The U.S. Food and Drug Administration?s (FDA) Oncologic Drugs Advisory Committee (ODAC) voted 13 to 0, with one abstention, in favor of recommending accelerated approval of a regimen of pertuzumab (Perjeta?, Genentech/Roche) for neoadjuvant treatment in women with high-risk, HER2-positive early stage breast cancer.
Breast cancer is the most common cancer among women worldwide. According to the American Cancer Society(ACS), approximately 235,000 women in the United States will be diagnosed with breast cancer. Based on long-term data, it is expected that in 2013 40,000 will die from the disease in the U.S. alone. 
TheHuman Epidermal growth factor Receptor 2 orHER2 is a protein involved in normal cell growth. However, HER2 is found in increased amounts on some types of cancer cells (HER2-positive), including some breast cancers.In these HER2-positive breast cancer, the increased amount of HER2 present on the surface of the tumor cellscontributes to cancer cell growth and survival.Known as ?HER2 positivity?, this particularly aggressive form of breast cancer affects approximately 25% of patients with breast cancer. This disease has a high risk of recurrence anddeath.
Although treatment with trastuzumab(Herceptin?, Genentech/Roche)andchemotherapy has improved outcomes for patients with high-risk HER2-positive early stage breast cancer,there remains a major unmet medical need. Depending ontumor stage and characteristics, the available data shows that 17-40% of patients treated with trastuzumab-basedtherapies in the early stage setting have their cancer return within five years.  Once breast cancer becomes metastatic, it is considered incurable. Studies have shown that treating patientswith breast cancer early, before the cancer has spread, can prevent disease recurrence,help patients live longer, and offer the best chance of a potential cure.
New treatment options
Pertuzumab, a humanized monoclonal antibody, manufactured through biotechnology methods, is a personalized medicine that targets the HER2 receptor. The drug is specifically designed to prevent the HER2 receptor from dimerizing or “pairing” 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 pertuzumab to HER2 may also signal the body?s immune system to destroy the cancer cells.
… If approved, the pertuzumab regimen will be the first neoadjuvant breast cancer treatment approved in the United States and the first treatment approved based on pathologic complete response data…
The FDA will make a decision on whether or not to approve the new treatment option with pertuzumab by October 31, 2013. If approved, the pertuzumab regimen will be the first neoadjuvant breast cancer treatment approved in the United States and the first treatment approved based on pathological complete response or pCR data, meaning that there is no tumor tissue detectable at the time of surgery.
Pertuzumab is already approved in a number of countries including the United States for the treatment of women with HER2-positive metastatic breast cancer, an advanced form of the disease in which the cancer has metastasized. In this indication, women with the diseasehave not received anti-HER2 therapy or chemotherapy for metastatic disease.The U.S. FDA approved pertuzumab in this setting in 2012. This approval was based on a number of studies showing that the combination of pertuzumab, trastuzumab and chemotherapy was the only regimen to have shown a significant improvement in progression free survival compared to trastuzumab plus chemotherapy in people with previously untreated HER2-positive metastatic breast cancer.
The drug application for neoadjuvant use follows a proposed new FDA pathway designed to more quickly bring promising medicines to people with earlier stages of breast cancer, where treatment may have a greater impact.
?The impact of treatment in breast cancer is greatest in the early stage, before the cancer has spread to other parts of the body,?commented Hal Barron, M.D., chief medical officer and head, Global Product Development at Genentech/Roche.?[Today,] more than 6,000 people in the United States [alone] die of HER2-positive breast cancer each year. The ODAC?s recommendation is a step toward bringing Perjeta to people with HER2-positive early stage breast cancer, where treatment can potentially prevent the disease from returning and spreading.?
Commenting on a previous regulatory review of pertuzumab,Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA?s Center for Drug Evaluation and Research, noted: ?Since trastuzumab was first approved more than a decade ago, continued research has allowed us to better understand the role HER2 plays in breast cancer. This research provided the background to combine two targeted drugs ? trastuzumab and pertuzumab with docetaxel to slow disease progression in breast cancer.?
Neoadjuvant treatment is a treatment option given after diagnosis but before surgery for early-stage breast cancer in which the cancer has not spread beyond the breast or lymph nodes.Pathological complete response (pCR) is a common measure of neoadjuvant treatment effect in breast cancer and can be assessed more quickly than traditional clinical trial endpoints in early stage breast cancer (including EFS – Event Free Survival or OS – Overall Survival). Hence, this treatment option may allow a doctor to quickly assess whether a medicine is working. Furthermore, a number of studies have shown that neoadjuvant treatment may reduce tumor size, making it is easier to surgically remove them. This approach may also allow a physician to assess the options for breast-conserving surgery. Finally, outcomes for patients have shown thatpatients who achieve a pCR as a result of neoadjuvant treatment have more favorable long-term outcomes.Even tough there are currently no FDA-approved neoadjuvant treatments for cancer, this treatment option has become increasingly common for patients with high-risk disease.
The FDA’s ODAC recommendation was based on a review of results from NeoSphere and TryPhaena, two Phase II studies of pertuzumab in high-risk, HER2-positive early stage breast cancer, as well as on longer-term safety data from the Phase III CLEOPATRA study of pertuzumab in HER2-positive metastatic breast cancer.
The ongoing Phase III APHINITY study will further evaluate pertuzumab in the adjuvant setting and compares pertuzumab, trastuzumab and chemotherapy with trastuzumab and chemotherapy in people with HER2-positive early stage breast cancer. 
Combining pertuzumab and trastuzumab is thought to provide a more comprehensive blockade of HER signaling pathways because the mechanisms of action of both drugs are believed to complement each other, as both bind to the HER2 receptor, but to different places.The study has completed enrollment with approximately 4,800 people, and the primary endpoint is invasive disease-free survival or IDFS. This study has been submitted as a confirmatory study to the FDA. Data of the study is expected in 2016.
study (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation), one of the studies reviewed by the FDA’s ODAC, 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 with tumors greater than two centimeters.  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. The study results showed that treatment with pertuzumab, trastuzumab and docetaxel chemotherapy significantly improved the rate of totalpCR by 17.8% compared to trastuzumab and docetaxel alone (39.3% vs. 21.5%, p=0.0063) and a pCR of:
- 21.5% for trastuzumab and docetaxel;
- 39.3% for pertuzumab, trastuzumab and docetaxel;
- 11.2% for pertuzumab and trastuzumab;
- 17.7% for pertuzumab and docetaxel.
The researchers conducting the study observed a number of common severe (grade 3 or higher) adverse events for the pertuzumab regimen, including neutropenia (44.9%, febrile neutropenia (8.4%) and diarrhea (5.6%).
Another study reviewed by the FDA Committee was the TryPhaena study (ToleRabilitY of Pertuzumab, Herceptin and AnthracyclinEs in NeoAdjuvant breast cancer).  This randomized, multicenter Phase II study was conducted in 225 people with HER2-positive, locally advanced, inflammatory or early stage breast cancer with tumors greater than two centimeters. Participants were randomized to one of three neoadjuvant pertuzumab 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. While the study was not powered to compare the three study arms, the study showed interesting results of total pCR in the three arms were:
- 56.2% for pertuzumab, trastuzumab and anthracycline-based chemotherapy, followed by pertuzumab, trastuzumab and docetaxel;
- 54.7% for anthracycline-based chemotherapy, followed by pertuzumab, trastuzumab and docetaxel;
- 63.6% for the anthracycline-free arm (pertuzumab, trastuzumab, docetaxel and carboplatin chemotherapy).
In this study, the researchers did not observe new or unexpected cardiac adverse events, or other adverse events, in any of the study arms. Furthermore, the observed adverse events were consistent with those seen in previous studies of pertuzumab, trastuzumab and chemotherapy, either in combination or alone. The most common severe adverse events in any of the three study arms were neutropenia (47.2%), leukopenia (19.4%) and febrile neutropenia (18.1%) in the concurrent arm, neutropenia (42.7%), leukopenia (12.0%) and febrile neutropenia (9.3%) in the sequential arm and neutropenia (46.1%), febrile neutropenia (17.1%), anemia (17.1%); the AEs of diarrhea, leukopenia, anemia and thrombocytopenia (decrease in platelets) all had an incidence of 11.8% in the anthracycline-free arm.
Note:Worldwide each year about 1.4 million new cases of breast cancer are diagnosed and over 450,000 women will die of the disease annually 
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 NCT00567190-A Study to Evaluate Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-positive Metastatic Breast Cancer (CLEOPATRA) [U.S.ClinicalTrials Database]
 NCRN089 – Pertuzumab+ trastuzumab in neoadjuvant HER2+ Br Ca (TryPhaena) [UKCRN Database]
 NCT00545688 – A Study of Pertuzumab in Combination With Herceptin in Patients With HER2 Positive Breast Cancer (NeoSphere) [U.S. ClinicalTrials][Roche Trial Database]
 NCRN250 – Traztuzumab + Pertuzumab in HER2+ as adjuvant therapy in HER2+ Br Ca (APHINITY) [UKCRN Database]
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