T-DM1 plus neratinib shows promise in metastatic HER2+ breast cancer

  • Abraham J & al.
  • J Clin Oncol
  • 23 Aug 2019

  • curated by Miriam Davis, PhD
  • Univadis Clinical Summaries
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Takeaway

  • Neratinib+ado-trastuzumab emtansine (T-DM1) showed safety and promising efficacy in a phase 1b dose-ranging study of patients with metastatic HER2-positive breast cancer who progressed on dual-antibody therapy with trastuzumab+pertuzumab.
  • Neratinib 160 mg/day was established as the optimal dose.

Why this matters

  • Resistance usually emerges with dual-antibody therapy, but the mechanism is poorly understood.
  • Findings warrant progression to a phase 2 trial of 160 mg/day neratinib plus T-DM1.

Study design

  • NSABP FB-10, a 3+3 dose escalation study of 27 patients receiving T-DM1 (3.6 mg/kg intravenously every 3 weeks) and dose-escalating oral neratinib (120, 160, 200, and 240 mg/day).
  • Funding: PUMA Biotechnology.

Key results

  • Cycle 1:
    • Dose-limiting toxicity was grade 3 diarrhea (n=6) and grade 3 nausea (n=1).
  • All cycles
    • Most common grade 3-4 toxicities were diarrhea (22%), nausea (11%), dehydration (11%), electrolyte abnormality (19%), thrombocytopenia (15%), elevated transaminase levels (7%), and fatigue (7%).
    • No grade 4 diarrhea; no grade 5 toxicities.
  • Complete response occurred in 3 patients with durations of 364, 510, and 969 days; confirmed partial response in 9 patients.
  • Possible resistance mechanisms to prior dual-antibody therapy may be loss of HER2 receptor and high cell surface expression of p95HER2 seen at baseline.

Limitations

  • Small sample size.
  • Open-label design.

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