SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced the U.S. Food and Drug Administration (FDA) issued a Refuse to File letter for accelerated approval for the company’s trastuzumab-DM1 (T-DM1) Biologics License Application (BLA). As planned, Genentech will continue with its ongoing Phase III registrational T-DM1 trial, EMILIA. Genentech will continue to work with the FDA and expects to submit a new T-DM1 BLA in mid-2012.
The BLA submitted in July 2010 requested accelerated approval for T-DM1 based on the results of a single-arm Phase II study, which showed T-DM1 shrank tumors in one-third of women with advanced HER2-positive breast cancer, who had received on average seven prior medicines, including two HER2-targeted medicines.
Consideration by the FDA for accelerated approval requires recognition of a defined patient population of unmet need (a life-threatening disease with limited treatment choices), for whom a medicine’s early safety and efficacy data are reasonably likely to predict clinical benefit. Following the pre-submission meeting with the FDA in March 2010, Genentech concluded it was appropriate to submit a BLA for accelerated approval. In its review of the BLA, the FDA stated the T-DM1 trials did not meet the standard for accelerated approval because all available treatment choices approved for metastatic breast cancer, regardless of HER2 status, had not been exhausted in the study population.
“We firmly believe in the potential of T-DM1 as a novel HER2-targeted option and remain fully committed to its ongoing development,” said Hal Barron, M.D., executive vice president, Product Development and chief medical officer.
Genentech will submit data from the amended Phase III randomized EMILIA study to the FDA to support a new T-DM1 BLA in mid-2012. The EMILIA study compares T-DM1 to lapatinib in combination with capecitabine in people with advanced HER2-positive breast cancer whose disease has worsened after receiving initial treatment.
T-DM1 is an antibody-drug conjugate (ADC), also known as an armed antibody, being studied for advanced HER2-positive breast cancer. T-DM1 attaches trastuzumab and the chemotherapy DM1 together using a stable linker, which is designed to keep T-DM1 in one piece until it reaches specific cancer cells. The antibody (trastuzumab) binds to the HER2-positive cancer cells, and is thought to block out-of-control signals that make the cancer grow while also calling on the body’s immune system to attack the cells. Then, once T-DM1 is absorbed into those cancer cells, it is designed to destroy them by releasing the DM1. Genentech licenses technology for T-DM1 under an agreement with ImmunoGen, Inc.
About Studies of T-DM1 and other HER2-Targeted Medicines
The FDA submission was based on a Phase II study known as TDM4374g, a single-arm, multi-center trial designed to assess single-agent T-DM1 in 110 women with advanced HER2-positive breast cancer whose disease had worsened after receiving at least two prior HER2-targeted treatments (Herceptin® [trastuzumab] and lapatinib) in the metastatic setting, as well as an anthracycline, a taxane and capecitabine. The primary endpoint of the study was objective response rate (a complete or partial tumor shrinkage of at least 30 percent, determined by two tumor assessments at least 28 days apart), as measured by an independent review facility.
Results from the study were presented at the 2009 San Antonio Breast Cancer Symposium and demonstrated that T-DM1 shrank tumors in 33 percent of women with advanced HER2-positive breast cancer that had worsened following treatment with an average of seven prior medicines for metastatic disease. In the study, most side effects were mild (Grade 1-2) and similar to those observed in previous clinical trials of T-DM1. The most common adverse events of any grade were fatigue (62 percent) and nausea (37 percent). The most common severe adverse events (Grade 3 or higher) were a low level of platelets in the blood (7 percent), fatigue (5 percent) and cellulitis (4 percent). No severe cardiac-specific side effects were observed. One patient with pre-existing, non-alcoholic fatty liver disease died with liver failure. The safety results were consistent with data from earlier studies, including a proof-of-concept Phase II study (TDM4258g), which also was included in the submission to the FDA.
Several other Phase II and III trials of T-DM1 and other HER2-targeted medicines are ongoing, including:
About Advanced HER2-Positive Breast Cancer
According to the American Cancer Society, breast cancer is the second leading cause of cancer death among women in the U.S. Women diagnosed with advanced (metastatic) disease have a poor prognosis and only 23 percent survive five years.
Approximately 15 to 30 percent of breast cancers are HER2-positive. When HER2-positive breast cancer is advanced, the disease has spread to other parts of the body, most commonly to the lungs, bones, liver and brain. There are no treatment guidelines or HER2-targeted treatment options for women with advanced HER2-positive breast cancer if the disease worsens following treatment with Herceptin and lapatinib.
Pertuzumab, a humanized monoclonal antibody, represents the first in a new class of investigational medicines known as HER (human epidermal growth factor receptor) dimerization inhibitors (HDIs). Pertuzumab is designed to bind to the HER2 receptor — a protein found on the surface of epithelial cells — and inhibit the ability of HER2 to interact with other HER family members (HER1/EGFR, HER2, HER3 and HER4). HER dimerization (receptor pairing) is believed to play an important role in the growth and formation of several different cancer types. Pertuzumab binds to a different part of the HER2 receptor than other approved products, known as the dimerization domain.
Herceptin is approved for the treatment of early-stage breast cancer that is HER2-positive and has spread into the lymph nodes, or is HER2-positive and has not spread into the lymph nodes, but has one high risk feature.* Herceptin can be used in several different ways:
* High risk can be defined as ER/PR-negative, tumor size >2 cm, age <35 years, or histological and/or nuclear Grade 2 or 3.
Herceptin has 2 approved uses in metastatic breast cancer:
Boxed WARNINGS and Additional Safety Information
Herceptin treatment can result in heart problems, including those without symptoms (reduced heart function) and those with symptoms (congestive heart failure). One adjuvant patient died from significantly weakened heart muscle. The risk and seriousness of these heart problems were highest in people who received both Herceptin and a certain type of chemotherapy (anthracycline).
Before taking the first dose of Herceptin, a patient’s doctor should check to see if there are any health conditions that may increase the patient’s chance of having serious heart problems. This includes a review of health history and tests to see how well the heart muscle is working. These tests may include an echocardiogram or a MUGA scan.
Some patients have had serious infusion reactions and lung problems; fatal infusion reactions have been reported. In most cases, these reactions occurred during or within 24 hours of receiving Herceptin.
The patient’s doctor may need to completely stop Herceptin treatment if the patient has a severe allergic reaction, swelling, lung problems, inflammation of the lung, or severe shortness of breath.
Worsening of low white blood cell counts associated with chemotherapy has also occurred.
Herceptin can cause harm to the fetus when taken by a pregnant woman. This may be related to a lowering of amniotic fluid levels in the second and third trimesters.
The most common side effects associated with Herceptin were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, shortness of breath, rash, low white and red blood cells, and muscle pain.
Because everyone is different, it is not possible to predict what side effects any one person will have. Patients with questions or concerns about side effects should talk to their doctor.
For Herceptin full prescribing information, including Boxed WARNINGS and additional important safety information, please visit http://www.herceptin.com.
Founded more than 30 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious or life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.
Krysta Pellegrino, 650-467-6800
Sonali Padhi, 650-467-0842
Diane Schrick, 650-225-1599
Karl Mahler, 011 41 61 687 85 03
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INDUSTRY KEYWORDS: Health Biotechnology Clinical Trials Oncology Pharmaceutical