Tucatinib Combined With Ado-Trastuzumab Emtansine in Advanced ERBB2/HER2-Positive Metastatic Breast Cancer: A Phase 1b Clinical Trial

Abstract

Importance: Treatment options for patients with disease progression after treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1) are limited. Tucatinib is an oral, potent, human epidermal growth factor receptor 2 (HER2)-specific tyrosine kinase inhibitor (TKI) being developed as a novel treatment for ERBB2/HER2-positive breast cancer.

Objective: To determine the maximum tolerated dosage of tucatinib in combination with T-DM1 in the treatment of patients with ERBB2/HER2-positive metastatic breast cancer with and without brain metastases.

Design, setting, and participants: In this phase 1b open-label, multicenter, clinical trial, 57 participants enrolled between January 22, 2014, and June 22, 2015, were 18 years of age or older with ERBB2/HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Data were analyzed between January and March 2018.

Interventions: Tucatinib 300 mg or 350 mg administered orally twice per day for 21 days and T-DM1 3.6 mg/kg administered intravenously once every 21 days.

Main outcomes and measures: Safety assessments, pharmacokinetics, and response were assessed using RECIST 1.1 every 2 cycles for 6 cycles, followed by every 3 cycles.

Results: Fifty-seven T-DM1-naive patients (median [IQR] 51 [44.0-63.0] years of age) who had undergone a median of 2 earlier HER2 therapies (range, 1-3) were treated. The tucatinib maximum tolerated dosage was determined to be 300 mg administered twice per day with dose-limiting toxic reactions seen at 350 mg twice per day. Pharmacokinetic analysis showed that there was no drug-drug interaction with T-DM1. Adverse events seen among the 50 patients treated at the maximum tolerated dosage regardless of causality included nausea (36 patients; 72%), diarrhea (30 patients; 60%), fatigue (28 patients; 56%), epistaxis (22 patients; 44%), headache (22 patients; 44%), vomiting (21 patients; 42%), constipation (21 patients; 42%), and decreased appetite (20 patients; 40%); the majority of adverse events were grade 1 or 2. Tucatinib-related toxic reactions that were grade 3 and above included thrombocytopenia (7 patients; 14%) and hepatic transaminitis (6 patients; 12%).

Conclusions and relevance: In this study, tucatinib in combination with T-DM1 appeared to have acceptable toxicity and to show preliminary antitumor activity among heavily pretreated patients with ERBB2/HER2-positive metastatic breast cancer with and without brain metastases.

Trial registration: ClinicalTrials.gov Identifier: NCT01983501.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Chamberlain, Mr Gray, and Mr Vo reported that they are employees of Cascadian Therapeutics, Inc, which provided clinical trial funding, and reported ownership interest with Cascadian Therapeutics, Inc. No other disclosures were reported.

Figures

Figure 1.. Maximum Tolerated Dosage of Tucatinib Combined With Ado-Trastuzumab Emtansine (T-DM1) Trial Profile

A flow diagram showing the progress of patients throughout the trial.

Figure 2.. Kaplan-Meier Plot of Progression-Free Survival (PFS) Among Patients Treated With the Maximum Tolerated Dosage of Tucatinib Combined With Ado-Trastuzumab Emtansine

Abbreviations: BM, brain metastases; Mets, metastases; NBM, no brain metastases; NE, nonevaluable.