ASCO 2014: Adding Lapatinib to Adjuvant Trastuzumab Does Not Improve Outcomes in Early-Stage HER2-Positive Breast Cancer


Key Points

  • There were no statistically significant differences in 4-year disease-free survival among women with early HER2-positive breast cancer who received adjuvant trastuzumab and lapatinib vs standard treatment with trastuzumab alone.
  • The 4-year disease-free survival rates were similar in the three treatment arms: 86% with trastuzumab alone, 88% with concurrent trastuzumab and lapatinib, and 87% with sequential trastuzumab then lapatinib.
  • The combination treatment was associated with higher rates of some side effects, such as diarrhea, skin rash/erythema, and hepatobiliary adverse events.

A large phase III study, ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation), found no statistically significant differences in 4-year disease-free survival among women with early HER2-positive breast cancer who received adjuvant treatment that combined the HER2-targeted drugs trastuzumab (Herceptin) and lapatinib (Tykerb) and those who received standard treatment with trastuzumab alone. The findings were presented at the 2014 ASCO Annual Meeting in Chicago (Abstract LBA4)

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 planned number of disease-free survival events was 850, but only 555 were actually observed.

The 4-year disease-free survival rates were similar in three treatment groups: 86% with trastuzumab alone; 88% with concurrent trastuzumab and lapatinib; and 87% with sequential trastuzumab then lapatinib.

Surprising Lack of Benefit

“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, MD, Deputy Director at Large at the Mayo Clinic Cancer Center in Jacksonville, Florida, who presented the findings at a press briefing on the Plenary Session. “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.”

Although postsurgery treatment with trastuzumab and chemotherapy has been shown to significantly reduce the risk of cancer recurrence and death for women with early-stage HER2-positive breast cancer, about 20% of patients experience a relapse within 10 years. 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 involved 946 medical centers in 44 countries and 8,381 women with newly diagnosed early-stage breast cancer. Following surgery, the patients were randomly assigned to anti-HER therapy. A majority of patients (n = 4,613) received anti-HER2 therapy after completing chemotherapy and the others received it concurrently with and then after chemotherapy. Patients with hormone receptor–positive cancers also received appropriate hormonal therapy.

Trial Did Not Meet Endpoint

The trial “did not meet its endpoint in terms of disease-free survival,” the study’s lead author Martine J. Piccart-Gebhart, MD, PhD, of the Jules Bordet Institute, Breast International Group, Belgium, acknowledged at the Plenary Session. She noted that lapatinib significantly increased adverse events, and “only 60% to 78% of patients in the lapatinib arms could receive at least 85% of the protocol-specified dose.” Diarrhea, skin rash/erythema, and hepatobiliary adverse events were increased.

Commenting on the study at the Plenary Session, ASCO Past President George Sledge, MD, noted that the study was “underpowered” because of the few number of events and was “a negative trial.” Dr. Sledge is Professor and Chief, Division of Oncology, at Stanford University in California. He called the trial “a serious disappointment not just for investigators, but for the entire field.” The trial “requires us to rethink our approach to the development of new drugs in early breast cancer,” he added. “If ALTTO has taught us anything, it is that hopes and beliefs are no substitute for the hard work of well-conducted definitive clinical trials,” Dr. Sledge concluded.

Use of Pathologic Complete Response as Surrogate Questioned

In the much smaller NeoALTTO trial that preceded ALTTO, neoadjuvant treatment with both lapatinib and trastuzumab doubled the pathologic complete response rates compared to trastuzumab alone. In ALTTO, however, the dual strategy was associated with increased in-breast response rate, but did not lead to better long-term outcome compared to single anti-HER2 therapy with trastuzumab.

“This study really operates on two levels. On the one hand, from a practical point of view, if this study had been positive, it would have changed practice tomorrow morning, because these drugs are available and the adjuvant setting is one where there is a tremendous drive to reduce recurrence and prevent early death from disease,” ASCO Immediate Past President Clifford A. Hudis, MD, FACP, who served as moderator of the ASCO plenary press briefing, told reporters. Dr. Hudis is Chief of the Breast Cancer Medicine Service at Memorial Sloan Kettering Cancer Center in New York.

“The second level on which it operates is a more technical one with tremendous potential implications right now,” Dr. Hudis continued. “Last year, the FDA, for the first time ever, approved a drug in the preoperative setting on the basis of an increased pathologic complete response rate. That drug, pertuzumab [Perjeta], is a drug that has been studied in the adjuvant setting, and the hope obviously is that by getting the drug into the market based on pathologic complete response rate, we would ultimately save lives. That may turn out to be true for that study.… But if the question that we have from a societal point of view is, ‘Can we routinely use the preoperative setting and the improvement of pathologic complete response as a reliable surrogate for disease-free and overall survival?’ Then the answer, at least from ALTTO right now, is maybe not. And this is going to cause a tremendous amount of high-level technical and scientific discussion in terms of drug development.”

This research was supported by GlaxoSmithKline and the National Cancer Institute. Dr. Piccart-Gebhart reported an employment or leadership position with PharmaMar; consultant or advisory role with Amgen, Astellas Pharma, AstraZeneca, Bayer, Invivis, Lilly, MDS, Novartis, Pfizer, Roche/Genentech, Sanofi, Symphogen, Synthon, and Verastem; and honoraria from Amgen, Astellas Pharma, AstraZeneca, Bayer, Invivis, Lilly, MSD, Novartis, Pfizer, Roche/Genentech, Sanofi, Symphogen, Synthon, and Verastem. Dr. Perez reported no potential conflicts of interest. For full disclosures of the study authors, view the study abstract at

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.