Compared with capecitabine-based regimens, trastuzumab deruxtecan (T-DXd) led to higher response rates and longer survival in the third-line setting for patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine (T-DM1), according to results from the phase 3 DESTINY-Breast02 trial.

In DESTINY-Breast01, T-DXd demonstrated robust activity in a pre-treated patient population with HER2-positive metastatic breast cancer, leading to regulatory approvals globally.1 However, DESTINY-Breast01 was a modestly sized, single-arm, phase 2 trial. DESTINY-Breast02 was designed to confirm the results of DESTINY-Breast01 in a randomized, phase 3 trial. Dr. Ian Krop (Yale Cancer Center) presented the primary results2 at the 2022 San Antonio Breast Cancer Symposium.

The study enrolled 608 patients with previously treated, HER2-positive, unresectable or metastatic breast cancer. Over 70% of patients had two or three prior lines of therapy, and all patients were pre-treated with trastuzumab and/or T-DM1. Patients were randomized 2:1 to receive T-DXd or treatment of physician’s choice (TPC: trastuzumab/capecitabine or lapatinib/capecitabine). The primary endpoint was progression-free survival (PFS).

T-DXd appeared to be superior to chemotherapy-based treatment: the median PFS in the T-DXd arm was 17.8 months versus 6.9 months in the TPC arm (HR, 0.359; P<0.000001). Respective PFS rates at 24 months of follow-up were 42.2% and 13.9%. PFS benefit of T-DXd over TPC was observed in all pre-specified subgroups. The median overall survival (a key secondary endpoint) rates were 39.2 months and 26.5 months in the T-DXd and TPC arms, respectively (HR, 0.658; P=0.0021). In the TPC arm, 26% of patients received T-DXd in the post-trial setting.

The objective response rate was 69.7% (14% complete response) in the T-DXd arm versus 29.2% (5% complete response) in the TPC arm. No new safety signals were observed for T-DXd. Drug-related interstitial lung disease (ILD; any grade) was observed in 10.4% and ILD grade of at least 3 was observed in 1.2% of patients treated with T-DXd.

“DESTINY-Breast02 confirms the favorable benefit/risk profile of T-DXd in patients with advanced HER2-positive metastatic breast cancer, as previously demonstrated by DESTINY-Breast01,” Dr. Krop concluded.

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