BIG 2-06

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A randomised, multi-centre, open-label, phase III study of adjuvant lapatinib, trastuzumab, their sequence and their combination in patients with HER2/ErbB2 positive primary breast cancer

The ALTTO study investigated whether combining trastuzumab (Herceptin) with another drug called lapatinib (Tykerb®) – given either alone, together or one after the other – benefits patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (when the cancer is limited to the breast and has not spread to other organs). It also assessed the safety of lapatinib and aims to identify specific molecular markers (indicators found in blood or other human tissue) to predict which patients will benefit most from lapatinib or trastuzumab.

Patients with HER2-positive breast cancer have a greater risk of cancer recurrence due to the aggressiveness of this disease subtype.

HER2-positive breast cancers are usually treated with trastuzumab, which has been shown to lower the rate of cancer recurrence and improve survival when given with chemotherapy.  Lapatinib is another drug developed to treat HER2-positive breast cancer.  It works inside the cells to slow or stop the processes that cause tumour growth and disease progression.  When the study was designed, it was thought that using both drugs (combined or in sequence) might work better than giving either drug alone.

Clinical studies for late stage (“advanced” or “metastatic”) breast cancer, when the disease has spread to other parts of the body, have shown that lapatinib is effective in patients who have already received several standard therapies.

In view of this, the ALTTO trial was set up is to explore if lapatinib is also effective in patients with early disease who are given an adjuvant therapy (treatment given after surgery).

The results of the study did not show that there was a benefit to adding lapatinib to the adjuvant treatment of patients with HER2-positive early breast cancer in comparison to the standard treatment with trastuzumab alone; moreover, lapatinib was associated with additional side-effects. Therefore, one year of trastuzumab as adjuvant treatment (following surgery and chemotherapy with or without radiotherapy) for this subtype of breast cancer remains the standard of care.

Dr Daniel Eiger, clinical research fellow at the Institut Jules Bordet, Brussels, Belgium, presented a mini oral session during the ESMO Breast Cancer Congress in May 2019 on the long-term cardiac outcomes of HER2+ breast cancer patients treated in the ALTTO trial.

Researchers reported the cardiac data from 4,190 patients who did not have any serious cardiac illness and who received one year of adjuvant trastuzumab alone, or trastuzumab and lapatinib concomitantly. Symptoms of heart failure in these patients were assessed tri-monthly during treatment, every 6 months until 2 years of treatment, and then once a year until 10 years after start of treatment.

It was found that dual HER2 blockade does not increase the rate of cardiotoxicity in comparison to trastuzumab alone.

After surgery and a standard treatment with chemotherapy, patients enrolled in ALTTO were randomly assigned to receive one of these four treatments for a period of 1 year:
• Trastuzumab alone
• Lapatinib alone
• Trastuzumab followed by lapatinib
• Lapatinib in combination with trastuzumab

ALTTO recruited 8,381 patients between 2007 and 2011.

Coordinating partners: Breast International Group (BIG), Institut Jules Bordet Clinical Trials Support Unit (IJB/ CTSU formerly BrEAST), Frontier Science Scotland (FSS), Alliance (previously North Central Cancer Treatment group [NCCTG]) in collaboration with the U.S. National Cancer Institute (NCI) and together with the sponsor (GlaxoSmithKline until 2015, then Novartis).

In addition to the coordinating partners, 19 academic research groups from the BIG network are participating in this study.

The recruitment opened in June 2007 and completed in July 2011.

Patients will be followed for at least 10 years after enrolment; as of 1 July 2016, all patients had been followed for at least 5 years.

946 hospitals and cancer centres in 44 countries are participating in the study.

Research project proposals (RPPs) requesting access to data only can be submitted at any time. For more information, please refer to the Policy for Access, RPP template completion instructions, RPP template, data checklist and list of already approved Research Projects.

RPPs requesting samples and data can’t be submitted at this time. Such an RPP can be submitted once a call is announced here.

GlaxoSmithKline (GSK) was the sponsor and funder of the study until 30 Nov 2015, after which these responsibilities were transferred to Novartis. The study was designed and conducted following BIG’s academic research principles.

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