Background: Zanidatamab (zani) is an anti-HER2 bispecific antibody against ECD4 and ECD2 with demonstrated activity and tolerability in a range of HER2-expressing cancers. This Phase (Ph) 2 study (NCT03929666) evaluates zani in combination with chemotherapy (chemo) as first-line treatment for patients (pts) with advanced HER2-expressing mGEA. Methods: Eligible pts for this ongoing, open-label study had not received any prior systemic therapy for mGEA. Pts received zani + physician’s choice of multi-agent chemo (mFOLFOX6, CAPOX, or FP). Antidiarrheal prophylaxis for cycle 1 was added after the first 25 pts were treated. Following demonstration of tolerability of the regimens in an initial safety cohort, the primary study objective was to evaluate antitumor activity. Results: Pts were enrolled between Aug 29, 2019 and Feb 18, 2022 with a data cutoff of July 28, 2022 (N=46 pts; zani + mFOLFOX6 [24], zani + CAPOX [20], or zani + FP [2]). Median age was 58 yrs; 85% male; 42 pts (91%) had HER2+ tumors (IHC 3+ or 2+ with ISH-positivity) based on central testing. Median duration of follow-up among all 46 pts was 21.5 months (mo) and 20 pts (43%) remain on treatment. In 38 response-evaluable pts with HER2+ tumors, confirmed objective response rate (cORR) was 79% (95% CI: 63-90%) and disease control rate was 92% (95% CI: 79-98%); 3 pts achieved complete response. Median duration of response (DOR) was 20.4 mo (95% CI: 6.8-not estimable [NE]), with 57% (17/30) pts having an ongoing response at data cut-off (1 pt has ongoing response >29 months). In all 42 pts with HER2+ tumors, median progression-free survival (PFS) was 12.5 mo (95% CI: 7.1-NE) and median overall survival (OS) was not yet reached. Survival rate at 18 mo was estimated to be 87.3%. The most common (≥25% pts) treatment-related (zani and/or chemo) adverse events (TRAE) in all pts were diarrhea, nausea, peripheral sensory neuropathy, decreased appetite, fatigue, vomiting, and hypokalemia. Diarrhea was the most common Gr3+ TRAE, lasting a median (interquartile range) of 3 (2-5) days, with the majority of events occurring in cycle 1; incidence of all Gr3+ events was 56% in 25 pts who did not receive prophylaxis and 14% in 21 pts who did. There were no treatment-related deaths. Conclusions: In pts with HER2+ mGEA, zani + chemo is a highly active treatment regimen with a manageable safety profile. This maturing data set demonstrates durable disease control with encouraging cORR, DOR, PFS and OS results. A global Ph 3 study (HERIZON-GEA-01; NCT05152147) evaluating zani in combination with physician’s choice of standard chemo with or without the PD-1 inhibitor, tislelizumab, for first-line treatment of advanced HER2+ mGEA is currently enrolling. Clinical trial information: NCT03929666.