Background: T-DXd is an antibody-drug conjugate composed of a humanized anti-HER2 monoclonal antibody, a tetrapeptide-based cleavable linker, and a topoisomerase I inhibitor payload. T-DXd is approved for HER2+ advanced/metastatic GC/GEJA after a prior trastuzumab-based regimen (US/Israel) and GC after chemotherapy (Japan). In DESTINY-Gastric01, T-DXd showed improved efficacy vs standard chemotherapy in Japanese and Korean pts (≥2 prior therapies) with advanced HER2+ GC/GEJA. Preclinical data of T-DXd combinations suggest encouraging antitumor activity. DESTINY-Gastric03 is the first study of T-DXd combinations in GC/GEJA. Methods: DESTINY-Gastric03 (NCT04379596) is a 2-part, phase 1b/2, multicenter, open-label, 3+3 dose-escalation (part 1) and -expansion (part 2) study in advanced/metastatic HER2+ GC/GEJA. In part 1, pts with locally confirmed HER2+ GC/GEJA (IHC 3+ or IHC 2+/ISH+) who progressed on/after ≥1 prior therapy including a trastuzumab-containing regimen received T-DXd intravenously (IV) every 3 weeks + assigned combination. Primary objectives were safety and recommended phase 2 dose (RP2D). Preliminary antitumor activity was a secondary objective; confirmed objective response rate (ORR) was a secondary endpoint. We report the T-DXd + fluoropyrimidine cohorts. Results: In part 1, 15 pts were assigned to T-DXd + IV 5-fluorouracil (5-FU) and 10 pts to T-DXd + oral capecitabine (Cap). In addition to trastuzumab, all pts had received prior treatment with 5-FU and/or Cap and a median of 2 (range, 1-5) prior lines of therapy. The most common grade ≥3 AEs (%) were anemia (33), decreased neutrophil count (33), nausea (13), and stomatitis (13) with T-DXd + 5-FU and decreased neutrophil count (40), anemia (30), and nausea (20) with T-DXd + Cap. Starting doses were T-DXd 5.4 mg/kg + 5-FU 800 mg/m² and T-DXd 5.4 mg/kg + Cap 1000 mg/m² twice daily (BID). There were 2 dose-limiting toxicities of grade 3 stomatitis with T-DXd 6.4 mg/kg + 5-FU 800 mg/m²; this exceeded the maximum tolerated dose and was discontinued. RP2Ds were T-DXd 6.4 mg/kg + 5-FU 600 mg/m² and T-DXd 6.4 mg/kg + Cap 1000 mg/m² BID. Preliminary confirmed and confirmed + unconfirmed ORR at the RP2D for T-DXd + Cap were 3/7 and 5/7, respectively; 3/3 pts at the starting dose of T-DXd + Cap had confirmed ORR. ORR data for T-DXd + 5-FU are not yet mature. Conclusions: In the first T-DXd + fluoropyrimidine combination study in HER2+ GC/GEJA, preliminary part 1 results suggest tolerability and feasibility of the RP2Ds for T-DXd + 5-FU and T-DXd + Cap. Preliminary ORR with the T-DXd + Cap RP2D (n = 7) showed efficacy with this combination in heavily pretreated, trastuzumab- and fluoropyrimidine-refractory, HER2+ GC/GEJA. This study is ongoing, with further combinations and follow-up planned. Clinical trial information: NCT04379596.