Background: About 55% of mBC typically categorized as HER2 negative, express low levels of HER2 (IHC 1+ or IHC 2+/ISH− by ASCO/CAP 2018 guidelines) with poor outcomes in later lines (Tarantino 2020). T-DXd has shown promising efficacy in HER2-low mBC in a phase 1 study (NCT02564900; Modi2020). This is the primary report from DESTINY-Breast04 (NCT03734029), the first randomized, multicenter, open-label, phase 3 study comparing efficacy and safety of T-DXd vs TPC in pts with HER2-low mBC treated with 1-2 prior lines of chemotherapy in the metastatic setting. Methods: 557 pts with centrally confirmed HER2-low mBC were randomly assigned 2:1 to T-DXd 5.4 mg/kg or TPC (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel). The primary endpoint was progression-free survival (PFS) determined by blinded independent central review (BICR) in pts with hormone receptor–positive (HR+) mBC. Key secondary endpoints (hierarchically tested after the primary endpoint) include PFS by BICR in the full analysis set (FAS; HR+/−) and overall survival (OS) in pts with HR+ mBC and in FAS. Other endpoints were objective response rate, duration of response, safety, and an exploratory analysis of pts with HR− mBC. Results: As of Jan 11, 2022, 373 and 184 pts (88.7% and 88.6% HR+ mBC) were assigned to T-DXd and TPC, respectively. Median follow-up was 18.4 months (mo; 95% CI, 17.9-19.1). Median treatment duration was 8.2 mo (range, 0.2-33.3) with T-DXd and 3.5 mo (range, 0.3-17.6) with TPC. Efficacy results are in the Table. 52.6% of pts with T-DXd vs. 67.4% of pts with TPC had grade (G) ≥ 3 treatment-emergent adverse events (TEAEs). With T-DXd, 45 pts (12.1%; 10.0% G1/2, 1.3% G3/4, 0.8% G5) had independently adjudicated drug-related interstitial lung disease [ILD]/pneumonitis vs. 1 pt (0.6% G1) with TPC. Conclusions: DESTINY-Breast04 is the first phase 3 trial of a HER2-directed therapy in pts with HER2-low mBC to show a statistically significant and clinically meaningful benefit in PFS and OS compared to standard-of-care treatment, regardless of HR status, with a generally manageable safety profile. Funding: Daiichi Sankyo, Inc., and AstraZeneca. Clinical trial information: NCT03734029.

^aBased on electronic data capture corrected for mis-stratification. ^bPFS by BICR. ^cT-DXd vs. TPC. ^dP values were determined by 2-sided log-rank test.m, median; NE, non-estimable.