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New breast cancer treatment Kadcyla given green light by regulators, UK

Kadcyla is now available for patients with advanced HER2-positive . Kadcyla is the first of its kind in , consisting of the HER2-targeted antibody, trastuzumab (contained in the medicine Herceptin), linked with the chemotherapy agent, DM1. In response to the pivotal clinical trial, the (EMA) has now granted a license for with advanced HER2-positive breast cancer who have previously received Herceptin and a taxane, separately or in combination.

Data from the Phase III EMILIA study showed that overall survival (OS) for patients with advanced HER2-positive breast cancer treated with Kadcyla was 30.9 months, compared to 25.1 months for patients treated with the only currently licensed treatment combination, lapatinib and capecitabine (co-primary endpoint, HR=0.68, 95% CI, p<0.001).[i] Patients treated with Kadcyla experienced median progression-free survival (PFS) for 9.6 months, compared to 6.4 months with lapatinib and capecitabine (co-primary endpoint, HR=0.65, 95% CI, p<0.001).[i] In addition, 43.6% of patients responded to treatment with Kadcyla, compared to 30.8% of patients treated with lapatinib and capecitabine (secondary endpoint, overall response rate or ‘ORR’, 95% CI, p<0.001).[i]

In the EMILIA study, the most common grade 3 or higher side effects for those patients receiving lapatinib plus capecitabine chemotherapy, compared to Kadcyla were diarrhoea (20.7% vs. 1.6%), hand-foot syndrome (16.4% vs. 0%) and vomiting (4.5% vs. 0.8%).[i]

Patients who received Kadcyla experienced fewer severe side effects than those who received lapatinib and capecitabine.[i] In the EMILIA study, the most common grade 3 (categorised as ‘severe’) side effects associated with Kadcyla versus lapatinib and capecitabine, were low platelet count (12.9% vs. 0.2%), increased levels of enzymes released by the liver and other organs (aspartate aminotransferase or ‘AST’: 4.3% vs. 0.8%; alanine aminotransferase or ‘ALT’: 2.9% vs. 1.4%) and anaemia (2.7% vs. 1.6%).[i] Like other treatments that target HER2, heart monitoring is required before and during treatment.

“Kadcyla represents a new way of targeting HER2-positive breast cancer, which ultimately means that we could extend patients’ lives compared to existing chemotherapy treatment. In addition, we should be able to reduce many of the symptomatic side effects associated with standard chemotherapy,” said Professor Paul Ellis, Professor of Cancer Medicine at King’s College London.

Kadcyla is an antibody-drug conjugate (ADC) and works in a different way to other breast cancer medicines.[ii] It uses a ‘stable linker’ to join the HER2-targeted antibody trastuzumab and chemotherapy together, enabling a two-stage attack on cancer cells. First, Kadcyla blocks the growth signals that lead to cancer cell survival and engages the immune system, before releasing the chemotherapy directly into the cancer cell to destroy it from within.[ii] Kadcyla is administered intravenously once every three weeks.[iii]

Roche looks forward to working with the National Institute of Health and Care Excellence (NICE) and the Scottish Medicines Consortium (SMC) to ensure patients and clinicians can access Kadcyla as soon as possible. In the meantime, patients may be able to access Kadcyla via the Cancer Drugs Fund (England); an Individual Patient Treatment Request (Scotland); an Individual Funding Request (Northern Ireland); an Individual Patient Funding Request (Wales) or through some private health insurance policies.

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. [iv] As a result, the cells receive a high number of ‘survive and multiply’ signals – causing rapid growth and thus potential spread of the tumour.[iv]

HER2-positive breast cancer accounts for around 25% of all breast cancers,[v] and is known to be a particularly aggressive form of the disease.[vi] 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 is an antibody-drug conjugate (ADC), being studied for HER2-positive breast cancer. It is designed to inhibit HER2 signalling and deliver the chemotherapy, a derivative of maytansine referred to as 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 Kadcyla is absorbed into those cancer cells it is designed to destroy them by releasing the DM1. Kadcyla attaches trastuzumab and DM1 together using a stable linker which is designed to keep Kadcyla in one piece until it reaches the specific cancer cells.[ii]

Kadcyla, as a single agent, is indicated for the treatment of adult patients with HER2-positive, unresectable locally advanced or metastatic breast cancer (mBC) who previously received trastuzumab and a taxane, separately or in combination.

About the EMILIA study

EMILIA is an international, Phase III, randomised, open-label study comparing Kadcyla alone to lapatinib in combination with capecitabine in 991 people with HER2-positive locally advanced or mBC whose disease progressed after initial treatment with Herceptin and a taxane-based chemotherapy.[i]

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, overall one-year survival rates, PFS as assessed by investigator, overall response rate, duration of response and quality of life.[i]

Results from the study showed:

  • OS was significantly longer for those receiving Kadcyla versus those receiving lapatinib and capecitabine: median OS was 30.9 vs. 25.1 months (HR=0.68; 95% CI 0.55-0.85, p<0.001).[i]
  • PFS was significantly longer for those receiving Kadcyla versus those receiving lapatinib and capecitabine: median PFS was 9.6 vs. 6.4 months respectively (HR=0.65, 95% CI, 0.55-0.77, p<0.001).[i]
  • The response rate (the percentage of patients with tumour shrinkage) was 43.6% for those who received Kadcyla (95% CI 38.6-48.6) versus 30.8% of patients who received lapatinib and capecitabine (95% CI 26.3-35.7, p<0.001).[i]
  • The duration of response was 12.6 months for those who received Kadcyla (95% CI 8.4-20.8) versus 6.5 months for patients who received lapatinib and capecitabine (95% CI 5.5-7.2).[i]
  • The time-to-symptom progression, a patient-reported measure of quality of life, was also improved in patients who received Kadcyla compared to patients who received lapatinib and capecitabine (7.1 months vs. 4.6 months, HR=0.8, 95% CI 0.67-0.95, p=0.012).[i] However, these data are from an open label study and no firm conclusions can be drawn.
  • Patients receiving Kadcyla experienced fewer severe side effects than those who received lapatinib and capecitabine:
    • Patients who received Kadcyla experienced fewer grade 3 or higher (severe) side effects than those who received lapatinib and capecitabine, at 40.8% versus 57% respectively.[i]

    • For patients receiving Kadcyla, compared to those receiving lapatinib and capecitabine, the most common (occurring in more than 2% of patients) grade 3 or higher side effects were low platelet count (12.9% vs. 0.2%) and increased levels of enzymes released by the liver and other organs (aspartate aminotransferase or ‘AST’: 4.3% vs. 0.8% and alanine aminotransferase or ‘ALT’: 2.9% vs. 1.4%) and anaemia: 2.7% vs. 1.6%.[i]
    • For those patients receiving lapatinib and capecitabine compared to those receiving Kadcyla, the most common grade 3 or higher symptomatic side effects were diarrhoea (20.7% vs. 1.6%), hand-foot syndrome (16.4% vs. 0%) and vomiting (4.5% vs. 0.8%).[i]

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 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.[vii],[viii]

Like most treatments, Herceptin can be associated with side effects. The most common of these are mild flu-like symptoms such as chills and/or fever that usually occur as a reaction to its administration.7 Herceptin can also have effects on the heart that are treatable in the majority of cases.[vii] It was first licensed in Europe in 2000 for the treatment of HER2-positive metastatic breast cancer, and in 2006 for early breast cancer. Herceptin is marketed in the US by Genentech, in Japan by Chugai and internationally by Roche. A summary of product characteristics is available on the EMC website: http://www.medicines.org.uk/EMC

Adverse reaction reporting

This medicinal product is subject to additional reporting. Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Roche is committed to the safety of its medicines. As such Roche encourages Adverse Events to be reported and hence the inclusion of this explanatory information.

Adverse events should be reported. Reporting forms and information can be found at http://www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Roche Products Ltd. Please contact Roche Drug Safety Centre by emailing [email protected] or calling +44(0)1707 367554.

Source

[i] Verma, S. et al. (2012) Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer. N Engl J Med; 367: 1783-1791.

[ii] 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.

[iii] Kadcyla® SmPC Roche Products Ltd. Kadcyla® SmPC. November 2013.

[iv]http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Breast/Symptomsdiagnosis/HormoneandHER2receptors/HormoneandHER2receptors.aspx Last accessed January 2014.

[v]http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Breast/Aboutbreastcancer/Typesandrelatedconditions/H ER2%20positive.aspx Last accessed January 2014.

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

[vii] Herceptin® SmPC Roche Products Ltd. Herceptin® SmPC. December 2013. Available at: http://www.medicines.org.uk/EMC. Last accessed January 2014.

[viii] 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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