On February 22nd, 2013, the U.S.Food and Drug Administration(FDA) approved ado-trastuzumab emtansine (T-DM1; Kadcyla?,Genentech), as a single medicine, for the treatment of people with HER2-positive metastatic breast cancer (mBC) who have received prior treatment withtrastuzumab(Herceptin?, Genentech) and a taxane chemotherapy. The newly approved drug isthe fourth medicine from Genentech to receive FDA approval for people with advanced cancers within the past two years.

An antibody-drug conjugate (ADC) is a new kind of targeted cancer medicine that can attach to certain types of cancer cells and deliver chemotherapy directly to them. Ado-trastuzumab emtansineis the first FDA-approved ADC for treating HER2-positive mBC, an aggressive form of the disease.

Like trastuzumab, the new drug binds to HER2-positive 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 the new drug is taken up by those cells, it is designed to destroy them by releasing the DM1 inside the cells.

ADCs – a novel approach
“This new drug represents a completely new way to treat HER2-positive metastatic breast cancer, andit helped people in the EMILIA study live nearly six months longer,” noted Hal Barron, M.D., chief medical officer and head, Global Product Development. “We currently have more than 25 antibody-drug conjugates in our pipeline and hope this promising approach will help us deliver more medicines to fight other cancers in the future.”

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Ado-trastuzumab emtansineis made up of the antibody, trastuzumab, and the chemotherapy, DM1. The two components are joined together using a stable linker. The new drug combines the mechanisms of action of both trastuzumab and DM1, and it is the first Genentech ADC approved by the FDA. Genentech has studied ADC science for more than a decade with eight ADCs in Phase I or Phase II studies for different types of cancer.

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Efficacy in HER2-positive mBC
The FDA approval of Ado-trastuzumab emtansineis based on results from EMILIA (TDM4370g/BO21977), an international, Phase III, randomized, open-label study comparing alone to lapatinib in combination with capecitabine(Xeloda?, Genentech) 991 people with HER2-positive locally advanced breast cancer or mBC who had previously been treated with trastuzumab (Herceptin?, Genentech))and a taxane chemotherapy. The results were presented as Late Breaking News during the 2012 meeting of the American Society of Clinical Oncology(ASCO) in Chicago. The results, presented by Kimberly L. Blackwell, MD, of Duke Cancer Institute, were highly anticipated and included:

  • The study met both co-primary efficacy endpoints of overall survival and progression-free survival (PFS; as assessed by an independent review committee).
  • People who received lived a median of 5.8 months longer (overall survival) than those who received the combination of lapatinib (Tykerb, GSK) and capecitabine, the standard of care in this setting (median overall survival: 30.9 months vs. 25.1 months).
  • People receiving Ado-trastuzumab emtansineexperienced a 32% reduction in the risk of dying compared to people who received lapatinib and capecitabine(HR=0.68; p=0.0006).
  • People who received Ado-trastuzumab emtansinelived significantly longer without their disease getting worse (PFS) compared to those who received lapatinib plus capecitabine(HR=0.65, 35% reduction in risk of disease worsening or death, p<0.0001; median PFS 9.6 months vs. 6.4 months).
  • No new safety signals were observed and adverse events (AEs) were consistent with those seen in previous studies, with fewer people who received Ado-trastuzumab emtansineexperiencing Grade 3 or higher (severe) AEs than those who received lapatinib plus capecitabine(43.1% vs. 59.2%).
  • For people receiving Ado-trastuzumab emtansine, the most common (occurring in more than 2% of participants) Grade 3 or higher AEs were low platelet count (14.5%), increased levels of enzymes released by the liver and other organs (8.0%), low red blood cell count (4.1%), low levels of potassium in the blood (2.7%), nerve problems (2.2%) and tiredness (2.5%).

Blackwell concluded that Ado-trastuzumab emtansinedemonstrated greater efficacy and safety than capecitabine/lapatinib and that the drug candidate should offer an important therapeutic option for the treatment of HER2-positive advanced breast cancer.

In his discussion, Louis M. Weiner, MD, of Georgetown Lombardi Comprehensive Cancer Center, stated that the EMELIA study provided convincing evidence that an immunoconjugate-targeting HER2 has indeed a potent antitumor activity. Her referred to immunoconjugates as the realization of Paul Ehrlich?s concept of a “magic bullet” developed more than 100 years ago.

Patient Assistance
Ado-trastuzumab emtansinewill be available to patients in the United States in March 2013. As part of this approval, Genentech plans to initiate patient assistance programs for people taking ado-trastuzumab emtansinethrough Genentech Access Solutions. These programs help patients who might not be able to afford this medicine. Patients who do not have health insurance, or who have reached the lifetime limit set by their insurance company, might qualify to receive ado-trastuzumab emtansinefree of charge. For people with insurance, Genentech Access Solutions offers co-pay assistance programs to help with the out-of-pocket costs of their medicine, including a co-pay card for those with private insurance. The card pays 80% of out-of-pocket costs for people who qualify (up to $9,000 or $24,000 per year, depending on the patient’s income).

Roche has also submitted a Marketing Authorization Application to other regulatory authorities around the world, including the European Medicines Agency (EMA), for ado-trastuzumab emtansinefor the treatment of people with HER2-positive mBC. This application is currently under review by the EMA.

For more information

Genentech licenses technology for Kadcyla under an agreement with ImmunoGen, Inc.

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