Nonsignificant Improvement in Disease-Free Survival With Adjuvant Lapatinib/Trastuzumab vs Trastuzumab in Early HER2-Positive Breast Cancer


Key Points

  • Concomitant lapatinib and trastuzumab was associated with nonsignificantly improved disease-free survival vs trastuzumab in patients with nonmetastatic HER2-positive breast cancer.
  • Lapatinib treatment was associated with added toxicity.

Results of a phase III trial, reported in the Journal of Clinical Oncology by Piccart-Gebhart et al, showed a modest and statistically nonsignificant increase in disease-free survival with concurrent adjuvant lapatinib (Tykerb) and trastuzumab (Herceptin) vs trastuzumab alone in patients with nonmetastatic HER2-positive breast cancer. No difference was observed for sequential trastuzumab then lapatinib vs trastuzumab alone.

Study Details

In this open-label Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, 8,381 patients were randomly assigned between July 2007 and July 2011 to receive 1 year of adjuvant therapy with trastuzumab, lapatinib, sequential trastuzumab then lapatinib, or concomitant lapatinib and trastuzumab. The lapatinib-alone arm was closed in 2011, due to futility to demonstrate noninferiority of lapatinib vs trastuzumab. A protocol modification required P ≤ .025 for significance in the two remaining pairwise comparisons for disease-free survival.

Disease-Free Survival

At a protocol-specified analysis at median follow-up of 4.5 years, the hazard ratios for disease-free survival were 0.84 (P = .048) for concomitant lapatinib-trastuzumab and 0.96 (P = .61) for sequential trastuzumab then lapatinib vs trastuzumab alone. Four-year disease-free survival was 88% and 87% vs 86%. Four-year overall survival was 95% (odds ratio = 0.80, P = .078) and 95% (odds ratio = 0.91, P = .433) vs 94%.


Patients receiving lapatinib had higher rates of diarrhea, cutaneous rash, and hepatic toxicity compared with trastuzumab patients. The incidence of cardiac toxicity was low in all treatment groups. Grade 3 or 4 adverse events occurred in 46% of the concomitant combination group, 32% of the sequential group, and 25% of the trastuzumab-alone group. Serious adverse events occurred in 21%, 17%, and 14%.

The investigators concluded: “[A]djuvant treatment with the combination of [lapatinib and trastuzumab] resulted in a nonsignificant improvement in [disease-free survival], which was not clinically meaningful because of the modest treatment effect and added toxicity…. One year of adjuvant [trastuzumab] remains standard of care.”

The study was supported by GlaxoSmithKline and the National Cancer Institute.

Martine Piccart-Gebhart, MD, PhD, of the Jules Bordet Institute, Brussels, Belgium, is the corresponding author of the Journal of Clinical Oncology article.

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®.