Trastuzumab Deruxtecan in HER2-Low Disease

FDA approval of T-DXd in pretreated HER2-low mTNBC is supported by the randomized phase 3 DESTINY-Breast04 trial (N=557; 88.7% HR+, 11.3% TNBC). Patients had median of 3 prior therapies (1, ~10%; 2, ~27%; ≥3, ~61%) and ~58% had HER2 IHC 1+. Updated 32-month data for the TNBC subgroup showed a 42% reduced risk for death and 71% reduced risk for disease progression versus physician’s choice of chemotherapy (capecitabine, gemcitabine, eribulin, paclitaxel, or nab-paclitaxel). The objective response rate (ORR) to T-DXd in this cohort was 50.0%.

T-DXd adverse events (AEs) include nausea (75%), diarrhea/constipation (22%), neutropenia (33%), anemia (33%), thrombocytopenia (24%), and alopecia (38%). ILD/pneumonitis is a rare (12%) but potentially fatal event characterized by cough, dyspnea, fever, and new respiratory symptoms. Diagnosis requires a high-resolution chest CT and management should include pulmonary consultation and steroids. Most cases in the DESTINY-Breast04 trial (37/45) were Grade 1-2.