Products

Date: 2017-12-20

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

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) Roche (Switzerland)

Disease:

• neoadjuvant treatment in people with HER2-positive early stage breast cancer
• adjuvant (after surgery) treatment of HER2-positive early breast cancer at high risk of recurrence

Latest news:

• • On December 20, 2017,  the FDA has approved Perjeta ® (pertuzumab), in combination with Herceptin® (trastuzumab) and chemotherapy (the Perjeta-based regimen), for adjuvant (after surgery) treatment of HER2-positive early breast cancer at high risk of recurrence. People should receive the adjuvant Perjeta-based regimen for one year (up to 18 cycles). The FDA has also converted the previously granted accelerated approval of the Perjeta-based regimen to full approval for neoadjuvant (before surgery) treatment of HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than two centimeters in diameter or node-positive). People receiving the neoadjuvant Perjeta-based regimen should continue Perjeta and Herceptin after surgery to complete one year of treatment.
• The FDA-approved use of the Perjeta-based regimen for adjuvant treatment of HER2-positive EBC at high risk of recurrence is based on results of the Phase III APHINITY study. At the time of the primary analysis with a median of 45.4 months follow-up:
• In the overall study population, Perjeta, Herceptin and chemotherapy significantly reduced the risk of invasive breast cancer recurrence or death by 18 percent compared to Herceptin and chemotherapy alone (HR=0.82, 95% CI 0.67-1.00, p=0.047).High-risk patients included patients such as those with lymph node-positive or hormone receptor-negative breast cancer. The subgroup results were as follows:
• Lymph node-positive subgroup (HR=0.77, 95% CI 0.62-0.96)
• Hormone receptor-negative subgroup (HR=0.76, 95% CI 0.56-1.04)
• Hormone receptor-positive subgroup (HR=0.86, 95% CI 0.66-1.13)
• Lymph node-negative subgroup (HR=1.13, 95% CI 0.68-1.86)
• The most common severe (Grade 3-4) side effects with the Perjeta-based regimen are low levels of white blood cells with or without a fever, diarrhea, decrease in certain types of white blood cells, decrease in red blood cells, fatigue, nausea and mouth blisters or sores. The most common side effects are diarrhea, nausea, hair loss, fatigue, nerve damage and vomiting.
• The supplemental Biologics License Application for the Perjeta-based regimen for adjuvant treatment of HER2-positive EBC was granted Priority Review, a designation given to medicines the FDA has determined to have the potential to provide significant improvements in the treatment, prevention or diagnosis of a disease.
• The following table is a summary of APHINITY study results supporting this approval.

• APHINITY Study Results Median follow-up for intent-to-treat (ITT) population 45.4 months (381 events)
  Primary endpoint: invasive disease-free survival (iDFS) HR=0.82, 95% CI 0.67-1.00, p=0.04 7*
  	Perjeta + Herceptin + chemotherapy  n=2,400	Placebo + Herceptin + chemotherapy  n=2,404
  iDFS at 3 years
  ITT population n=4,804	94.1% 171 events	93.2% 210 events
  	HR=0.82, 95% CI 0.67-1.00, p=0.047*
  Node-positive subgroup † n=3,005	92.0% 139 events n=1,503	90.2% 181 events n=1,502
  	HR=0.77, 95% CI 0.62-0.96
  Node-negative subgroup † n=1,799	97.5% 32 events n=897	98.4% 29 events n=902
  	HR=1.13, 95% CI 0.68-1.86
  Hormone receptor-positive subgroup † n=3,082	94.8% 100 events n=1,536	94.4% 119 events n=1,546
  	HR=0.86, 95% CI 0.66-1.13
  Hormone receptor-negative subgroup † n=1,722	92.8% 71 events n=864	91.2% 91 events n=858
  	HR=0.76, 95% CI 0.56-1.04
  Anthracycline chemotherapy subgroup† n=3,742	93.8% 139 events n=1,865	93.0% 171 events n=1,877
  	HR=0.82, 95% CI 0.66-1.03
  Non-anthracycline chemotherapy subgroup † n=1,062	94.9% 32 events n=535	94.0% 39 events n=527
  	HR=0.82, 95% CI 0.51-1.31
  Safety
  Heart failure ‡	0.6%	0.2%
  Most common (?5%) severe (Grade 3-4) adverse events
  Neutropenia Decrease in a certain type of white blood cell	16%	16%
  Febrile neutropenia Fever associated with decrease in a certain type of white blood cell	12%	11%
  Diarrhea	10%	4%
  Neutrophil count decreased Decrease in a certain type of white blood cell	10%	10%
  Anemia Decrease in red blood cells	7%	5%

  * Analysis stratified by nodal status, protocol version, central hormone receptor status and adjuvant chemotherapy regimen. Stratification factors are defined according to the randomization data for iDFS. ^† Exploratory analyses without adjusting for multiple comparisons. Results are considered descriptive. ^‡ Symptomatic heart failure (New York Heart Association class III or IV) with left ventricular ejection fraction (LVEF) drop ?10 percent from baseline and to below 50 percent.
• • On 25 June 2015, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a change to the terms of the marketing authorisation for Perjeta®. The CHMP adopted a new indication as follows: “Perjeta® is indicated for use in combination with trastuzumab and chemotherapy for the neoadjuvant treatment of adult patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer at high risk of recurrence ”. The full indications for Perjeta will be as follows: “Metastatic Breast Cancer: Perjeta® is indicated 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 antiHER2 therapy or chemotherapy for their metastatic disease. Neoadjuvant Treatment of Breast Cancer: Perjeta® is indicated for use in combination with trastuzumab and chemotherapy for the neoadjuvant treatment of adult patients with HER2-positive, locally advanced, inflammatory,or early stage breast cancer at high risk of recurrence.”
• • On September 30, 2013, the FDA has granted accelerated approval to Perjeta® (pertuzumab) as part of a complete treatment regimen for patients with early stage breast cancer before surgery (neoadjuvant setting). Perjeta® is the first FDA-approved drug for the neoadjuvant treatment of breast cancer. Perjeta®’s new use is intended for patients with HER2-positive, locally advanced, inflammatory or early stage breast cancer (tumor greater than 2 cm in diameter or with positive lymph nodes) who are at high risk of having their cancer return or spread (metastasize) or of dying from the disease. It is to be used in combination with trastuzumab and other chemotherapy prior to surgery and, depending upon the treatment regimen used, may be followed by chemotherapy after surgery. Following surgery, patients should continue to receive trastuzumab to complete one year of treatment. This accelerated approval for neoadjuvant treatment is based on a study designed to measure pCR. In the study, 417 participants were randomly assigned to receive one of four neoadjuvant treatment regimens: trastuzumab plus docetaxel, Perjeta® plus trastuzumab and docetaxel, Perjeta® plus trastuzumab or Perjeta plus docetaxel. About 39 percent of participants who received Perjeta plus trastuzumab and docetaxel achieved pCR, compared to about 21 percent who received trastuzumab plus docetaxel. The confirmatory trial for this accelerated approval is being conducted in participants with HER2-positive breast cancer who had prior breast cancer surgery and are at high risk of having their cancer return. More than 4,800 participants are enrolled in this trial, which will provide further data on efficacy, safety and long-term outcomes. A full review of data from the ongoing Phase III APHINITY study will be required for the accelerated approval to be converted to a full approval. APHINITY compares Perjeta®, Herceptin® and chemotherapy with Herceptin and chemotherapy for adjuvant (post-surgery) treatment in people with HER2-positive early stage breast cancer. Data from APHINITY are expected in 2016.
• Roche is discussing the option of submitting Perjeta® in the neoadjuvant setting to regulatory authorities in other countries around the world. Perjeta is already approved in a number of countries including the United States for people with HER2-positive metastatic breast cancer (an advanced form of the disease in which the cancer has spread to other parts of the body) or locally recurrent, unresectable (inoperable) breast cancer who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease.
• • On September 12, 2013, Genentech, a member of the Roche Group, has announced that the FDA Oncologic Drugs Advisory Committee (ODAC) voted 13 to 0, with one abstention, in favor of recommending accelerated approval of a Perjeta® (pertuzumab) regimen for neoadjuvant treatment (use before surgery) in people with high-risk, HER2-positive early stage breast cancer. The FDA will make a decision on whether or not to approve Perjeta for this use by October 31, 2013.
• The ODAC recommendation was based on a review of results from NEOSPHERE and TRYPHAENA, two Phase II studies of Perjeta in high-risk, HER2-positive early stage breast cancer, as well as on longer-term safety data from the Phase III CLEOPATRA study of Perjeta in HER2-positive metastatic breast cancer (See below).
• The ongoing Phase III APHINITY study will further evaluate Perjeta® in the adjuvant setting (after surgery) and compares Perjeta, Herceptin® (trastuzumab) and chemotherapy with Herceptin® and chemotherapy in people with HER2-positive early stage breast cancer. The study has completed enrollment with approximately 4,800 people, and the primary endpoint is invasive disease-free survival (IDFS). Genentech has proposed this study as a confirmatory study to the FDA. Data are expected in 2016.
• • On July 1, 2013, Genentech has announced that the FDA has accepted the company's supplemental Biologics License Application (sBLA) for the use of a Perjeta® (pertuzumab) regimen before surgery (neoadjuvant treatment) in people with HER2-positive early stage breast cancer. The FDA has granted a Priority Review of the application and will make a decision on approval by October 31, 2013.
• The application is based primarily on results from NEOSPHERE and TRYPHAENA, two Phase II studies of Perjeta® in HER2-positive early stage breast cancer, as well as on longer-term safety data from the Phase III CLEOPATRA study of Perjeta® in HER2-positive metastatic breast cancer.
• The NEOSPHERE study (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) is a randomized, multicenter, international Phase II study that was conducted in 417 people with newly diagnosed HER2-positive, locally advanced, inflammatory or early stage breast cancer. Participants were randomized to four study arms and received four cycles (12 weeks) of neoadjuvant treatment. The primary endpoint was pCR. Secondary endpoints included clinical response, time to clinical response, safety profile, disease-free survival (DFS), breast-conserving surgery rate and biomarker assessment. Study data showed the following:
• Treatment with Perjeta®, Herceptin® and docetaxel chemotherapy significantly improved the rate of pCR by 58 percent compared to Herceptin and docetaxel alone (45.8 percent vs. 29.0 percent, p=0.014).
• pCR of 29.0 percent for Herceptin and docetaxel
• pCR of 45.8 percent for Perjeta, Herceptin and docetaxel
• pCR of 16.8 percent for Perjeta and Herceptin
• pCR of 24.0 percent for Perjeta and docetaxel
• The combination of Perjeta, Herceptin and docetaxel was not associated with a significant increase in adverse events (AEs) or cardiac AEs, compared to Herceptin and docetaxel. The most common severe (Grade 3 or higher) AEs for the Perjeta regimen were neutropenia (decrease in a certain type of white blood cell, 44.9 percent), febrile neutropenia (fever associated with decrease in a certain type of white blood cell, 8.4 percent) and diarrhea (5.6 percent).
• The TRYPHAENA study (ToleRabilitY of Pertuzumab, Herceptin and AnthracyclinEs in NeoAdjuvant breast cancer) is a randomized, multicenter Phase II study that was conducted in 225 people with HER2-positive, locally advanced, inflammatory or early stage breast cancer. Participants were randomized to one of three neoadjuvant Perjeta regimens. The primary endpoint was cardiac safety. Secondary endpoints included pCR, clinical response, breast-conserving surgery rate, DFS, progression-free survival (PFS), overall survival (OS) and biomarker assessment. Study data showed the following:
• The study was not powered to compare the three study arms. The rate of pCR in the three arms were as follows:
• pCR of 61.6 percent for Perjeta, Herceptin and anthracycline-based chemotherapy, followed by Perjeta, Herceptin and docetaxel
• pCR of 57.3 percent for anthracycline-based chemotherapy, followed by Perjeta, Herceptin and docetaxel
• pCR of 66.2 percent for the anthracycline-free arm (Perjeta, Herceptin, docetaxel and carboplatin chemotherapy)
• No new or unexpected cardiac AEs, or other AEs, were observed in any of the study arms. AEs observed were consistent with those seen in previous studies of Perjeta, Herceptin and chemotherapy, either in combination or alone.
• The most common severe AEs in any of the three study arms were:
• In the concurrent arm: neutropenia (47.2 percent), leukopenia (decrease in overall white blood cells, 19.4 percent) and febrile neutropenia (18.1 percent)
• In the sequential arm: neutropenia (42.7 percent), leukopenia (12.0 percent) and febrile neutropenia (9.3 percent)
• In the anthracycline-free arm: neutropenia (46.1 percent), febrile neutropenia (17.1 percent), anemia (decrease in red blood cells, 17.1 percent); the AEs of diarrhea, leukopenia, anemia and thrombocytopenia (decrease in platelets) all had an incidence of 11.8 percent
• Perjeta® (pertuzumab) is approved for use in combination with Herceptin® (trastuzumab) and docetaxel chemotherapy in people with HER2-positive breast cancer that has spread to different parts of the body (metastatic) and who have not received anti-HER2 therapy or chemotherapy for metastatic disease.

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: 2013-09-30/2017-12-20

UE authorization: 2015-08-28

Favourable opinion UE: 2015-06-25

Favourable opinion USA: 2013-09-12

Orphan status USA:

Orphan status UE:

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

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