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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

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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).

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Acknowledgments

Authors received funds from Puma Biotechnology, Inc.

Conflict of interest

M. Buyse declares remuneration from and stock ownership in the International Drug Development Institute (IDDI). All other authors declare no potential conflicts of interest.

Author information

Authors and Affiliations

  1. National Surgical Adjuvant Breast and Bowel Project (NSABP), East Commons Professional Building, 4 Allegheny Center, 5th Floor, Pittsburgh, PA, 15212, USA

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

  2. Magee-Womens Hospital, University of Pittsburgh, Pittsburgh, PA, USA

    Rachel C. Jankowitz

  3. West Virginia University, Morgantown, WV, USA

    Jame Abraham

  4. Cancer Institute of New Jersey, New Brunswick, NJ, USA

    Antoinette R. Tan

  5. Carolinas Medical Center, Levine Cancer Institute, Charlotte, NC, USA

    Steven A. Limentani

  6. International Drug Development Institute (IDDI), Louvain-la-Neuve, Belgium

    Marc Buyse

  7. Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh, PA, USA

    Norman Wolmark

Authors
  1. Rachel C. Jankowitz
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  2. Jame Abraham
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  9. Samuel A. Jacobs
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Corresponding author

Correspondence to Samuel A. Jacobs.

Additional information

Clinical Trial Registration: NSABP FB-8: NCT01423123.

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Jankowitz, R.C., Abraham, J., Tan, A.R. et al. 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. Cancer Chemother Pharmacol 72, 1205–1212 (2013). https://doi.org/10.1007/s00280-013-2262-2

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  • DOI: https://doi.org/10.1007/s00280-013-2262-2

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