Abstract OT-28-01: HER2CLIMB-02: A randomized, double-blind, phase 3 study of tucatinib or placebo with T-DM1 for 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 , O’Shaughnessy Joyce , Dong Cassie , Walker Luke , Rustia Evelyn , Borges Virginia F. 
Published: February 2021

Abstract
Background - Tucatinib (TUC), an oral tyrosine kinase inhibitor (TKI) highly selective for HER2 with minimal inhibition of EGFR, is approved in the US for use in combination with trastuzumab (Tras) and capecitabine for treatment (tx) of adult patients (pts) with metastatic HER2+ breast cancer (MBC), including pts with brain metastases (BM), who have received 1 or more prior anti-HER2-based regimens in the metastatic setting. Ado-trastuzumab emtansine (T-DM1), approved for tx of pts with HER2+ MBC after Tras and a taxane, has led to significant improvements in progression-free survival (PFS) and overall survival (OS). Still, further improvements are needed, including pts with active BM. A phase 1b trial evaluated TUC (300 mg PO BID) with T-DM1 in 50 pts with HER2+ MBC who received prior tx with Tras and a taxane (Borges 2018). Common AEs included nausea (72%), diarrhea (60%), and fatigue (56%); mostly grade 1/2. Median PFS was 8.2 months and the objective response rate (ORR) in pts with measurable disease (n=34) was 47%. Sixty percent of pts treated with TUC + T-DM1 had BM at baseline and showed a brain specific response rate (RECISTv1.1) of 36% in pts with measurable BM. This encouraging clinical activity, including in pts with BM, provides rationale for a randomized trial to further evaluate this combination.
Trial design - HER2CLIMB-02 is a randomized, double-blind, placebo-controlled phase 3 study to evaluate efficacy and safety of TUC + T-DM1 in pts with unresectable locally advanced or metastatic HER2+ breast cancer; ~460 pts will be randomized 1:1 to receive 21-day cycles of TUC (300 mg PO BID) or placebo with T-DM1 (3.6 mg/kg IV). Pts must have had prior tx with Tras and a taxane in any setting, be ≥18 yrs, with an ECOG ≤1 and histologically confirmed HER2+ MBC. Prior tx with any investigational antiHER2 or anti-EGFR agent or HER2 TKI is not permitted. Prior pertuzumab tx is allowed, but not required. Baseline brain MRIs are required for all pts; pts with stable, progressing, or untreated BM not requiring immediate local therapy are eligible. While on tx, radiographic disease evaluations (RECISTv1.1) will occur every 6 weeks for the first 24 weeks, and then every 9 weeks. The primary endpoint is PFS per investigator, with OS and ORR as key secondary endpoints. Enrollment is ongoing in the US (NCT03975647) and planned for Canada, the EU, and the Asia/Pacific region.
Citation Format: Sara Hurvitz, Linda Vahdat, Nadia Harbeck, Antonio C. Wolff, Sara M. Tolaney, Sherene Loi, Norikazu Masuda, Joyce O’Shaughnessy, Cassie Dong, Luke Walker, Evelyn Rustia, Virginia F. Borges. HER2CLIMB-02: A randomized, double-blind, phase 3 study of tucatinib or placebo with T-DM1 for unresectable locally-advanced or metastatic HER2+ breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-28-01.