Results from the ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) study, an international phase III clinical trial of two targeted therapies for HER2-positive breast cancer, suggest that post-surgery or adjuvant treatment using a combination of two HER2-targeted drugs ? trastuzumab (Herceptin?; Genentech/Roche) and lapatinib (Tykerb?; GlaxoSmithKline/GSK), is not more effective than standard treatment with trastuzumab alone.

Researchers were interested in finding out whether one drug is better than the other at helping women live longer without a recurrence of their disease, or if the two drugs work better together. They found no statistically significant differences between treatment arms in four-year disease-free survival, which ranged between 86% and 88%. These findings were presented during the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO), being held from may 30 – June 3 in Chicago, Ill.

Encouraged but surprised
?We were encouraged to see that most patients with HER2-positive early breast cancer are doing well with standard trastuzumab therapy,? noted senior study author Edith A. Perez, MD, Deputy Director at Large, Serene M. and Frances C. Durling Professor of Medicine, Division of Hematology/Oncology and Group Vice Chair, Alliance for Clinical Trials in Oncology at the Mayo Clinic Cancer Center in Jacksonville, FL. ?But we were surprised that adding lapatinib did not provide further benefit, since the combination of these drugs was promising when given prior to surgery in a smaller study. A key lesson of this trial is that we need robust clinical trials in specific disease settings to fully assess and understand the value of new treatment regimens.?

…the increased in-breast response rate seen for this drug combination when used pre-operatively did not predict improved disease-free survival… for now this trial provides reassurance that trastuzumab is a safe and potent adjuvant treatment for HER2-positive breast cancer…

Post-surgery treatment with trastuzumab and chemotherapy significantly reduces the risk of cancer recurrence and death for women with early-stage HER2-positive breast cancer. However, about 20% of patients experience a relapse within 10 years, with the cancer usually appearing in other parts of the body. The goal of this trial was to further reduce the relapse rate by using two drugs that target the HER2 pathway, instead of one.

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Trial design
The ALTTO trial is the largest-ever adjuvant clinical trial in HER2-positive breast cancer, including 946 medical centers in 44 countries and 8,381 women with newly diagnosed early-stage breast cancer. After surgery, the patients were randomly assigned to treatment with lapatinib plus trastuzumab (concurrent arm), trastuzumab followed by lapatinib (sequential arm), or trastuzumab alone for one year.

A majority of these patients, 4,613 women, received these anti-HER2 therapies after completing chemotherapy, and the rest received them both concurrently with chemotherapy and then after. Patients with hormone receptor-positive cancers also received appropriate hormonal therapy.

At a median follow-up of 4.5 years, treatment with lapatinib plus trastuzumab (either sequential or concurrent) was associated with a numerically lower risk of a disease-free survival event, which was defined as recurrence of invasive breast cancer, development of a second primary cancer, or death from any cause, compared to trastuzumab alone. This finding was, however, not statistically significant. The four-year disease-free survival rates were similar in the three treatment arms ? 86%in the trastuzumab arm, 88% in the concurrent arm, and 87% in the sequential arm.

Compared to trastuzumab alone, the combination treatment was associated with much higher rates of certain side effects, including diarrhea, skin rash, and liver problems.

Anthracycline chemotherapy
Another important finding from this trial was that the rates of serious heart-related side effects were very low. Even though anthracycline chemotherapy has been more extensively studied, in recent years, many doctors have stopped using anthracycline chemotherapy, such as doxorubicin, due to concerns about heart toxicities. Instead, they are using the TCH (docetaxel, carboplatin, trastuzumab) regimen. But in ALTTO the rate of congestive heart failure was less than 1%, even though 95% of women received anthracycline chemotherapy. This safety, along with the patient outcome in terms of breast cancer, provides additional reassurance that using anthracycline-based chemotherapy followed by trastuzumab is safe for women with early-stage HER2-positive breast cancer.

The ALTTO study was accompanied by a large collection of blood and tissue specimens that will help researchers further understand the biology of breast cancer and provide insight as to why certain patients experience a relapse and others do not.

In the much smaller NeoALTTO smaller trial, which preceded the ALTTO study, dual treatment with lapatinib and trastuzumab called neoadjuvant therapy doubled the pathological complete response, in which no evidence of invasive cancer found in the breast or lymph nodes at the time of surgery. These rates compared to treatment with trastuzumab alone. However, ALTTO did not show that the dual strategy, despite increasing the in-breast response rate, led to better long-term outcome compared to single anti-HER2 therapy with trastuzumab. The ALTTO study will influence the design of future breast cancer clinical trials, as it calls into question the use of in-breast pathological complete response as a surrogate marker of long-term treatment impact when comparing one specific treatment against another.

Well-designed Clinical Trials
?These results illustrate the importance of conducting well-designed clinical trials,? said 2013 – 2014 ASCO president Clifford A. Hudis, MD, FACP., Chief, Breast Cancer Medicine Service, at Memorial Sloan Kettering, New York, NY. ?In this case, the increased in-breast response rate seen for this drug combination when used pre-operatively did not predict improved disease-free survival. Other studies using different drugs could reach different conclusions, but for now this trial provides reassurance that trastuzumab is a safe and potent adjuvant treatment for HER2-positive breast cancer.

For more information:
Piccart-Gebhart MJ, Holmes AP, Baselga J, De Azambuja E, Dueck AC, Viale G, Zujewski JA, et al. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T?L), or their combination (T+L) in the adjuvant treatment of HER2-positive early breast cancer (EBC). ASCO 2014 Annual Meeting. Plenary Session, Sunday June 1, 1:00 PM to 4:00 PM, Abstract No: LBA4, Citation: J Clin Oncol 32:5s, 2014 (suppl; abstr LBA4) [Abstract]

Photo: Edith Perez, MD, Plenary Session at the American Society of Clinical Oncology Annual Meeting, Sunday June 1, 2014. Photo Courtesy: ?ASCO/Silas Crews.

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