1. Compared to trastuzumab emtansine, trastuzumab deruxtecan is associated with a lower risk of disease progression or death in patients with HER2-positive metastatic breast cancer.

2. Trastuzumab deruxtecan was associated with interstitial lung disease and pneumonitis.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Approximately 20% of breast cancers express HER2, and although there are HER2-targeted therapies, they are not curative and most patients will have disease progression. The current standard treatment for HER2-positive metastatic breast cancer that progresses after trastuzumab with a taxane is trastuzumab emtansine. However, trastuzumab deruxtecan has been proposed to have durable antitumor activity. There is a gap in knowledge as to understanding the efficacy of trastuzumab deruxtecan compared to currently available HER2-directed regimens such as trastuzumab emtansine. This study found that trastuzumab deruxtecan is associated with an increased reduction in risk of disease progression or death in patients with HER2-positive metastatic breast cancer. This study was limited by factors such as including patients from countries in which trastuzumab emtansine was not yet readily available. Nevertheless, this study’s findings are significant, as they demonstrate that trastuzumab deruxtecan is superior to trastuzumab emtansine in reducing the risk of progression or death in HER2-positive metastatic breast cancer.

Click to read the study in NEJM

Relevant Reading: Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer

In-Depth [randomized control trial]: This multicenter, open-label randomized control trial studied 524 patients. Patients who had HER2-positive unresectable or metastatic breast cancer that had progressed during or after treatment with trastuzumab and a taxane were eligible for the study. Patients with brain metastases that were symptomatic or required treatment or had previously been treated with trastuzumab emtansine were excluded from the study. The primary outcome measure was progression-free survival. Outcomes in the primary analysis were assessed via a stratified log-rank test and analysis of progression-free survival. Based on the analysis, 75.8% of patients on trastuzumab deruxtecan had no disease progression at 12 months (95% confidence interval [ CI], 69.8 to 80.7) compared to 34.1% of patients on trastuzumab emtansine (95% CI, 27.7 to 40.5). 94.1% of patients on trastuzumab deruxtecan were alive at 12 months (95% CI, 90.3 to 96.4) while 85.9% of patients on trastuzumab emtansine were alive at 12 months (95% CI, 80.9 to 89.7). Overall response in these patients was 79.7% (95% CI, 74.3 to 84.4) for trastuzumab deruxtecan and 34.2% (95% CI, 28.5 to 40.3) for trastuzumab emtansine. Drug-related interstitial lung disease or pneumonitis occurred in 10% of patients receiving trastuzumab deruxtecan and in 1.9% of patients receiving trastuzumab emtansine. The incidence of a drug-related adverse event was 98.1% with trastuzumab deruxtecan and 86.6% with trastuzumab emtansine. Overall, this study demonstrated that trastuzumab deruxtecan is superior to trastuzumab emtansine in reducing the risk of progression or death in HER2-positive metastatic breast cancer patients, and is an effective new treatment for these patients.

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