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NICE rejects Perjeta® (pertuzumab) following the Department of Health indecision on funding proposals, calling into question future access when the Cancer Drug Fund ends in January 2014.
The Department of Health (DH) could be set to let down thousands of patients with an aggressive form of advanced breast cancer. The DH has not made a decision on a patient access scheme proposed by Roche, despite having had several weeks for review. The scheme, already given the green light by NICE's own independent group of experts, is with the DH for ministerial ratification, but has not materialised. With the Cancer Drugs Fund in England due to come to an end in six months, this inability to make a decision casts a looming shadow of doubt over the future availability of this life extending personalised cancer drug.
Perjeta has shown that on average, advanced HER2-positive patients live 6.1 months longer without their cancer getting worse, compared with those receiving Herceptin® (trastuzumab) and chemotherapy alone (primary endpoint, progression-free survival or 'PFS') (median PFS 18.5 vs. 12.4 months, HR=0.62, p<0.0001) and could represent a new standard of care for this disease.
David Miles, Consultant Oncologist, Mount Vernon Cancer Centre, London, said: "Perjeta is already being used in England to help fight this aggressive form of breast cancer. This drug offers the sort of benefits that we haven't seen since the introduction of Herceptin more than 10 years ago. To recommend stopping the funding for Perjeta would be a retrograde step in the treatment of HER2+ breast cancer, and a blow for all those affected by this devastating disease."
Roche is extremely disappointed that once again NICE and the DH have failed to safeguard funding for yet another advanced breast cancer treatment; Perjeta could become the seventh such cancer treatment to be rejected by NICE since 2011.,,,,, This is a poor and unacceptable record which serves to highlight some serious flaws in an aged and creaking system.
Roche therefore urges the DH to review the patient access scheme as soon as possible so that NICE can revise its modeling based on the funding proposals set out by Roche.
Further data from the Phase III CLEOPATRA study, showed that the combination of Perjeta plus Herceptin and chemotherapy reduces the risk of death by 34% (overall survival, HR=0.66; 95%, CI 0.52-0.84, p=0.0008)8and more patients respond to the combination treatment compared with Herceptin and chemotherapy alone (80% compared with 69%, 95% CI, 4.2 to 17.5; p=0.0011).
Perjeta maintains a quality of life comparable with Herceptin and chemotherapy in relation to the frequency of side effects. In the CLEOPATRA study, the combination of Perjeta, Herceptin and chemotherapy was associated with higher rates of diarrhoea (66.8% v. 46.3%), rash (33.7% v. 24.2%), mucosal inflammation (27.8% v. 19.9%), febrile neutropaenia (13.8% v. 7.6%) and dry skin (10.6% v. 4.3%). These side effects were primarily low grade (1 and 2), manageable and occurred during docetaxel therapy (which was administered for at least six cycles in the CLEOPATRA study). There was no increase in cardiac side effects or left ventricular systolic dysfunction (LVSD).
HER2 is a receptor found on the surface of all cells. Like a satellite dish, it sends messages or 'signals' into the cell telling it to survive and multiply. In HER2-positive breast cancer, there are too many HER2 receptors on the surface of cancerous cells. As a result, the cells receive a high number of 'survive and multiply' signals - causing rapid growth and spread of the tumour. HER2-positive breast cancer accounts for up to 25% of all breast cancers, and is known to be a particularly aggressive form of the disease. It becomes 'advanced' or 'metastatic' when it has spread to other parts of the body, outside the breast where it was first diagnosed.
Perjeta is the first in a new class of personalised treatments known as 'HER2 dimerisation inhibitors' (or 'HDIs') and works in a different way to any other cancer medicine. It works synergistically with Herceptin to block cancer cell survival and growth signals,, specifically targeting the HER2 receptor - a protein found in high quantities on the surface of cells in HER2-positive breast cancers.
Perjeta is unique in that it is designed specifically to prevent the HER2 receptor from 'dimerising' or pairing with other HER receptors, a process that is believed to play an important role in the growth and formation of several different cancer types.
Perjeta works with Herceptin to provide a double-action blockade effect:,
Herceptin works by attaching to the HER2 receptor and blocking the 'survive and multiply' signals it sends directly into the cell. But even with these 'direct' signals blocked, the HER2 receptor finds another way to send even more powerful signals into the cell - by 'dimerising' (or pairing / coupling) with other members of the HER family, such as HER1, HER3 and HER4.
The HER2 to HER3 pairing combination creates the most potent pathway for 'survive and multiply' signals to reach the cell.10
Perjeta has been specifically designed to block HER2 from pairing with any of the HER family receptors. By combining it with Herceptin, a more comprehensive blockade of HER2 signaling is created, which in turn, leads to inhibited growth and - ultimately - cell death.,
Perjeta received marketing authorisation in February 2013. A summary of product characteristics is available on the EMA website.
CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab) is an international, Phase III, randomised, double-blind, placebo-controlled study. The study evaluated the efficacy and safety profile of Perjeta combined with Herceptin and chemotherapy compared with Herceptin and chemotherapy alone in 808 people with previously untreated HER2-positive advanced breast cancer.1
Participants in the Perjeta, Herceptin and chemotherapy arm received:
Participants in the Herceptin and chemotherapy arm received:
Patients in the study were treated until disease progression which was an average of 18.5 months (PFS) in the Perjeta, Herceptin and chemotherapy arm.
The primary endpoint of the study was progression free survival (PFS) as assessed by an independent review committee. Secondary endpoints were overall survival (OS), PFS by investigator assessment, safety profile, overall response rate (ORR), duration of response, time to symptom progression and correlation of biomarkers with clinical outcomes.1d
The risk of death over the course of the study was reduced by 34% in patients with previously untreated advanced HER2-positive breast cancer, compared with the current gold standard of care - Herceptin and chemotherapy (docetaxel) (overall survival, HR=0.66; 95%, CI 0.52-0.84, p=0.0008).8
Data from the study also demonstrate a clear and improving survival benefit associated with the introduction of Perjeta over Herceptin and chemotherapy alone. After one year of the trial, 94% of patients in the Perjeta arm were still alive, compared with 89% in the comparator arm; at two years the additional benefit of Perjeta is even greater at 81% vs. 69%; and at three years it is greater still, at 66% vs. 50% (HR= 0.66; 95% CI 0.52 - 0.84).8
There was a significant improvement in progression free survival (PFS) for patients who received the combination of Perjeta, Herceptin and chemotherapy (n=402) compared with those who received Herceptin and chemotherapy alone (n=406) (median PFS 18.5 vs. 12.4 months, HR=0.62, p<0.0001, according to independent review).1
Overall response rate (ORR) was 80 percent in the Perjeta, Herceptin and chemotherapy arm and 69 percent in the Herceptin plus chemotherapy arm, (10.8% difference; 95% CI, 4.2 to 17.5; P=0.0011).1
The most common side effects in the Perjeta, Herceptin and chemotherapy arm were diarrhoea (66.8%), alopecia (60.9%), neutropoenia (52.8%), nausea (42.3%) and fatigue (37.6%). These side effects were also the most common in the Herceptin and chemotherapy arm of the study, however the incidence of these events was different: diarrhoea (46.3%), alopecia (60.5%), neutropoenia (49.6%), nausea (41.6%) and fatigue (36.8%).
The combination of Perjeta, Herceptin and chemotherapy was not associated with a higher incidence of cardiac side effects or left ventricular dysfunction compared with Herceptin and chemotherapy.1f Perjeta has not been studied in patients with: a pre-treatment LVEF value of ? 50%; a prior history of congestive heart failure (CHF); LVEF that declines to < 50% during prior trastuzumab adjuvant therapy;1g or with conditions that could impair left ventricular function such as uncontrolled hypertension (high blood pressure), recent myocardial infarction (heart attack), serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m2 of doxorubicin or its equivalent.
Herceptin is a humanised antibody designed to target and block the function of HER2, a protein produced by a specific gene with cancer-causing potential. The mode of action of Herceptin activates the body's immune system and suppresses HER2 to target and destroy the tumour. Herceptin has demonstrated efficacy in treating both early and advanced (metastatic) HER2-positive breast cancer as well as HER2-positive advanced (metastatic) stomach cancer. Given on its own as monotherapy as well as in combination with or following standard chemotherapy, Herceptin has been shown to improve disease-free survival, overall survival and response rates while maintaining quality of life in people with HER2-positive breast and stomach cancer., Like most treatments, Herceptin can be associated with side effects. The most common of these are mild flu-like symptoms such as chills and/or fever that usually occur as a reaction to its administration.[16a] Herceptin can also have effects on the heart that are treatable in the majority of cases. It was first licensed in Europe in 2000 for the treatment of HER2-positive metastatic breast cancer, and in 2006 for early breast cancer. Herceptin is marketed in the US by Genentech, in Japan by Chugai and internationally by Roche.
A summary of product characteristics is available on the EMA website.
 Baselga J. A Phase III, Randomized, Double-Blind, Placebo-Controlled Registration Trial to Evaluate the Efficacy and Safety of Placebo + Trastuzumab + Docetaxel vs. Pertuzumab + Trastuzumab + Docetaxel in Patients with Previously Untreated HER2-Positive Metastatic Breast Cancer (CLEOPATRA). Oral Presentation, SABCS 9th December abstract #S5-5
 National Institute for Health and Clinical Excellence. Bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer.
 National Institute for Health and Clinical Excellence. Fulvestrant for the treatment of locally advanced or metastatic breast cancer.
 National Institute for Health and Clinical Excellence. Eribulin for the treatment of locally advanced or metastatic breast cancer.
 National Institute for Health and Clinical Excellence. Lapatinib or trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone-receptor-positive breast cancer that overexpresses HER2.
 National Institute for Health and Clinical Excellence. Bevacizumab in combination with capecitabine for the first-line treatment of metastatic breast cancer.
 National Institute for Health and Clinical Excellence. Everolimus in combination with exemestane for treating advanced HER2 negative hormone-receptor-positive breast cancer after endocrine therapy.
 Swain SM et al. (2012) Confirmatory overall survival analysis of CLEOPATRA: A randomized, double-blind, placebo-controlled Phase III study with pertuzumab, trastuzumab, and docetaxel in patients with HER2-positive first-line MBC. Poster P5-18-26 presented at SABCS; December 08 2012, San Antonio, Texas, USA
 macmillan.org.uk - HER2andbreastcancer.aspx [Last accessed August 2013]
 Baselga J, Swain SM. (2010) CLEOPATRA: A Phase III Evaluation of Pertuzumab and Trastuzumab for HER2-Positive Metastatic Breast Cancer. Clin Breast Cancer. Dec 1;10(6):489-91
 Boekhout, A.H. et al. (2011) Clinical Pharmacology: Concise Drug Reviews. Trastuzumab. The Oncologist; 16: 800?810
 Nahta R et al. (2004) The HER-2-Targeting Antibodies Trastuzumab and Pertuzumab Synergistically Inhibit the Survival of Breast Cancer Cells. Cancer Research;64:2343?2346
 Franklin MC et al. (2004) Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell;5:317?28
 Perjeta® SmPC Roche Products Ltd. Perjeta® SmPC. March 2013
 Baselga, J et al. (2012) Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer. N Engl J Med 366(2):109-119
 Herceptin® SmPC Roche Products Ltd. Herceptin® SmPC. January 2013 available at: www.medicines.org.uk/EMC
 Rugo H et al. (2010) Effect of Trastuzumab on Health-Related Quality of Life in Patients With HER2-Positive Metastatic Breast Cancer: Data From Three Clinical Trials. Clin Breast Cancer 1;10(4):288-9
Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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