Findings from a large phase III study, ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation), suggest that post-surgery (adjuvant) treatment using a combination of two HER2-targeted drugs – trastuzumab and lapatinib – is no more effective than standard treatment with trastuzumab alone for women with early HER2-positive breast cancer.
In the study, researchers found no statistically significant differences between treatment arms in four-year disease-free survival, which ranged between 86 and 88 percent.
“We were encouraged to see that most patients with HER2-positive early breast cancer are doing well with standard trastuzumab therapy,” said senior study author Edith A. Perez, Deputy Director at Large 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.”
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 percent 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.
The trial – the largest-ever adjuvant clinical trial in HER2-positive breast cancer – involved 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) received these anti-HER2 therapies after completing chemotherapy, and the rest received it 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 – defined as recurrence of invasive breast cancer, development of a second primary cancer, or death from any cause – compared to trastuzumab alone, but the finding was not statistically significant.
The four-year disease- free survival rates were similar in the three treatment arms – 86 percent in the trastuzumab arm, 88 percent in the concurrent arm, and 87 percent in the sequential arm.
Compared to trastuzumab alone, the combination treatment was associated with much higher rates of certain side effects, such as diarrhoea, skin rash, and liver problems.
Another important finding from this trial was that the rates of serious heart-related side effects were very low. In recent years, many doctors have stopped using anthracycline chemotherapy (such as doxorubicin) due to concerns about heart toxicities and are using the TCH (docetaxel, carboplatin, trastuzumab) regimen instead, even though anthracycline chemotherapy has been more extensively studied.
But in ALTTO the rate of congestive heart failure was less than 1 percent, even though 95 percent 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 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 a much smaller trial that preceded this study, NeoALTTO, dual treatment with lapatinib and trastuzumab before surgery (called neoadjuvant therapy) doubled the pathological complete response (no evidence of invasive cancer found in the breast or lymph nodes at the time of surgery) rates compared to 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.