Daiichi Sankyo Company, Limited and AstraZeneca HER2 directed antibody drug conjugate (ADC), demonstrated superior progression-free survival (PFS) versus trastuzumab emtansine (T-DM1), a HER2 directed ADC currently approved to treat patients with HER2 positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane. Results were presented as the first late-breaking presentation (#LBA1) in the ESMO Presidential Symposium at theEuropean Society for Medical Oncology (#ESMO21) 2021 Virtual Congress. At a pre-specified interim analysis of DESTINY-Breast03, ENHERTU demonstrated a 72% reduction in the risk of disease progression or death compared to T-DM1 (hazard ratio [HR] = 0.28; 95% CI: 0.22-0.37; p=7.8x10-22). After 15.5 and 13.9 months of follow-up in the ENHERTU and T-DM1 arms respectively, the median PFS for patients treated with ENHERTU was not reached (95% CI: 18.5-NE) compared to 6.8 months for T-DM1 (95% CI: 5.6-8.2) as assessed by blinded independent central review (BICR). In the key secondary endpoint analysis of PFS assessed by investigators, patients treated with ENHERTU experienced a three-fold improvement in PFS of 25.1 months (95% CI: 22.1-NE) compared to 7.2 months (95% CI: 6.8-8.3) for T-DM1 (HR=0.26; 95% CI: 0.20-0.35; p=6.5x10-24). A consistent PFS benefit was observed in key subgroups of patients treated with ENHERTU, including those with a history of stable brain metastases. There was a strong trend towards improved overall survival (OS) with ENHERTU (HR=0.56; 95% CI: 0.36-0.86; p=0.007172), however, this analysis is not yet mature and is not statistically significant. Nearly all patients treated with ENHERTU were alive at one year (94.1%; 95% CI: 90.3-96.4) compared to 85.9% of patients treated with T-DM1 (95% CI: 80.9-89.7). Confirmed objective response rate (ORR) was more than doubled in the ENHERTU arm versus the T-DM1 arm (79.7%; n=208; 95% CI: 74.3-84.4) versus 34.2% (n=90; 95% CI: 28.5-40.3; p<0.0001). Forty-two (16.1%) complete responses (CR) and 166 (63.6%) partial responses (PR) were observed in patients treated with ENHERTU compared to 23 (8.7%) CRs and 67 (25.5%) PRs in patients treated with T-DM1. The safety profile of the most common adverse events with ENHERTU in DESTINY-Breast03 was consistent with previous clinical trials with no new safety concerns identified. The most common grade 3 or higher drug-related treatment emergent adverse events in the ENHERTU arm were neutropenia (19.1%), thrombocytopenia (7.0%), leukopenia (6.6%), nausea (6.6%), anemia (5.8%), fatigue (5.1%), vomiting (1.6%), increase in ALT (1.6%), decreased appetite (1.2%), increase in AST (0.8%), diarrhea (0.4%) and alopecia (0.4%). Overall, 10.5% of patients had confirmed interstitial lung disease (ILD) or pneumonitis related to treatment as determined by an independent adjudication committee. The majority of ILD events (9.7%) were primarily low grade (grade 1 (2.7%) or grade 2 (7.0%)) with two grade 3 (0.8%) events reported. No grade 4 or grade 5 ILD or pneumonitis events occurred. All patients in DESTINY-Breast03 received at least one prior cancer therapy, including trastuzumab (ENHERTU = 99.6%; T-DM1 = 99.6%), pertuzumab (ENHERTU = 62.1%; T-DM1 = 60.1%), an anti-HER2 TKI (ENHERTU = 16.1%; T-DM1 = 13.7%) or another anti-HER2 antibody or ADC (ENHERTU = 0.8%; T-DM1 = 1.1%). At the start of the trial, 23.8% of patients in the ENHERTU arm and 19.8% of patients in the T-DM1 arm had stable brain metastases. As of data cut-off on May 21, 2021, 132 patients remained on treatment with ENHERTU and 47 patients on T-DM1.