- 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.
- 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.
- 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.
- Small sample size.
- Open-label design.