Abstract OT2-01-01: Randomized, double-blind, phase 3 study of tucatinib or placebo in combination with T-DM1 for subjects with unresectable locally-advanced or metastatic HER2+ breast cancer
Authors: Hurvitz Sara , Vahdat Linda , Harbeck Nadia , Wolff Antonio C , Tolaney Sara M , Loi Sherene , Masuda Norikazu , Dong Cassie , Walker Luke , Rustia Evelyn , Borges Virginia 
Published: March 2020

Abstract
Background: Tucatinib is an orally-available, reversible HER2 small molecule tyrosine kinase inhibitor (TKI) being developed as a novel treatment for patients with HER2+ metastatic breast cancer (mBC), including patients with brain metastases. Two key features of tucatinib are its potency and selectivity for HER2, compared to the epidermal growth factor receptor (EGFR). Ado-trastuzumab emtansine (T-DM1) is approved for the treatment of patients with HER2+ mBC after prior treatment with trastuzumab and a taxane. While treatment with T-DM1 has led to significant improvements in progression-free survival (PFS) and overall survival, further improvements in therapy are needed, especially for patients with active brain metastases. Based upon evidence that dual targeting of HER2 may lead to further improvements in efficacy in mBC, a phase 1b trial enrolled subjects with HER2+ mBC, previously treated with trastuzumab and taxane, to receive tucatinib (300 mg orally [PO] twice a day [BID]) with T-DM1 (Borges et al, 2018). Forty-six percent of these subjects had received prior pertuzumab. The combination of tucatinib with T-DM1 demonstrated a median PFS of 8.2 months (95% CI, 4.8-10.3) and an objective response rate of 47% in subjects with measurable disease. Sixty percent of subjects treated with this combination had baseline brain metastases and showed a brain-specific response rate (using modified RECIST v1.1 criteria) of 36% in subjects with measurable central nervous system disease. Tucatinib with T-DM1 was found to have a tolerable safety profile, the most common adverse events were nausea (72%), diarrhea (60%), and fatigue (56%), with the majority of events being grade 1 or 2. This encouraging clinical activity, including in subjects with brain metastases, provides rationale for a randomized trial to further evaluate this combination.
Study Design: This is a randomized, double-blind, placebo-controlled, international, multicenter, phase 3 study designed to evaluate the efficacy and safety of tucatinib in combination with T-DM1 in subjects with unresectable locally-advanced or metastatic HER2+ breast cancer. Subjects must have had prior treatment with a taxane and trastuzumab in any setting (adjuvant, neoadjuvant, or metastatic). The primary objective of the study is to compare PFS between the treatment arms per investigator assessment, with overall survival as a key secondary endpoint. In this study, subjects must be ≥18 years, with an ECOG of ≤1 and have histologically confirmed HER2+ mBC. Prior treatment with any investigational anti-HER2 or anti-EGFR agent or HER2 TKI agent is not permitted. Prior pertuzumab therapy is allowed, but not required. Subjects with stable, progressing, or untreated brain metastases not requiring immediate local therapy, are eligible for inclusion in the trial.
Approximately 460 subjects will be randomized 1:1 to receive 21-day cycles of either tucatinib (300 mg PO BID) or placebo in combination with T-DM1 (3.6 mg/kg intravenously). Disease response and progression will be assessed using RECIST v1.1. While on study treatment, radiographic disease evaluations will be performed every 6 weeks for the first 24 weeks, and every 9 weeks thereafter. A subset of subjects will participate in a pharmacokinetic substudy.
Citation Format: Sara Hurvitz, Linda Vahdat, Nadia Harbeck, Antonio C Wolff, Sara M Tolaney, Sherene Loi, Norikazu Masuda, Cassie Dong, Luke Walker, Evelyn Rustia, Virginia Borges. Randomized, double-blind, phase 3 study of tucatinib or placebo in combination with T-DM1 for subjects with unresectable locally-advanced or metastatic HER2+ breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-01-01.