Adjuvant Herceptin Therapy

• HERceptin Adjuvant (HERA) trial: 
  • An international, multicenter, phase 3 randomized trial of 5,102 women with HER2-positive early breast cancer
  • After completing all primary therapy (including, surgery, chemotherapy, and radiotherapy as indicated):
    • Patients were randomly assigned to receive trastuzumab for 1 or 2 years, or to the observation group
  • Primary endpoint was disease-free survival
  • Results reported that:
    • One year of adjuvant trastuzumab after chemotherapy for patients with HER2-positive early breast cancer significantly improved long-term disease-free survival, compared with observation, while two years of trastuzumab had no additional benefit
• ALTTO (Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimization) Study: 
  • Was the first trial to test the hypothesis that dual anti-HER2 blockade could further improve survival outcomes of patients with HER2-positive early breast cancer compared with adjuvant trastuzumab
  • The study compared the efficacy of the addition of lapatinib to trastuzumab (sequentially after completion of 12 weeks of trastuzumab or concurrently with 52 weeks of trastuzumab) vs. trastuzumab alone for 1 year
  • Adjuvant treatment that included lapatinib did not significantly improve survival compared with trastuzumab alone and added toxicity
• NSABP B-44, also known as the BETH Study (Treatment of HER2 Positive Breast Cancer With Chemotherapy Plus Trastuzumab vs. Chemotherapy Plus Trastuzumab Plus Bevacizumab):
  • Was a phase 3 study evaluating the addition of bevacizumab, a vascular endothelial growth factor (VEGF-A) to trastuzumab
  • Patients were randomized to 1 of 4 treatment arms in 2 cohorts: 
    • Cohort 1: 
      • The nonanthracycline regimen TCH (docetaxel, carboplatin, and trastuzumab [Herceptin]) or TCH plus bevacizumab
    • Cohort 2: 
      • Anthracycline-based therapy with T-FEC-H (docetaxel, fluorouracil, epirubicin, cyclophosphamide, plus trastuzumab) with or without bevacizumab
    • The study concluded that the addition of bevacizumab (Avastin) to adjuvant chemotherapy did not improve invasive disease-free survival or overall survival in patients with high-risk HER2-positive breast cancer
    • BETH also demonstrated that the non–anthracycline-containing chemotherapy arm was as effective in prolonging survival as the anthracycline-containing arm
• Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET) Trial: 
  • Is a multicenter, randomized, phase 3 trial designed to investigate extended adjuvant therapy with neratinib
  • Patients received one year of extended adjuvant therapy with neratinib, an irreversible pan-HER tyrosine kinase inhibitor, administered after chemotherapy and trastuzumab
  • The results showed:
    • That one year of neratinib significantly improved 5-year invasive disease-free survival without increasing the risk of long-term toxicity
• APHINITY trial (BIG 4-11): 
  • A randomized comparison of chemotherapy (C) plus trastuzumab (T) plus placebo versus chemotherapy plus trastuzumab (T) plus pertuzumab (P) as adjuvant therapy in patients with HER2-positive early breast cancer
  • In previous neoadjuvant trials:
    • Pertuzumab significantly prolonged progression free and overall survival and increased pathologic complete response (pCR) rates when added to trastuzumab and chemotherapy
  • The investigated the role of pertuzumab when added to trastuzumab after surgery and chemotherapy in the adjuvant setting
  • A small benefit in favor of the combination was observed:
    • Which was more pronounced in node-positive patients
• References
  • Cameron D, Piccart-Gebhart MJ, Gelber RD, Proctor M, Goldhirsch A, de Azambuja E, et al. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet. 2017;389(10075):1195-1205.
  • Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, Viale G, et al. 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. J Clin Oncol.2016;34(10):1034-1042.
  • Slamon DL, Swain SM, Buyse M, Martin M, Geyer CE. Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab ± bevacizumab in patients with HER2-positive, node-positive, or high-risk node-negative breast cancer [Abstract]. Cancer Res. 2013;73(suppl 24): S1-03.
  • Martin M, Holmes FA, Ejlertsen B, Delaloge S, Moy B, Iwata H, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(12):1688-1700.
  • von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377(2):122-131.

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