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New Breast Cancer Drug (Perjeta) Boosts Survival When Added To The Current Gold Standard Therapy

New survival data from the Phase III CLEOPATRA study, revealed at the San Antonio Breast Cancer Symposium (SABCS), demonstrate that Perjeta reduces the risk of death by 34% in patients with previously untreated advanced HER2-positive breast cancer, compared with the current gold standard of care – Herceptin and chemotherapy (docetaxel) (HR= 0.66; 95% CI 0.52-0.84).1 This means that, over the course of the study, patients receiving Perjeta were a third less likely to have passed away than those receiving Herceptin and chemotherapy alone.1

Data from the study also demonstrate a clear and improving survival benefit associated with the introduction of Perjeta over Herceptin and chemotherapy alone.1 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).1

“These results are really impressive, they show a rare magnitude of survival benefit for metastatic HER2-positive breast cancer patients,” said Dr. David Miles, Consultant Medical Oncologist, Mount Vernon Cancer Centre. “The strategy of using two HER2-targeted drugs with complementary mechanisms of action not only controls this aggressive disease, but also demonstrates that Perjeta will actually extend the lives of more patients while maintaining a quality of life comparable to Herceptin and chemotherapy in relation to the frequency of side effects.”

The most common side effects associated with Perjeta, Herceptin and chemotherapy were diarrhoea (68.1%), alopecia (hair loss) (60.8%), neutropenia (low white blood cell count) (52.9%), nausea (43.9%) and fatigue (38%).1a These side effects were also most common in the Herceptin and chemotherapy arm of the study, however the incidence of these events was slightly different: diarrhoea (48.2%), alopecia (60.6%), neutropenia (49.7%), nausea (42.4%) and fatigue (37.4%).1a

Perjeta works in a different way to any other cancer medicine. It is the first in a new class of targeted treatments, known as HER2 dimerisation inhibitors (or ‘HDIs’), which work to block cancer cell growth and survival signals.[ii]a The drug is given together with Herceptin and chemotherapy as a first treatment option for advanced breast cancer.1 Perjeta works synergistically with Herceptin to target the HER2 receptor, creating a double-action blockade effect:[iii],[iv]

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 HER4.3a When certain HER receptors pair (specifically HER2 and HER3), a ‘communication superhighway’ is opened up, creating a pathway for even stronger ‘survive and multiply’ signals to reach the cell.3a

Perjeta has been specifically designed to block the pairing of 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.3a,[v]

Typically, the analysis of survival data are triggered after a ‘median’ has been reached in both arms – meaning that, on both arms of the study, 50% or more of patients have passed away. By comparing the length of time patients on each arm of the study lived, scientists and statisticians can compare how much extra time a new medicine gives to patients. However, in the CLEOPATRA study, Perjeta proved to be so effective that a median had still not been reached in an updated overall survival analysis requested by the European Medicines Agency (EMA). The result was so positive the trial had to be ‘unblinded’ to allow patients on the comparator arm to benefit from Perjeta. The data presented at SABCS are based on more than 50% of deaths in the Herceptin plus chemotherapy arm, but only around 40% of deaths in the Perjeta arm.1 This indicates that patients in the Perjeta arm are living for significantly longer, but its exact survival benefit cannot be calculated until a median has been reached.

About HER2-positive breast cancer

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.[vi] 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.6

HER2-positive breast cancer accounts for up to 25% of all breast cancers3b, and is known to be a particularly aggressive form of the disease.[vii] It becomes ‘advanced’ or ‘metastatic’ when it has spread to other parts of the body, outside the breast where it was first diagnosed.

About Perjeta® (pertuzumab)

Perjeta is an innovative treatment, known as a monoclonal antibody, being studied in early and advanced stages of HER2-positive breast cancer. Perjeta is unique in that it is designed specifically to prevent the HER2 receptor from ‘dimerising’ or pairing with other HER receptors (HER1, HER3 and HER4), a process that is believed to play an important role in the growth and formation of several different cancer types.2a By preventing HER2 receptor pairing, Perjeta is thought to block cell signalling, which may inhibit cancer cell growth or lead to the death of the cancer cell.2a

Perjeta was granted license for use in the US by the Food and Drug Administration (FDA) earlier this year. An application has been made to the EMA for its use in Europe and if accepted, patients can expect to gain access to treatment in early 2013.

About the CLEOPATRA study

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.2b

Participants in the Perjeta, Herceptin and chemotherapy arm received:

  • Perjeta 840 mg loading dose followed by 420 mg every three weeks[viii]
  • Herceptin 8 mg/kg loading dose followed by 6 mg/kg every three weeks8
  • Chemotherapy (docetaxel) 75-100 mg/m2 every three weeks for six cycles or until progression8

Participants in the Herceptin and chemotherapy arm received:

  • Herceptin 8 mg/kg loading dose followed by 6 mg/kg every three weeks8
  • Chemotherapy (docetaxel) 75-100 mg/m2 every three weeks for six cycles or until progression8

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.2c

Results from the study showed:

  • 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) (HR= 0.66; 95% CI 0.52-0.84).1
  • There was a significant improvement in progression free survival (PFS) for patients who received the combination of Perjeta, Herceptin and chemotherapy (n=406) compared with those who received Herceptin and chemotherapy alone (n=402) (median PFS 18.5 vs. 12.4 months, HR=0.62, p=<0.0001, according to independent review).2d
  • 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 = 0.001).2e
  • The most common adverse events (AEs) in the Perjeta, Herceptin and chemotherapy arm were diarrhoea (68.1%), alopecia (60.8%), neutropoenia (52.9%), nausea (43.9%) and fatigue (38.0%).1 These AEs were also most common in the Herceptin and chemotherapy arm of the study, however the incidence of these events was slightly different: diarrhoea (48.2%), alopecia (60.6%), neutropoenia (49.7%), nausea (42.4%) and fatigue (37.4%).1a
  • The combination of Perjeta, Herceptin and chemotherapy was not associated with a higher incidence of cardiac AEs or left ventricular dysfunction compared with Herceptin and chemotherapy.1b

Ongoing studies with Perjeta

MARIANNE compares three different treatment regimens: the addition of Perjeta to T-DM1 (also currently in Phase III clinical trials), Herceptin plus chemotherapy alone and T-DM1 alone, in patients with HER2-positive advanced breast cancer who have not received prior treatment. PHEREXA compares Herceptin and chemotherapy, with and without Perjeta, in HER2-positive advanced breast cancer patients who have progressed after previous Herceptin-based therapy in a metastatic setting.

APHINITY compares Herceptin and chemotherapy with Perjeta and chemotherapy as adjuvant therapy in patients with operable HER2-positive early breast cancer.

About Herceptin® (trastuzumab)

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.[ix],[x] 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.9a Herceptin can also have effects on the heart that are treatable in the majority of cases.9a It was first licensed in Europe in 2000 for the treatment of HER2-positive mBC, 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: http://www.ema.europa.eu


[i] 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

[ii] 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

[iii] 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

[iv] 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

[v] Franklin MC et al. (2004) Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell;5:317–28

[vi]http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Breast/Symptomsdiagnosis/HormoneandHER2receptors/HER2andbreastcancer.aspx Last accessed September 2012

[vii] Boekhout, A.H. et al. (2011) Clinical Pharmacology: Concise Drug Reviews. Trastuzumab. The Oncologist; 16: 800–810

[viii]Perjeta® Draft SmPC Roche Products Ltd. Perjeta® Draft SmPC. November 2012 [ix] Herceptin® SmPC Roche Products Ltd. Herceptin® SmPC. September 2011 available at: http://www.medicines.org.uk/EMC

[x] 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