Adjuvant Lapatinib and Trastuzumab for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Results From the Randomized Phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Trial

Abstract

Background: Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2-positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain.

Methods: In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2-positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T→L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T.

Results: Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P ≤ .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4% reduction was observed with T→L compared with T (HR, 0.96; 97.5% CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms.

Conclusion: Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care.

Conflict of interest statement

Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

© 2015 by American Society of Clinical Oncology.

Figures

Fig 1.

Study design. The numbers of patients in the intention-to-treat population for L+T, T→L, L, and T were 1,155, 1,143, 1,168, and 1,147, respectively, for design 1; 833, 837, 827, and 840 for design 2; and 105, 111, 105, and 110 for design 2B. Design 1: neoadjuvant or adjuvant chemotherapy completed before randomization; anti-HER2 agents were given alone. Design 2: anthracycline component of adjuvant chemotherapy before randomization; taxanes were given concomitantly with anti-HER2 agents. Design 2B: nonanthracycline chemotherapy was given concomitantly with anti-HER2 agents. ALTTO, Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization; HER2, human epidermal growth factor receptor 2; L, lapatinib; L+T, lapatinib plus trastuzumab; mFU, median follow-up; *R, time to randomization; T, trastuzumab; T→L, sequence of trastuzumab followed by lapatinib. †In Design 2B T was given for 18 weeks and L for 28 weeks.

Fig 2.

(A) Kaplan-Meier of DFS in the intention-to-treat population for all four study arms. (B) Kaplan-Meier of OS in the intention-to-treat population for all four study arms. ALTTO, Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization; DFS, disease-free survival; L, lapatinib; L+T, lapatinib plus trastuzumab; OS, overall survival; T, trastuzumab; T→L, trastuzumab followed by lapatinib.

Fig 3.

Whisker plot of DFS in the ITT population for L+T v T. Shorter median clinical follow-up for concurrent chemotherapy timing (3.9 years) compared with sequential chemotherapy timing (4.9 years). DFS, disease-free survival; HR, hormone receptor; ITT, intention to treat; L+T, lapatinib plus trastuzumab; T, trastuzumab.