Second-Line T-DXd Improves Progression-Free Survival Across HER2-Positive Metastatic Breast Cancer Subgroups

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The antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd) lengthened progression-free survival and improved the objective response rate compared with the antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) after trastuzumab and taxane therapy in women with HER2-positive metastatic breast cancer and those with stable brain metastasis at baseline, according to a subgroup analysis of the phase III -DESTINY-Breast03 trial presented at the 2021 San Antonio Breast Cancer Symposium.1

“T-DXd demonstrated a consistent efficacy benefit over T-DM1 across patient subgroups,” said lead author Sara A. Hurvitz, MD, Director of the Breast Cancer Clinical Research Program, Co-Director of the Santa Monica University of California, Los Angeles (UCLA) Outpatient Hematology/Oncology Practice, and Professor of Medicine at the David Geffen School of Medicine at UCLA. “In patients with and without brain metastases, T-DXd had greater efficacy than T-DM1. T-DXd is associated with substantial intracranial response and a reduction in central nervous system disease. T-DXd demonstrated a manageable and tolerable safety profile, with no difference in the frequency of interstitial lung disease in Asian and non-Asian subgroups.

Sara A. Hurvitz, MD

Sara A. Hurvitz, MD

Dr. Hurvitz concluded: “These data do support T-DXd as a standard for second-line treatment of HER2-positive breast cancer with brain metastasis and for patients who have had disease progression on currently available therapies.”

Study Details

DESTINY-Breast03 was a randomized, multicenter, open-label phase III clinical trial comparing T-DXd vs T-DM1 in women with HER2-positive metastatic breast cancer who experienced disease progression on first-line therapy with trastuzumab and taxane chemotherapy. Patients were randomly assigned 1:1 to T-DXd (n = 261) or T-DM1 (n = 263), and those with clinically stable brain metastasis were eligible. The primary endpoint was progression-free survival.

In the primary analysis of the study,2 T-DXd prolonged progression-free survival by 72% compared with T-DM1. Median progression-free survival was not reached in the T-DXd arm vs 6.8 months in the T-DM1 arm. The 12-month progression-free survival rate was 75.8% with T-DXd vs 34.1% with T-DM1. Median overall survival was not evaluable in either arm. The estimated 12-month overall survival rates were 94.1% with T-DXd vs 85.9% with T-DM1. The confirmed objective response rate was 79.1% vs 34.2%, respectively. Complete response rates were 16.1% vs 8.7%, respectively.

At the 2021 San Antonio meeting, Dr. Hurvitz presented data from the subgroup analysis. In patients with brain metastases at baseline (n = 82), median progression-free survival was 15 months with T-DXd vs 3 months with T-DM1—a 75% improvement. In patients without brain metastasis at baseline (n = 442), median progression-free survival was not reached with T-DXd vs 7.1 months with T-DM1.

Among patients with brain metastases, the confirmed objective response rate with T-DXd was 67.4% vs 20.5% with T-DM1. Among patients without brain metastasis at baseline, confirmed objective response rates were 82.1% vs 36.6%, respectively.

A consistent progression-free survival and objective response rate benefit was observed in all subgroups for T-DXd over T-DM1, including those with hormone receptor–positive and –negative disease, regardless of the number of prior lines of therapy and whether or not visceral disease or brain metastases were present at baseline.

The intracranial objective response rate by blinded central review showed that the best response was 63.9% with T-DXd compared with 33.4% with T-DM1. A complete response in the brain was achieved in 27.8% with T-DXd vs 2.8% with T-DM1.

At the time of data cutoff, 84 (32.2%) of the patients treated with T-DXd had progressive disease vs 155 (58.9%) of those who received T-DM1 in the overall trial. In patients with stable brain metastases at baseline, progressive disease was found in 48.8% of the T-DXd arm vs 69% of those treated with T-DM1.

Treatment-emergent adverse events reported in at least 20% of patients enrolled in the overall trial were nausea, vomiting, and fatigue of any grade. In the T-DXd arm, 19% had grade 3 or 4 neutropenia, and 24.9% had grade 3 or 4 thrombocytopenia in the T-DM1 arm. Drug-related interstitial lung disease was reported in 27 patients (10.5%) in the T-DXd group and 5 patients (1.9%) in the T-DM1 group, and the rates were comparable in Asians and non-Asians.

Further Discussion

During the discussion following her presentation, Dr. Hurvitz was asked about the sequencing of tucatinib and T-DXd, given the excellent control of brain metastasis in HER2-positive metastatic breast cancer seen with tucatinib in the HER2CLIMB trial.3

“In my opinion, these data support the use of T-DXd in the second-line setting as a standard of care. The progression-free survival [with T-DXd] in this trial exceeds that of tucatinib. I would see tucatinib playing an important role in the third-line setting. The question is what do we do for patients with brain metastasis for second-line treatment? I think that’s where tucatinib comes in. The data on T-DXd and brain metastasis are intriguing, but we need further study,” Dr. Hurvitz said. 

DISCLOSURE: Dr. Hurvitz has an immediate family member who holds stock or other ownership interests in Ideal Implant and ROMTech; has received institutional research funding from Ambrx, Amgen, AstraZeneca, Arvinas, Bayer, CytomX, Daiichi Sankyo, Dignitana, Genentech/Roche, Gilead, GSK, Immunomedics, Lilly, MacroGenics, Novartis, Pfizer, OBI Pharma, Pieris, Puma Biotechnology, Radius, Sanofi, Seattle Genetics/Seagen, Zymeworks, Phoenix Molecular Designs, and Samumed; and has been reimbursed for travel or accommodations by Lilly.


1. Hurvitz S, et al: Trastuzumab deruxtecan (T-DXd; DS-8201a) vs trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer. 2021 San Antonio Breast Cancer Symposium. Abstract GS3-01. Presented December 9, 2021.

2. Cortes J, et al: Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM) in patients with HER2+ metastatic breast cancer. ESMO Congress 2021. Abstract LBA1. Presented September 18, 2021.

3. Curigliano G, et al: Updated results of tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with or without brain metastasis. 2021 ASCO Annual Meeting. Abstract 1043.

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