Safety and Efficacy of T-DM1 Plus Neratinib in Patients With Metastatic HER2-Positive Breast Cancer: NSABP Foundation Trial FB-10

Abstract

Purpose: Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer eventually develop resistance to dual-antibody therapy with trastuzumab plus pertuzumab. Mechanisms of resistance have not been well elucidated. We evaluated the safety, tolerability, and efficacy of ado-trastuzumab emtansine (T-DM1) plus neratinib in patients who progressed on trastuzumab plus pertuzumab.

Patients and methods: In this 3 + 3 dose-escalation study, patients with metastatic breast cancer who progressed on trastuzumab, pertuzumab, and a taxane were treated with T-DM1 at 3.6 mg/kg intravenously every 3 weeks and dose-escalating neratinib at 120, 160, 200, or 240 mg/d orally.

Results: Twenty-seven patients were treated across four dose-levels of neratinib. Dose-limiting toxicity in cycle 1 was grade 3 diarrhea in six patients and grade 3 nausea in one; no patient experienced grade 4 diarrhea, and there were no grade 5 toxicities. Other grade 3 to 4 toxicities included nausea (11%), dehydration (11%), electrolyte abnormality (19%), thrombocytopenia (15%), elevated transaminase levels (7%), and fatigue (7%). Twelve (63%) of 19 evaluable patients had an objective response. Responses occurred at all neratinib doses. Plasma cell-free DNA at baseline showed ERBB2 (HER2) amplification in 10 of 27 patients. Deep and more durable responses occurred in patients with cell-free DNA ERBB2 amplification. Two complete responders had high expression of total HER2 and p95HER2 in baseline tissue.

Conclusion: 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.

Trial registration: ClinicalTrials.gov NCT02236000.

Figures

FIG 1.

Neratinib pharmacokinetics. (A) Neratinib concentration versus time over 24 hours. The outlier at 200 mg/d (upper arrow) developed a dose-limiting toxicity; the outlier at 160 mg/d (lower arrow) was taking pantoprazole. (B) Neratinib trough concentration at 24 hours (C24) on day 1, cycle 2, after dosing, with indication of response. CR, complete response; PD, progressive disease; PR, partial response.

FIG 2.

Response Evaluation Criteria in Solid Tumors (RECIST) response and duration. (A) Best response and duration in cell-free DNA in patients with and without ERBB2 amplification. Although response by dose level is not shown here, objective responses and stable disease (SD) were seen at all dose levels, including two complete responses (CRs) and three partial responses (PRs) in six patients treated with neratinib 120 mg/d, one CR and three PRs in nine patients treated with 160 mg/d, two PRs and one SD in eight patients treated with 200 mg/d, and one PR and one SD in three patients treated with 240 mg/d. (B) Best response above and below the adjusted ERBB2 copy number threshold of 6.5. DLT, dose-limiting toxicity; PD, progressive disease.

FIG 3.

Response in a patient who expressed p95HER2. (A) Anti–human epidermal growth factor receptor 2 (HER2) antibodies from Dako (Agilent, Santa Clara, CA), Ventana Medical Systems (Oro Valley, AZ), and Leica Biosystems (Wetzlar, Germany), currently used for diagnostic immunohistochemical (IHC) evaluation of breast cancer, do not distinguish between expression of full-length HER2 and the truncated p95HER2. In contrast, the antibody developed by Monogram Biosciences specifically detects the truncated p95HER2 form of the receptor and is used in the VeraTag assay. (B) Pink circles indicate the pretreatment total HER2 (H2T) and p95HER2 levels for two patients who achieved complete response (one of whom is represented in the photos in panel C) superimposed for comparison on a previously published scattergram of values obtained from a similar cohort of patients with trastuzumab-treated, metastatic HER2-positive breast cancer (LOD, p95HER2 below the limit of detection). (C) The patient initially presented with locally advanced disease with progressive chest wall disease on trastuzumab plus pertuzumab therapy. By cycle 3, the patient had complete disappearance of chest wall disease and had a clinical complete response. Abs, antibodies; LOD, logarithm of odds; RF, relative fluorescence; TK, tyrosine kinase. Panel B scattergram reproduced with permission.