BIG 1-06

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NeoAdjuvant Lapatinib and/or Trastuzumab Treatment Optimisation study

A randomised, multicentre open-label phase III study of neoadjuvant lapatinib, trastuzumab and their combination plus paclitaxel in women with HER2/ErbB2-positive primary breast cancer.

Developed in parallel with its sister trial ALTTO (link to trial summary), the NeoALTTO study was set up to investigate whether combining trastuzumab (Herceptin®) with another drug called lapatinib (Tykerb®) – given either alone, together or one after the other – could benefit patients with human epidermal growth factor receptor 2 (HER2)-positive, ErbB2-positive primary breast cancer in the neoadjuvant (pre-surgical) setting.

It also aims to assess the safety of lapatinib and 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, by working inside the cells to slow or stop the processes that cause tumour growth and disease progression.
This drug has proven to be effective in patients with HER2-positive advanced or metastatic breast cancer that has progressed after treatment with several standard therapies. Because of this, the investigators of NeoALTTO wanted to explore if lapatinib also worked in patients with early disease.

When the study was designed, it was hypothesised that using both lapatinib and trastuzumab (combined or in sequence) might work better than giving either drug alone. The trial focused on patients who were candidates to receive therapy prior to surgery (“neoadjuvant” treatment).

The primary analysis of this study, published in The Lancet 2012, showed that dual HER2-targeted therapy with lapatinib and trastuzumab resulted in more patients achieving a pathological complete response (pCR), meaning a disappearance of all visible signs of cancer, compared to a single HER2-targeted therapy (trastuzumab).

The pCR was significantly higher in the group of patients receiving lapatinib and trastuzumab than in the group receiving trastuzumab alone. No significant difference in pCR was found between the lapatinib and the trastuzumab groups. The event-free survival (EFS) or overall survival (OS) did not differ between treatment groups; however, patients who achieved pCR had longer event-free and overall survival than patients without pCR.

Several studies are ongoing to identify biomarkers of response or resistance to the drugs used in the study.

At ASCO 2017, an updated analysis of Neo-ALTTO was presented. Patients had been followed for a median period of 6.7 years. The 6-year EFS (no signs of breast cancer returning) and OS were not significantly different between the  different types of treatment, although the combination of trastuzumab with lapatinib showed numerically higher EFS compared to trastuzumab alone (74% vs 67%), especially in patients with hormone receptor negative disease (74% vs 63%). In addition, this analysis showed that patients who achieved a pCR had a significantly higher 6-year EFS and OS compared to those without pCR.

Updated results were published in the European Journal of Cancer in 2019. The updated analysis, performed with a median follow-up of 6,7 years, reported a 6-year event free survival (EFS) rate of 67%, 67% and 74% for lapatinib, trastuzumab and the combination, respectively. The difference in EFS rates between the combination group and the groups treated with a single anti-HER2 agent was not significant. Similarly, no significant differences were found in overall survival (OS) rates, with 6-year OS rates of 82%, 79% and 85% being reported for lapatinib, trastuzumab and the combination, respectively.

Notably, a landmark analysis did show that patients who had achieved a pCR did have a significantly better EFS and OS rate than those who had residual disease after neoadjuvant treatment, reporting EFS and OS rates of 77% vs 65% and 89% vs 77%, respectively. This effect was limited to the patients with hormone receptor-negative tumours.

A long-term analysis, based on a median follow up of 9.7 years, showed that women who achieved pCR have significantly higher survival rates (EFS and OS) compared to those who did not. It confirms that pCR is likely an indicator of long-term benefit in HER2-positive breast cancer. This trend is more important in patients whose disease is hormone receptor-negative and in the population receiving the combination of lapatinib and trastuzumab. In the overall population, the survival rates by treatment arm did not differ significantly; however, patients who reached a pCR in the combination arm were nearly double compared to patients in the single drug arms. The analysis did not report any new or long-term safety concerns.

To our knowledge, NeoALTTO is the neoadjuvant study with dual HER2 blockade in early breast cancer with the longest clinical follow-up (almost 10 years).

The NeoALTTO trial compares three anti-HER2 (ErbB2) targeted therapies:

Before surgery, patients enrolled in NeoALTTO were randomly assigned to receive one of these three treatments for a period of 1 year, together with the standard chemotherapy treatment:

1) Trastuzumab alone
2) Lapatinib alone
3) Lapatinib in combination with trastuzumab

NeoALTTO recruited 455 women with HER2-positive primary breast cancer between 2008 and 2010.

Coordinating partners: Institut Jules Bordet – Clinical Trials Support Unit / IJB-CTSU (formerly BrEAST), Frontier Science Scotland (FSS), SOLTI and the Breast International Group (BIG)

Pharmaceutical partner: Novartis (global sponsor for all countries with the exception of US, where Alliance is the sponsor)

Enrolment began in January 2008 and completed in May 2010.

Patients will be followed for at least 10 years after enrolment; exploratory (translational) research using the biological samples and data from this study is ongoing.

Patients were enrolled from 86 sites in 23 countries; 8 BIG member groups participated 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 November 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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