In the phase Ib NSABP Foundation Trial FB-10 reported in the Journal of Clinical Oncology, Jame Abraham, MD, and colleagues found evidence of activity of the combination of ado-trastuzumab emtansine (T-DM1) plus neratinib in metastatic HER2-positive breast cancer and identified the dose of the combination for phase II testing.
Jame Abraham, MD
In the multicenter, dose-escalation study, 27 patients who had shown disease progression on trastuzumab, pertuzumab, and a taxane were treated between February 2015 and July 2017 with T-DM1 at 3.6 mg/kg every 3 weeks and oral neratinib at 120, 160, 200, or 240 mg/d.
Responses
Among 19 patients evaluable for efficacy, 12 (63%) had an objective response, with responses being observed at all neratinib doses. Complete response was observed in three patients, with response durations of 364, 510, and 969+ days. Stable disease was observed in an additional two patients.
Plasma cell-free DNA testing at baseline showed ERBB2 (HER2) amplification in 10 of 27 patients. Patients with ERBB2 amplification exhibited deep and more durable responses, with seven with amplification or mutation having complete (three patients) or partial (four patients) response. Two patients with a complete response had high levels of expression of total HER2 and p95HER2 in baseline tissue samples.
KEY POINTS
- Objective response was observed in 12 of 19 patients.
- Patients with baseline ERBB2 amplification exhibited deep and more durable responses.
Toxicity
Dose-limiting toxicities consisted of grade 3 diarrhea in six patients and grade 3 nausea in one patient. Other grade 3 or 4 toxicities included nausea (in 11% of patients), dehydration (in 11%), electrolyte abnormality (in 19%), thrombocytopenia (in 15%), elevated transaminase levels (in 7%), and fatigue (in 7%). The dose selected for phase II testing was T-DM1 at 3.6 mg/kg and neratinib at 160 mg/d.
The investigators concluded, “We report the recommended phase II dose of T-DM1 3.6 mg/kg and neratinib 160 mg/d for this combination. Possible resistance mechanisms to HER2 antibodies may be loss of the HER2 receptor and high expression of p95HER2. These data provide the basis for an ongoing phase II study to better define the activity of this regimen.”
Samuel A. Jacobs, MD, of the NSABP Foundation, Pittsburgh, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported in part by PUMA Biotechnology. For full disclosures of the study authors, visit jco.ascopubs.org.
