ALTTO (BIG 2-06)

Intro text: 

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.

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.

  • Piccart-Gebhart M, Holmes E, Baselga J, et al. Adjuvant Lapatinib and Trastuzumab for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Results From the Randomized Phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Trial. J Clin Oncol. 2016 Apr 1;34(10):1034-42.
  • Sonnenblick A, de Azambuja E, Agbor-Tarh D, Bradbury I, Campbell C, Huang Y, Dueck AC, Pritchard KI, Wolff AC, Jackisch C, Lang I, Untch M, Smith I, Boyle F, Xu B, Gomez H, Perez EA, Piccart M, Azim HA Jr. Lapatinib-Related Rash and Breast Cancer Outcome in the ALTTO Phase III Randomized Trial. J Natl Cancer Inst. 2016 Apr 20;108(8). pii: djw037. doi: 10.1093/jnci/djw037. Print 2016 Aug.
  • McCullough AE, Dell’Orto P, Reinholz MM, Gelber RD, Dueck AC, Russo L, Jenkins RB, Andrighetto S, Chen B, Jackisch C, Untch M, Perez EA, Piccart-Gebhart MJ, Viale G. Central pathology laboratory review of HER2 and ER in early breast cancer: an ALTTO trial [BIG 2-06/NCCTG N063D (Alliance)] ring study. Breast Cancer Res Treat 143:485-492, 2014
  • Metzger-Filho O, de Azambuja E, Bradbury I, Saini KS, Bines J, Simon SD, Dooren VV, Aktan G, Pritchard KI, Wolff AC, Smith I, Jackisch C, Lang I, Untch M, Boyle F, Xu B, Baselga J, Perez EA, Piccart-Gebhart M. Analysis of regional timelines to set up a global phase III clinical trial in breast cancer: The adjuvant lapatinib and/or trastuzumab treatment optimization experience. Oncologist. 2013;18(2):134-40. Epub 2013 Jan 28

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.

ClinicalTrials.gov identifier: NCT00490139