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Updated: Jan 20, 2026

Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
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Safety and Efficacy of T-DM1 Plus Neratinib in Patients With Metastatic HER2-Positive Breast Cancer: NSABP Foundation

Jame Abraham1,2, Albert J Montero1,2, Rachel C Jankowitz1,3,4

  • 1NSABP Foundation, Pittsburgh, PA.

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
|August 24, 2019
PubMed
Abstract

Insights

This study found that combining ado-trastuzumab emtansine (T-DM1) with neratinib is a safe and effective treatment for HER2-positive metastatic breast cancer resistant to dual-antibody therapy. The recommended Phase II dose is T-DM1 3.6 mg/kg and neratinib 160 mg/d.

Area of Science:

  • Oncology
  • Pharmacology
  • Genetics

Background:

  • HER2-positive metastatic breast cancer often develops resistance to trastuzumab and pertuzumab therapies.
  • Understanding resistance mechanisms is crucial for developing new treatment strategies.

Purpose of the Study:

  • To evaluate the safety, tolerability, and efficacy of ado-trastuzumab emtansine (T-DM1) combined with neratinib in patients with HER2-positive metastatic breast cancer who progressed on prior dual-antibody therapy.
  • To identify potential resistance mechanisms to HER2-targeted therapies.

Main Methods:

  • A 3+3 dose-escalation study treated 27 patients with metastatic breast cancer who progressed on trastuzumab, pertuzumab, and taxanes.
  • Patients received T-DM1 (3.6 mg/kg IV every 3 weeks) and escalating doses of neratinib (120-240 mg/d orally).
  • Safety, tolerability, objective response rate, and correlation with HER2 amplification in cell-free DNA were assessed.

Main Results:

  • The recommended Phase II dose was determined to be T-DM1 3.6 mg/kg and neratinib 160 mg/d.
  • Objective responses were observed in 12 (63%) of 19 evaluable patients across all neratinib doses.
  • Patients with baseline ERBB2 (HER2) amplification in cell-free DNA showed deeper and more durable responses.

Conclusions:

  • The combination of T-DM1 and neratinib demonstrates promising activity and acceptable toxicity in patients with heavily pretreated HER2-positive metastatic breast cancer.
  • Potential resistance mechanisms include loss of HER2 receptor or high expression of p95HER2.
  • Further investigation in a Phase II study is warranted to confirm these findings.

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