapy.
In CLEOPATRA, the most common adverse reactions (rate greater than 30 percent) seen with Perjeta® in combination with Herceptin® and docetaxel chemotherapy were diarrhoea, hair loss, low white blood cell count with or without fever, upset stomach, fatigue, rash and peripheral neuropathy (numbness, tingling or damage to the nerves). The most common Grade 3–4 adverse reactions (rate greater than 2 percent) were low white blood cell count with or without fever, decrease in a certain type of white blood cell, diarrhoea, damage to the nerves, decrease in red blood cell count, weakness and fatigue.
The FDA recently approved Perjeta® in combination with Herceptin and docetaxel chemotherapy for the treatment of people with HER2-positive mBC who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease, based on the results of the CLEOPATRA study . Roche has also submitted a Marketing Authorisation Application to the European Medicines Agency (EMA) for Perjeta® for people with previously untreated HER2-positive mBC.
