Cancer Chemotherapy and Pharmacology

, Volume 72, Issue 6, pp 1205–1212 | Cite as

Safety and efficacy of neratinib in combination with weekly paclitaxel and trastuzumab in women with metastatic HER2-positive breast cancer: an NSABP Foundation Research Program phase I study

  • Rachel C. Jankowitz
  • Jame Abraham
  • Antoinette R. Tan
  • Steven A. Limentani
  • Marni B. Tierno
  • Laura M. Adamson
  • Marc Buyse
  • Norman Wolmark
  • Samuel A. Jacobs
Original Article



Neratinib is an oral, small-molecule inhibitor that irreversibly binds to pan-HER (ErbB) receptor tyrosine kinases. Studies suggest that dual anti-HER therapies utilized in breast cancer patients are more efficacious than single agents in both the metastatic and neoadjuvant settings. In this phase I study, neratinib was combined with trastuzumab and paclitaxel in metastatic HER2-positive patients.


Twenty-one patients entered this dose-escalation study to determine the maximum-tolerated dose, safety, and efficacy of neratinib (120 up to 240 mg/day) with trastuzumab (4 mg/kg IV loading dose, then 2 mg/kg IV weekly), and paclitaxel (80 mg/m2 IV days 1, 8, and 15 of a 28-day cycle) in women with HER2-positive metastatic breast cancer previously treated with anti-HER agent(s) and a taxane.


The recommended phase II dose of neratinib with trastuzumab and paclitaxel was 200 mg/day. Common grade 3/4 adverse events were diarrhea (38 %), dehydration (14 %), electrolyte imbalance (19 %), and fatigue (19 %). With mandated primary diarrheal prophylaxis, ≥grade 3 diarrhea was not observed. Objective responses, complete (CR) and partial (PR), occurred in eight patients (38 %), with a clinical benefit of CR + PR+ stable disease (SD) ≥24 weeks in 11 patients (52 %). Median time-to-disease progression was 3.7 months.


Dual anti-HER blockade with neratinib and trastuzumab resulted in significant clinical benefit despite prior exposure to trastuzumab, lapatinib, T-DM1, a taxane, and multiple lines of chemotherapy. In selected populations, inhibiting multiple ErbB-family receptors may be more advantageous than single-agent inhibition. Based on favorable tolerance and efficacy, this three-drug combination will be further assessed in a randomized phase II neoadjuvant trial (NSABP FB-7:NCT01008150).


HER2 Neratinib Paclitaxel Trastuzumab Phase I Breast cancer 


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Rachel C. Jankowitz
    • 1
    • 2
  • Jame Abraham
    • 1
    • 3
  • Antoinette R. Tan
    • 1
    • 4
  • Steven A. Limentani
    • 1
    • 5
  • Marni B. Tierno
    • 1
  • Laura M. Adamson
    • 1
  • Marc Buyse
    • 1
    • 6
  • Norman Wolmark
    • 1
    • 7
  • Samuel A. Jacobs
    • 1
  1. 1.National Surgical Adjuvant Breast and Bowel Project (NSABP)PittsburghUSA
  2. 2.Magee-Womens HospitalUniversity of PittsburghPittsburghUSA
  3. 3.West Virginia UniversityMorgantownUSA
  4. 4.Cancer Institute of New JerseyNew BrunswickUSA
  5. 5.Carolinas Medical Center, Levine Cancer InstituteCharlotteUSA
  6. 6.International Drug Development Institute (IDDI)Louvain-la-NeuveBelgium
  7. 7.Allegheny Cancer Center at Allegheny General HospitalPittsburghUSA

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