By Dr. Arya Mariam Roy
of Roswell Park Comprehensive Cancer Center
Tucatinib, a HER2-directed tyrosine kinase inhibitor (TKI), has been approved in combination with trastuzumab and capecitabine for previously treated HER2+ metastatic breast cancer (mBC) based on the HER2CLIMB data. This combination has shown significant benefits in CNS metastasis as well (1). Combination treatments of HER2-targeted agents are crucial as brain metastasis remains high in HER2+ mBC. T-DM1, a HER2-directed antibody-drug conjugate, is approved for use in previously treated HER2+ mBC. Based on preclinical data and the phase 1/2 trial demonstrating anti-tumor activity with the combination of tucatinib and T-DM1, the HER2CLIMB-02 study was designed (2, 3). Dr. Hurvitz presented the primary analysis data of the HER2CLIMB-02 trial at the 2023 San Antonio Breast Cancer Conference (Hurvitz et al. HER2CLIMB-02: Randomized, Double-Blind Phase 3 Trial of Tucatinib and Trastuzumab Emtansine for Previously Treated HER2-Positive Metastatic Breast Cancer. SABCS 2023).
HER2+ metastatic/locally advanced breast cancer patients with progression after trastuzumab and taxane were randomized 1:1 to the T-DM1 + tucatinib vs T-DM1 + placebo arm. The study included previously treated stable, progressing, or untreated brain metastases not requiring immediate local therapy. The primary outcome was progression-free survival (PFS) per RECIST v1.1. Key secondary outcomes included overall survival (OS), PFS in patients with brain metastasis, confirmed objective response rate (cORR), and OS in patients with brain metastasis. In the T-DM1 + tucatinib arm, 21.9% had active brain metastasis, and 21.5% had treated/stable brain metastasis. In the T-DM1 + placebo arm, 24.3% had active, and 20.4% had treated/stable brain metastasis. The median PFS in the T-DM1 + tucatinib arm was 9.5 months, compared to 7.4 months in the T-DM1 + placebo arm (HR = 0.76, 95% CI = 0.61 – 0.95, p = 0.0163). In patients with brain metastases, T-DM1 + tucatinib showed a benefit in PFS (7.8 vs. 5.7 months, HR = 0.64, 95% CI = 0.46 – 0.89). The cORR was also higher in the T-DM1 + tucatinib arm (42% vs. 36.1%). Median follow-up was 24.4 months. Interim OS in the intervention arm was not reached, and in the T-DM1 + placebo arm, it was 38 months (HR= 1.23, 95% CI = 0.87 – 1.74). Discontinuation rates due to treatment emergent adverse events (TEAEs) were higher in the T-DM1 + tucatinib arm, with 17.3% discontinuing tucatinib and 20.3% discontinuing T-DM1. In the T-DM1 + placebo arm, only 6.9% and 11.2% discontinued tucatinib and T-DM1, respectively. Grade >=3 TEAEs were more frequent in the T-DM1 + tucatinib arm (68.8% vs. 41.2%). The most common grade >=3 TEAE in the T-DM1 + tucatinib arm was ALT increase (16.5% vs. 2.6%). Grade >=3 diarrhea was reported in 4.8% of the T-DM1 + tucatinib arm and 0.9% of the T-DM1 + placebo arm.
Although there were more hepatic events in the T-DM1 + tucatinib arm, these events were transient in most cases and reversible. HER2CLIMB-02 shows a statistically significant improvement in PFS with the combination of T-DM1 + tucatinib in previously treated patients with metastatic or locally advanced HER2+ BC and demonstrates benefits in patients with brain metastases in this population. Several questions exist about the sequencing of this combination, considering the benefit of T-DXd over T-DM1 based on the Destiny-Breast 03 trial and the efficacy of T-DXd in brain metastases (4). None of the patients in the HER2CLIMB-02 study received T-DXd prior to the T-DM1 + tucatinib combination regimen. Similarly, the utility and sequencing of later lines of other anti-HER2 agents, including other TKIs and the combination regimen of tucatinib + capecitabine + trastuzumab, are uncertain at this time. Mature OS data from the HER2CLIMB-02 study and a head-to-head comparison of these treatment regimens are needed to determine the sequencing of combination regimens with improved efficacy and manageable toxicities.
References
1. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N
Engl J Med. 2020;382(6):586.
2. Borges VF, Ferrario C, Aucoin N, Falkson C, Khan Q, Krop I, 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(9):1214-20.
3. Olson D, Taylor J, Willis K, Hensley K, Allred S, Zaval M, et al. HER2-Selective and Reversible Tyrosine Kinase Inhibitor Tucatinib Potentiates the Activity of T-DM1 in Preclinical Models of HER2-positive Breast Cancer. Cancer Res Commun. 2023;3(9):1927-39.
4. Hurvitz SA, Hegg R, Chung WP, Im SA, Jacot W, Ganju V, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet. 2023;401(10371):105-17.
