Background: T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor. In a phase 1 trial of T-DXd (5.4 or 6.4 mg/kg), the objective response rate (ORR) was 43.2% (19/44) and median progression-free survival (mPFS) was 5.6 mo in patients with advanced HER2+ gastric cancer (GC). DESTINY-Gastric01 (DS8201-A-J202; NCT03329690) is an open-label, multicenter, randomized, phase 2 study of T-DXd in HER2-expressing advanced GC or GEJ adenocarcinoma; results are from the primary analyses for ORR and interim overall survival (OS) in HER2+ patients. Methods: Patients with centrally confirmed HER2+ (IHC 3+ or IHC 2+/ISH+ on archival tissue) GC that progressed on ≥ 2 prior lines were randomized 2:1 (T-DXd 6.4 mg/kg q3w or physician’s choice [PC] irinotecan or paclitaxel). All patients received prior HER2 therapy. Stratification factors were region, ECOG PS (0;1), and HER2 status. The primary endpoint was unconfirmed ORR by independent central review. Secondary endpoints were OS (alpha controlled), PFS, disease control rate (DCR), duration of response (DOR), and safety. Results: 187 patients received T-DXd (n = 125) or PC (n = 62 [55 irinotecan; 7 paclitaxel]); 79.7% Japan, 20.3% Korea. Patients had a median of 2 prior lines of therapy, and 44.4% had ≥ 3. At data cutoff (8 Nov 2019), 22.4% of T-DXd and 4.8% of PC patients remained on treatment. ORR was 51.3% (61/119; 11 CR and 50 PR) with T-DXd vs 14.3% (8/56; all PR) with PC (P< .0001); confirmed ORR, 42.9% vs 12.5% (P< .0001); DCR, 85.7% vs 62.5% (P = .0005); mDOR, 11.3 vs 3.9 mo; mPFS, 5.6 vs 3.5 mo (HR, 0.47 [95% CI, 0.31-0.71]; P = .0003). OS was significantly prolonged with T-DXd (mOS, 12.5 vs 8.4 mo; HR, 0.59 [95% CI, 0.39-0.88]; P = .0097; prespecified O'Brien Fleming boundary, P = .0202); 12-month OS, 52.1% vs 28.9%. Grade ≥ 3 AEs occurred in 85.6% of patients with T-DXd vs 56.5% with PC; the most common were neutrophil count decreased (51.2%; 24.2%), anemia (37.6%; 22.6%), and white blood cell count decreased (20.8%; 11.3%). 12 patients (9.6%) had T-DXd–related interstitial lung disease (ILD; 2 grade 3, 1 grade 4, no grade 5) vs 0 with PC. 1 drug-related death (pneumonia [non-ILD] in the T-DXd arm) occurred. Conclusions: T-DXd demonstrated statistically significant and clinically meaningful improvements in ORR and OS compared with standard chemotherapy (paclitaxel or irinotecan) in patients with HER2+ advanced gastric or GEJ adenocarcinoma. Clinical trial information: NCT03329690.