Trastuzumab Deruxtecan in Residual HER2-Positive Early Breast Cancer.

Phase 3 DESTINY-Breast05 compared adjuvant trastuzumab deruxtecan (T‑DXd, 5.4 mg/kg) with trastuzumab emtansine (T‑DM1, 3.6 mg/kg) in 1635 patients with HER2‑positive early breast cancer who had high-risk residual invasive disease after neoadjuvant therapy (node-positive at surgery or initially inoperable).

After a median follow‑up of ~30 months, T‑DXd markedly improved invasive disease‑free survival (primary endpoint): invasive events or death occurred in 6.2% with T‑DXd vs 12.5% with T‑DM1 (HR 0.47; 95% CI 0.34–0.66), with 3‑year invasive disease‑free survival of 92.4% vs 83.7%.

Disease‑free survival (key secondary endpoint, including noninvasive breast and second nonbreast primaries) showed an identical hazard ratio (0.47; 95% CI 0.34–0.66), with 3‑year disease‑free survival 92.3% vs 83.5%.

Toxicity profiles differed:

• T‑DXd: mainly associated with gastrointestinal events (nausea 71.3%, vomiting 31.0%, constipation 32.0%) and hematologic toxicity (neutropenia 31.6%).
• T‑DM1: showed more hepatotoxicity (AST 50.2%, ALT 45.3%) and thrombocytopenia (49.8%).
• Drug‑related interstitial lung disease (ILD): more frequent with T‑DXd (9.6% vs 1.6%), including two ILD‑related deaths, underscoring the need for careful pulmonary monitoring and early management.

Overall, in high‑risk HER2‑positive early breast cancer with residual disease post‑neoadjuvant therapy, T‑DXd substantially improves invasive disease‑free outcomes compared with T‑DM1, at the cost of higher ILD risk and a predominantly GI/hematologic toxicity profile.