HER2CLIMB-02: A Randomized, Double-Blind, Phase 3 Study of Tucatinib with T-DM1 for the Treatment of Unresectable Locally Advanced or Metastatic HER2-Positive Breast Cancer

Conference Correspondent 

Tucatinib (Tukysa) has been approved in the United States for use in combination with trastuzumab (Herceptin) and capecitabine (Xeloda) for the treatment of adult patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer, including patients with brain metastases, who have received ≥1 previous anti-HER2–based regimens in the metastatic setting. This medication is an oral tyrosine kinase inhibitor that is highly selective for HER2 while minimally inhibiting EGFR.

Previous studies highlighting trastuzumab emtansine (Kadcyla) treatment leading to significant improvements in progression-free survival and overall survival, led to its approval for the treatment of patients with HER2-positive metastatic breast cancer after trastuzumab and a taxane. However, further therapeutic advances are essential.

In a phase 1b clinical trial, 300 mg oral tucatinib was administered twice a day with trastuzumab emtansine in 50 patients with HER2-positive metastatic breast cancer who received previous treatment with trastuzumab and a taxane.1 In this study, common adverse events were mostly grade 1/2, and included nausea reported at 72%, diarrhea (60%), and fatigue (56%). The objective response rate in patients with measurable disease (N = 34) was 47% and the median progression-free survival was 8.2 months.

A brain-specific response rate of 36% was measured using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria and observed in patients with measurable brain metastases, within the 60% of patients treated with tucatinib plus trastuzumab emtansine who had brain metastases at baseline. These results provided the basis of trials to further investigate the efficacy of this combination.

The HER2CLIMB-02 double-blind, phase 3 trial was designed to evaluate the efficacy and safety of tucatinib plus trastuzumab emtansine in patients with unresectable locally advanced or metastatic HER2-positive breast cancer.

Approximately 460 patients will be randomized 1:1 to receive tucatinib 300 mg orally twice daily in 21-day cycles or placebo with trastuzumab emtansine (3.6 mg/kg intravenous). To be included in the study, patients are required to have a history of previous treatment with trastuzumab and a taxane in any setting, age ≥18 years, with an Eastern Cooperative Oncology Group performance status ≤1, and histologically confirmed HER2-positive metastatic breast cancer. However, patients will be excluded if they had a history of any previous treatment with any investigational anti-HER2 or anti-EGFR agent or HER2 tyrosine kinase inhibitor. Previous treatment with pertuzumab (Perjeta) is permissible but not required.

Baseline brain magnetic resonance images are required for all patients who are eligible for the study, which includes those who have stable, progressing, or untreated brain metastases not requiring immediate local therapy. Each patient while receiving treatment will be evaluated using radiographic disease evaluations (RECIST version 1.1) every 6 weeks for the first 24 weeks, and then every 9 weeks. Progression-free survival based on investigator assessment will be the primary end point, with secondary end points being overall survival and objective response rate.

Source: Hurvitz S, Vahdat L, Harbeck N, et al. 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. Presented at: San Antonio Breast Cancer Symposium, December 8-11, 2020. Abstract OT-28-01.


1. Borges VF, Ferrario C, Aucoin N, et al. Tucatinib combined with ado-trastuzumab emtansine in advanced ERBB2/HER2-positive metastatic breast cancer: a phase 1b clinical trial. JAMA Oncol. 2018;4:1214-1220.

Related Items

Subscribe Today!

To sign up for our newsletter or print publications, please enter your contact information below.

I'd like to receive: