Results of the first randomized phase II study, known as TDM4450g, in patients with previously untreated HER2-positive metastatic breast cancer (mBC) were presented today at the 2011 European Multidisciplinary Cancer Congress in Stockholm.

Breast cancer is the most common cancer among women worldwide. Each year about 1.4 million new cases of breast cancer are diagnosed worldwide and over 450,000 people will die of the disease annually.[1] In HER2-positive breast cancer, increased quantities of the HER2 receptor are present on the surface of the tumour cells. This is known as ‘HER2 positivity’ and affects approximately 15-20% of people with breast cancer.[2]

TDM4450g, an international, multicentre, two-arm, open-label study enrolled 137 patients in 108 sites worldwide and compared trastuzumab emtansine (also known as T-DM1) to standard treatment with trastuzumab (Herceptin®, Roche/Genentech) plus docetaxel chemotherapy. The results showed that people who received trastuzumab emtansine experienced a 41% 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 trastuzumab plus chemotherapy, with the rate of Grade 3 or higher adverse events reduced by nearly half (46.4% vs. 89.4%).

Selectively delivered
“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.”

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An earlier analysis of this study presented at the 35th Congress of the European Society of Medical Oncology (ESMO) in 2010 [4] showed encouraging results in tumor shrinkage (overall response rate ORR) in patients with a minimum of 4 months of follow-up. In addition, the study showed that trastuzumab emtansine (TDM1)significantly reduced the burden of typical side effects associated with conventional chemotherapy.

Power of the Linker
Trastuzumab emtansine is an investigational medicine known as an antibody-drug conjugate (ADC) that attaches trastuzumab and the chemotherapy DM1 together using a stable linker. Trastuzumab emtansine is designed to inhibit HER2 signalling 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.

Study Protocol
Patients participating in the trial were randomized 1-to-1 to either trastuzumab emtansine or trastuzumab 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.

Trial Results
– There was a significant improvement in PFS for patients in the trastuzumab emtansine arm (N=67) compared to the trastuzumab 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 trastuzumab plus chemotherapy arm (64.2% compared to 58.0%).
– There was a significant reduction in common and severe (Grade 3 or higher) adverse events (AEs) in the trastuzumab emtansine arm compared to the trastuzumab plus chemotherapy arm. The most common AEs in the trastuzumab emtansine arm were fatigue (49.3%), nausea (47.8%), increased levels of a specific enzyme released by the liver and other organs (aspartate aminotransferase or AST, 39.1%) and fever (39.1%).
– The most common adverse events in the trastuzumab plus chemotherapy arm were hair loss (66.7%), a decreased number of a specific type of white blood cells (neutropenia, 63.6%), diarrhoea (45.5%), and fatigue (45.5%). Consistent with previously reported results, severe (Grade 3 or higher) AEs were reported less frequently in the trastuzumab emtansine arm than in the trastuzumab plus chemotherapy arm (46.4% vs. 89.4%) as were treatment discontinuations due to AEs (7.2 percent vs. 28.8%).
– The most frequent severe AEs in the trastuzumab emtansine arm were increased levels of two different liver enzymes (ALT and AST) and low platelet count (all 8.7%). The most frequent severe AEs in the trastuzumab plus chemotherapy arm were a decreased number of a specific type of white blood cell (neutropenia, 60.6%), a decrease in the overall number of white blood cells (leucopoenia, 25.8%) and fever associated with a decreased number of a specific type of white blood cell (febrile neutropenia, 13.6%).
– The researchers so far concluded the overall survival (OS) 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 trastuzumab plus chemotherapy).

Personalised healthcare
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. Furthermore, Trastuzumab emtansine is used in conjunction with a companion diagnostic test developed through Roche Tissue Diagnostics group (Ventana Medical Systems, Inc.). The phase III clinical trial program includes the application of two companion diagnostic HER2 tests suitable for selecting patients for treatment with trastuzumab emtansine. Ventana Medical Systems, Inc. currently offers the PATHWAY anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody and INFORM HER2 Dual ISH DNA Probe Cocktail for determination of the HER2 protein expression and gene status respectively.

Ongoing trials
There are three phase III studies of trastuzumab emtansine ongoing:

  • MARIANNE is comparing three different treatment 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 as neoadjuvant/adjuvant treatment for early breast cancer is currently ongoing.

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