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Breast Cancer Patients Live Nearly Six Months Longer With New Precision Drug Compared To Current Treatment Option

Data from the Phase III EMILIA study, presented at the European Society for Medical Oncology (ESMO) show that T-DM1 ( emtansine) prolongs the lives of patients with advanced HER2-positive breast when compared with the only approved licensed treatment combination, lapatinib and capecitabine, (30.9 months vs. 25.1 months, HR=0.682; P=0.0006), while significantly reducing the side effects of chemotherapy.1 T-DM1 is expected to gain a licence for use in the UK late 2013.

T-DM1 is known as an ‘antibody-drug conjugate’ (ADC), and is the first medicine of its kind for ; it incorporates the HER2-targeted antibody, Herceptin, with the , DM1 (emtansine) as a single therapy. T-DM1 has been designed to seek out and destroy only the cancerous cells in a two-stage attack.[2] First, it attaches to the HER2 growth receptor (found on the surface of the cell) and blocks signals that encourage the cancer to grow and spread; next, it penetrates the cell’s outer defences and releases a payload of chemotherapy to destroy it from within.2 This targeted approach means that healthy cells are preserved, and the unpleasant side effects commonly associated with chemotherapy are substantially reduced.1a

“These results are truly outstanding and will positively alter the outlook and outcomes for patients with HER2-positive breast cancer”, said Professor Paul Ellis, Professor of Cancer Medicine at King’s College London. “For T-DM1 to offer such a significant survival benefit, while also improving the quality of patients’ lives by reducing the side effects of chemotherapy, is a remarkable achievement – particularly as HER2-positive breast cancer is so difficult to treat in its advanced stages.”

Patients who received T-DM1 experienced fewer, less severe side effects than those who received lapatinib plus capecitabine:

Fewer patients who received T-DM1 experienced Grade 3 (categorised as ‘severe’) or higher side effects than those who received lapatinib plus capecitabine (40.8 percent versus 57 percent)1b

The most common Grade 3 or higher side effects associated with T-DM1 in the EMILIA study were low platelet count (12.9 percent versus 0.2 percent), increased levels of enzymes released by the liver and other organs (aspartate aminotransferase: 4.3 percent versus 0.8 percent; alanine aminotransferase: 2.9 percent versus 1.4 percent and anaemia 2.7 percent versus 1.6 percent).1c In most patients these levels had returned to normal by the time of the next dose of T-DM1.

The technique of attaching a chemotherapy agent to an antibody like Herceptin could change the way other breast cancers are treated in future; indeed T-DM1 is already being trialled in the earlier stages of the disease where side effects caused by chemotherapy, like diarrhoea and hair loss, have a significant impact on patients.

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About HER2-positive breast cancer

HER2 is a receptor found on the surface of all cells. Like a satellite dish, it sends messages or ‘signals’ into the cell telling it to survive and multiply. In HER2-positive breast cancer, there are too many HER2 receptors on the surface of cancerous cells. As a result, the cells receive a high number of ‘survive and multiply’ signals – causing rapid growth and spread of the tumour.[3]

HER2-positive breast cancer accounts for around 25% of all breast cancers,[4] and is known to be a particularly aggressive form of the disease.[5] It becomes ‘advanced’ or ‘metastatic’ when it has spread to other parts of the body, outside the breast where it was first diagnosed.

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 (mBC). It is designed to inhibit HER2 signalling and deliver the chemotherapy, a derivative of maytansine referred to as DM1, directly inside HER2-positive . The antibody (trastuzumab) binds to the HER2-positive , 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 . Once T-DM1 is absorbed into those it is designed to destroy them by releasing the DM1. T-DM1 attaches trastuzumab and DM1 together using a stable linker which is designed to keep T-DM1 in one piece until it reaches specific .2

About the EMILIA study1

EMILIA is an international, Phase III, randomised, open-label study comparing T-DM1 alone to lapatinib in combination with Xeloda (capecitabine) in 991 people with HER2-positive mBC whose disease progressed after initial treatment with Herceptin and a taxane-based chemotherapy.

The co-primary efficacy endpoints of the study are overall survival and progression-free survival (PFS, as assessed by an independent review committee). Other study endpoints include safety profile, one-year and two-year survival rates, PFS as assessed by investigator, overall response rate, duration of response and quality of life.

Results from the study showed:

OS was significantly longer for those receiving T-DM1 vs. those receiving lapatinib and capecitabine: median OS was 30.9 months vs. 25.1 months, HR=0.682; [95% CI, 0.55, 0.85] P=0.00061

PFS was significantly longer for those receiving T-DM1 vs. those receiving lapatinib and capecitabine: median PFS was 9.6 months versus 6.4 months, respectively (HR=0.650 [95% CI, 0.549–0.771]; P< .0001)[6]

The response rate (the percentage of patients with tumour shrinkage) was 43.6 percent for those who received T-DM1 versus 30.8 percent of patients who received lapatinib plus capecitabine1d

The duration of response was 12.6 months for those who received T-DM1 versus 6.5 months for patients who received lapatinib plus capecitabine1e

The time-to-symptom progression, a patient-reported measure of quality of life, was also improved in patients who received trastuzumab emtansine: 7.1 months in patients who received trastuzumab emtansine versus 4.6 months in patients who received lapatinib plus capecitabine6a

Patients receiving T-DM1 experienced fewer, less severe side effects than those receiving lapatinib plus capecitabine:

Fewer patients who received trastuzumab emtansine experienced Grade 3 or higher (severe) AEs than those who received lapatinib plus Xeloda, at 40.8 percent versus 57 percent, respectively1b

For people receiving trastuzumab emtansine, compared to those receiving lapatinib plus Xeloda, the most common (occurring in more than 2 percent of patients) Grade 3 or higher AEs were low platelet count (12.9 percent versus 0.2 percent), increased levels of enzymes released by the liver and other organs (in most patients these levels had returned to normal by the time of the next dose of trastuzumab emtansine; aspartate aminotransferase: 4.3 percent versus 0.8 percent; alanine aminotransferase: 2.9 percent versus 1.4 percent) and anaemia (2.7 percent versus 1.6 percent)1c

For those patients receiving lapatinib plus Xeloda compared to those receiving trastuzumab emtansine, the most common Grade 3 or higher AEs were diarrhoea (20.7 percent versus 1.6 percent), hand-foot syndrome (16.4 percent versus 0) and vomiting (4.5 percent versus 0.8 percent)1f

Ongoing studies with T-DM1

There are two ongoing Phase III studies of T-DM1:

MARIANNE is comparing three different treatment regimens (T-DM1 alone, T-DM1 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.
TH3RESA is comparing third-line T-DM1 to physician’s choice of treatment in HER2-positive mBC.
In addition, a Phase II study evaluating T-DM1 as neoadjuvant / adjuvant treatment for early breast cancer is currently ongoing.

About Herceptin® (trastuzumab)

Herceptin is a humanised antibody designed to target and block the function of HER2, a protein produced by a specific gene with cancer-causing potential. The mode of action of Herceptin is unique in that it activates the body’s immune system and suppresses HER2 to target and destroy the tumour. Herceptin has demonstrated efficacy in treating both early and advanced (metastatic) HER2-positive breast cancer as well as HER2-positive advanced (metastatic) stomach cancer.

Given on its own as monotherapy as well as in combination with or following standard chemotherapy, Herceptin has been shown to improve disease-free survival, overall survival and response rates while maintaining quality of life in people with HER2-positive breast and stomach cancer.[7],[8] It was first licensed in Europe in 2000 for the treatment of HER2-postivie mBC, and in 2006 for early breast cancer. Herceptin is marketed in the United States by Genentech, in Japan by Chugai and internationally by Roche.

[1] Verma, S. et al. Updated Overall Survival Results from EMILIA, a Phase 3 study of trastuzumab emtansine (T-DM1) vs. capecitabine and lapatinib in HER2-positive locally advanced or metastatic breast cancer (MBC); Abstract # LBA12. Presented at the European Society of Medical Oncology (ESMO) conference, 1 October 2012

[2] LoRusso, P.M et al. (2011) Trastuzumab Emtansine: A Unique Antibody-Drug Conjugate in Development for Human Epidermal Growth Factor Receptor 2-Positive. Clin Cancer Res; 17:6437-6447

[3]http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Breast/Symptomsdiagnosis/HormoneandHER2receptors/HER2andbreastcancer.aspx Last accessed September 2012

[4] http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Breast/Aboutbreastcancer/Typesandrelatedconditions/HER2%20positive.aspx Last accessed September 2012

[5] Boekhout, A.H. et al. (2011) Clinical Pharmacology: Concise Drug Reviews. Trastuzumab. The Oncologist; 16: 800–810

[6] Blackwell, K. et al. (2012). Primary results from EMILIA, a Phase 3 Study of Trastuzumab Emtansine (T-DM1) vs. Capecitabine and Lapatinib in HER2-Positive Locally Advanced or Metastatic Breast Cancer Previously Treated with Trastuzumab and a Taxane. American Society of Clinical Oncology, Chicago

[7] Herceptin® SmPC Roche Products Ltd. Herceptin® SmPC. September 2011 available at: http://www.medicines.org.uk/EMC

[8] Rugo H et al. (2010) Effect of Trastuzumab on Health-Related Quality of Life in Patients With HER2-Positive Metastatic Breast Cancer: Data From Three Clinical Trials. Clin Breast Cancer 1;10(4):288-9

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