Genentech, a member of the Roche Group, today announced the results of the Phase II study TDM4450g in people with previously untreated HER2-positive metastatic breast cancer (mBC).
The study compared trastuzumab emtansine (also known as T-DM1) to standard treatment with Herceptin® (trastuzumab) plus docetaxel chemotherapy. The results showed that people who received trastuzumab emtansine experienced a 41 percent reduction in the risk of their disease worsening or death (progression-free survival, PFS) and lived a median of five months longer without their disease worsening (HR=0.59, median PFS 14.2 months vs. 9.2 months). In addition, people who received trastuzumab emtansine experienced fewer common and severe adverse events compared to those who received Herceptin plus chemotherapy, with the rate of Grade 3 or higher adverse events reduced by nearly half (46.4 percent vs. 89.4 percent).
The data will be presented at the 2011 European Multidisciplinary Cancer Congress in Stockholm on September 25 and were featured in the official press program (Abstract #5001 [LB]).
“The improvement in progression-free survival with fewer side effects seen with trastuzumab emtansine is very exciting,” said Hal Barron, M.D., chief medical officer and head, Global Product Development. “We believe this investigational antibody-drug conjugate approach, in which chemotherapy is attached to the antibody and selectively delivered to tumor cells, is an important potential weapon for fighting cancer and we look forward to the Phase III study results with trastuzumab emtansine.”
Trastuzumab emtansine is an investigational medicine known as an ADC that attaches trastuzumab and the chemotherapy DM1 together using a stable linker. It is designed to target and inhibit HER2 signaling and deliver the chemotherapy directly inside HER2-positive cancer cells. Trastuzumab emtansine reinforces Roche’s personalized healthcare approach of developing targeted medicines to fight cancer. Building on the results of trastuzumab emtansine studies to date, Roche/Genentech have approximately 30 ADCs in the pipeline.
About the TDM4450g study
TDM4450g is a Phase II, international, multicenter, two-arm, open-label study that enrolled 137 patients with previously untreated, HER2-positive mBC from 108 sites. Patients were randomized 1-to-1 to either trastuzumab emtansine or Herceptin plus docetaxel chemotherapy. The primary endpoints of the study included PFS and safety profile. Secondary endpoints included overall survival (OS), one-year-survival rate, objective response rate (ORR), duration of objective response and clinical benefit rate (CBR). Patients in the Herceptin plus chemotherapy arm were allowed to receive trastuzumab emtansine upon disease progression.
•There was a significant improvement in PFS for patients in the trastuzumab emtansine arm (N=67) compared to the Herceptin plus chemotherapy arm (N=70) (median PFS 14.2 vs. 9.2 months, HR=0.59, p=0.035).
•ORR was greater in the trastuzumab emtansine arm compared to the Herceptin plus chemotherapy arm (64.2 percent compared to 58.0 percent).
•There was a significant reduction in common and severe (Grade 3 or higher) adverse events (AEs) in the trastuzumab emtansine arm compared to the Herceptin plus chemotherapy arm:
•The most common AEs in the trastuzumab emtansine arm were fatigue (49.3 percent), nausea (47.8 percent), increased levels of a specific enzyme (asparate aminotransferase or AST) released by the liver and other organs (39.1 percent) and fever (39.1 percent). The most common adverse events in the Herceptin plus chemotherapy arm were hair loss (66.7 percent), a decreased number of a specific type of white blood cell (neutropenia, 63.6 percent), diarrhea (45.5 percent) and fatigue (45.5 percent).
•Consistent with previously reported results, severe (Grade 3 or higher) AEs were reported less frequently in the trastuzumab emtansine arm than in the Herceptin plus chemotherapy arm (46.4 percent vs. 89.4 percent) as were treatment discontinuations due to AEs (7.2 percent vs. 28.8 percent).
•The most frequent severe AEs in the trastuzumab emtansine arm were increased levels of two different liver enzymes (AST and alanine aminotransferase, or ALT) and low platelet count (all 8.7 percent). The most frequent severe AEs in the Herceptin plus chemotherapy arm were a decreased number of a specific type of white blood cell (neutropenia, 60.6 percent), a decrease in the overall number of white blood cells (leukopenia, 25.8 percent) and fever associated with a decreased number of a specific type of white blood cell (febrile neutropenia, 13.6 percent).
•The overall survival data are not mature at this point in time. The number of deaths in each arm of the study was identical and no deaths were considered by investigators to be related to treatment (trastuzumab emtansine or Herceptin plus chemotherapy).
About trastuzumab emtansine
Trastuzumab emtansine (the recommended International Non-proprietary Name for T-DM1) is an antibody-drug conjugate (ADC) being studied for HER2-positive breast cancer. It is designed to inhibit HER2 signaling and deliver the chemotherapy DM1 directly inside HER2-positive 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 cancer cells. Once trastuzumab emtansine is absorbed into those cancer cells, it is designed to destroy them by releasing the DM1. Trastuzumab emtansine attaches trastuzumab and DM1 together using a stable linker, which is designed to keep trastuzumab emtansine in one piece until it reaches specific cancer cells.
There are three ongoing Phase III studies of trastuzumab emtansine:
•MARIANNE is comparing three different regimens (trastuzumab emtansine alone, trastuzumab emtansine in combination with pertuzumab, and Herceptin plus a taxane chemotherapy) in patients with HER2-positive mBC who have not been previously treated for their metastatic disease.
•EMILIA is comparing trastuzumab emtansine to lapatinib in combination with capecitabine in patients with HER2-positive mBC whose disease progressed after initial treatment. Roche plans to support a global regulatory submission for trastuzumab emtansine based on the results of the EMILIA trial in 2012.
•TH3RESA is comparing third-line trastuzumab emtansine to physician’s choice of treatment in HER2-positive mBC.
In addition, a Phase II study evaluating trastuzumab emtansine in the neoadjuvant/adjuvant setting for early breast cancer is currently ongoing.
Genentech licenses technology for trastuzumab emtansine under an agreement with ImmunoGen, Inc.
About Breast Cancer
Breast cancer is the most common cancer among women worldwide. According to the American Cancer Society, approximately 230,000 women will be diagnosed with breast cancer and 40,000 will die from the disease in 2011. In HER2-positive breast cancer, increased quantities of the human epidermal growth factor receptor 2 (HER2) are present on the surface of the tumor cells. This is known as “HER2 positivity” and affects approximately 15-25 percent of people with breast cancer. HER2-positive cancer is a particularly aggressive form of breast cancer.
Herceptin is a targeted medicine (not a chemotherapy) designed to specifically block the HER2 protein on the surface of some cancer cells. Based on preclinical studies, Herceptin may work by attaching to HER2 receptors to stop signals that make the tumor cells grow and divide, and also by signaling the body’s immune system to destroy the cancer cells.
Adjuvant Breast Cancer:
Herceptin is approved for the treatment of early-stage breast cancer that is Human Epidermal growth factor Receptor 2-positive (HER2-positive) and has spread into the lymph nodes, or is HER2-positive and has not spread into the lymph nodes. If it has not spread into the lymph nodes, the cancer needs to be estrogen receptor/progesterone receptor (ER/PR)-negative or have one high risk feature.* Herceptin can be used in several different ways:
•As part of a treatment course including the chemotherapy drugs doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel. This treatment course is known as “AC?TH”
•With the chemotherapy drugs docetaxel and carboplatin. This treatment course is known as “TCH”
•Alone after treatment with multiple other therapies, including an anthracycline-based therapy (a type of chemotherapy)
*High risk is defined as estrogen receptor/progesterone receptor (ER/PR)-negative with one of the following features: tumor size >2 cm, age <35 years, or tumor grade 2 or 3.
Metastatic Breast Cancer:
Herceptin has two approved uses in metastatic breast cancer:
•Herceptin in combination with the chemotherapy drug paclitaxel is approved for the first-line treatment of HER2-positive metastatic breast cancer
•Herceptin alone is approved for the treatment of HER2-positive breast cancer in patients who have received one or more chemotherapy courses for metastatic disease
Metastatic Gastric Cancer:
Herceptin is approved in combination with the chemotherapy drugs cisplatin, and either capecitabine or 5-fluorouracil, for metastatic HER2-positive stomach cancer or cancer of the gastroesophageal junction, in patients who have not received prior medicines for their metastatic disease.
Important Safety Information
Herceptin treatment can result in heart problems, including those without symptoms (such as reduced heart function) and those with symptoms (such as congestive heart failure). One patient died in an adjuvant (early) breast cancer trial 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 and during treatment, 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 the patient’s health history and tests to see how well the heart muscle is working. These tests may include an echocardiogram or a MUGA scan. Some early breast cancer patients may also need to have a test done after they have finished taking Herceptin to see how well their heart muscle is working.
Some patients have had serious infusion reactions and lung problems; fatal infusion reactions have been reported. These reactions usually occur 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.
Herceptin can cause harm to the fetus (unborn baby), in some cases death to the fetus, when taken by a pregnant woman. Women who could become pregnant need to use effective birth control methods during Herceptin treatment and for at least six months after treatment with Herceptin. Nursing mothers treated with Herceptin should discontinue nursing or discontinue Herceptin.
Worsening of low white blood cell counts associated with chemotherapy has also occurred.
Patients must have a HER2 test to determine if their breast or stomach cancer is HER2-positive before using Herceptin, as benefit has only been shown in patients who are HER2-positive.
The most common side effects associated with Herceptin in patients with breast cancer are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, shortness of breath, rash, low white and red blood cells, and muscle pain.
The most common side effects associated with Herceptin in patients with stomach cancer are low white blood cell counts, diarrhea, fatigue, low red blood cell counts, inflammation of the lining of the mouth, weight loss, upper respiratory tract infections, fever, low platelet counts, swelling of mucus membranes, swelling of the nose and throat, and a change in taste.
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.
Patients should read the Herceptin Full Prescribing Information including Boxed WARNINGS, at 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.