As reported in The New England Journal of Medicine by Javier Cortés, MD, PhD, and colleagues, the phase III DESTINY-Breast03 trial has shown significantly prolonged progression-free survival with fam-trastuzumab deruxtecan-nxki (T-DXd) vs ado-trastuzumab emtansine (T-DM1) in patients with metastatic HER2-positive breast cancer who were previously treated with trastuzumab and a taxane.

In the open-label trial, 524 patients from sites in 15 countries were randomly assigned between July 2018 and June 2020 to receive T-DXd at 5.4 mg/kg every 3 weeks (n = 261) or T-DM1 at 3.6 mg/kg every 3 weeks. The primary endpoint was progression-free survival on blinded independent central review.

Javier Cortés, MD, PhD

Progression-Free Survival

At prespecified interim analysis, median follow-up was 16.2 months (range = 0–32.7 months) in the T-DXd group and 15.3 months (range = 0–31.3 months) in the T-DM1 group. Median progression-free survival was not reached (95% confidence interval [CI] = 18.5 months–not estimable) in the T-DXd group vs 6.8 months (95% CI = 5.6–8.2 months) in the T-DM1 group; rates at 1 year were 75.8% (95% CI = 69.8%–80.7%) with T-DXd and 34.1% (95% CI = 27.7%–40.5%) with T-DM1 (hazard ratio [HR] = 0.28, 95% CI = 0.22–0.37, P < .001). The independent data and safety monitoring committee recommended that the trial be unblinded in July 2021, since the prespecified efficacy boundary of superiority had been crossed.

At data cutoff (May 2021), death had occurred in 12.6% of patients in the T-DXd group and 20.2% of the T-DM1 group. Overall survival at 1 year was 94.1% (95% CI = 90.3%–96.4%) with T-DXd and 85.9% (95% CI = 80.9%–89.7%) with T-DM1 (HR = 0.55, 95% CI = 0.36–0.86, P = .007), with the prespecified significance boundary of P < .000265 not being reached. Objective response was observed in 79.7% (95% CI = 74.3%–84.4%) vs 34.2% (95% CI = 28.5%–40.3%) of patients, with complete response in 16.1% vs 8.7%.

Adverse Events

Treatment-related grade 3 or 4 adverse events occurred in 45.1% of the T-DXd group vs 39.8% of the T-DM1 group. The most common were neutropenia (19.1%) and thrombocytopenia (7.0%) in the T-DXd group, and thrombocytopenia (24.9%) and increased aspartate aminotransferase (5.0%) in the T-DM1 group. Irrespective of causality attribution, serious adverse events occurred in 19.1% vs 18.0% of patients, and adverse events led to discontinuation of treatment in 13.6% vs 7.3%. Adjudicated drug-related interstitial lung disease or pneumonitis of any grade occurred in 10.5% of the T-DXd group (grade 3 in 2 patients, none grade ≥ 4) and in 1.9% of the T-DM1 group (none grade ≥ 3). Interstitial lung disease or pneumonitis led to treatment discontinuation in 8.2% vs 1.1% of patients.

The investigators concluded, “Among patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane, the risk of disease progression or death was lower among those who received T-DXd than among those who received T-DM1. Treatment with T-DXd was associated with interstitial lung disease and pneumonitis.”

Dr. Cortés, of the International Breast Cancer Center, Quirónsalud Group, Barcelona, is the corresponding author for The New England Journal of Medicine article.

Disclosure: The study was funded by Daiichi Sankyo and AstraZeneca. For full disclosures of the study authors, visit nejm.org.