Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients (pts) with HER2-positive (HER2+) unresectable and/or metastatic breast cancer (mBC): Safety follow-up of the randomized, phase 3 study DESTINY-Breast03.

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1000 Background: In the DESTINY-Breast03 (NCT03529110) primary analysis (data cutoff [DCO], May 21, 2021), T-DXd showed superiority over T-DM1 in pts with HER2+ mBC, with a significant improvement of progression-free survival by blinded independent central review (HR, 0.284; 95% CI, 0.217-0.373; P < 0.001), and a safety profile consistent with prior studies. This analysis provides updated safety data with longer follow-up. Methods: Pts were randomized 1:1 to T-DXd or T-DM1. Prespecified safety analysis of treatment-emergent adverse events (TEAEs) was conducted; endpoints included time to event, duration of event, and resolution. Results: At DCO (September 7, 2021), 116 (45.1%) pts vs 39 (14.9%) pts remained on treatment in the T-DXd vs T-DM1 arms; median treatment duration was 16.1 mo (range, 0.7-33.0) for T-DXd vs 6.9 mo (range, 0.7-28.5) for T-DM1. Any-grade (G), G≥3, and serious AE (SAE) rates were similar for T-DXd vs T-DM1 (99.6% vs 95.4%; 53.3% vs 49.8%; and 21.0% vs 19.2%), while exposure-adjusted incidence rates (EAIRs; per pt-year) for G≥3 and SAEs were lower for T-DXd vs T-DM1 (0.42 vs 0.70 and 0.17 vs 0.27). Median time to TEAE associated with drug discontinuation or dose reduction was longer with T-DXd vs T-DM1 (224.0 vs 147.0 d and 96.0 v 19.0 d, respectively). Most TEAEs in ≥20% of pts were hematologic or gastrointestinal. Median time to first onset of select any-G TEAEs was 70.0 vs 42.0 d for anemia, 196.0 vs 168.0 d for lymphopenia, 132.0 vs 8.0 d for thrombocytopenia, 22.0 vs 24.0 d for fatigue, 74.5 vs 92.0 d for leukopenia, and 64.0 vs 105.0 d for neutropenia, with T-DXd vs T-DM1, respectively. In both arms, most nausea and vomiting events were G1/2; while G≥3 events with T-DXd vs T-DM1 were 6.6% vs 0.4% for nausea and 1.6% vs 0.8% for vomiting, respectively. Rates of nausea, vomiting, and alopecia were highest in cycle 1 and lower in subsequent cycles for T-DXd. Rates of hematologic events were generally lower in earlier cycles vs cycle ≥8 in both arms. Rates of adjudicated, drug-related ILD/pneumonitis were 10.9% (1 G2 event since previous DCO) with T-DXd vs 1.9% with T-DM1, with no G4/5 events. Median time to first adjudicated, drug-related ILD/pneumonitis event was 5.9 vs 9.5 mo for T-DXd vs T-DM1, respectively; at DCO, most events resolved (57.1% vs 80.0%), and follow-up is ongoing. Conclusions: In this updated safety analysis, T-DXd demonstrated a tolerable safety profile consistent with prior studies. Despite longer treatment duration with T-DXd, EAIRs of G≥3 and SAEs were lower for T-DXd vs T-DM1. Rates of ILD/pneumonitis for T-DXd were similar to those in the previous DCO. Nausea, vomiting, and alopecia rates decreased over time. This longer safety update reinforces the consistent safety profile of T-DXd, supporting the clinical benefit of T-DXd over T-DM1 in patients with HER2+ mBC. Clinical trial information: NCT03529110.