Abstract LB331: First-line (1L) trastuzumab deruxtecan (T-DXd) + rilvegostomig (rilve) + fluoropyrimidine (FP) in HER2-positive (HER2+) gastric cancer (GC), gastroesophageal junction adenocarcinoma (GEJA), or esophageal adenocarcinoma (EA): DESTINY-G

Abstract Background: T-DXd monotherapy is approved in several countries for advanced HER2+ GC/GEJA after an indicated HER2-directed regimen. 1L rilve (a monovalent, Fc-reduced, bispecific IgG1 antibody against PD-1 and TIGIT receptors) + chemotherapy showed encouraging efficacy and a manageable safety profile in advanced GCs. We report early data from DG-03 Part 4 arm A evaluating 1L T-DXd + rilve + FP in HER2+ GCs. Methods: DG-03 (NCT04379596) is a Phase 1b/2, open-label, multipart trial. Part 4 arm A enrolled patients (pts) with previously untreated advanced/metastatic HER2+ (IHC 3+ or IHC 2+/ISH+; local test) GC/GEJA/EA. Pts received T-DXd + rilve + FP (5-fluorouracil or capecitabine). PD-L1 status was assessed by central test retrospectively. Primary endpoint was confirmed objective response rate (ORR) by investigator assessment (INV) per RECIST 1.1; safety was also assessed. Results: At data cutoff (Oct 16, 2025), 30 pts were enrolled and received treatment (Tx). Median duration of follow up was 7.6 (range, 1.9-12.6) months; median duration of Tx exposure for T-DXd and rilve was 7.0 (range, 1.8-11.3) months. Confirmed ORR by INV (n/n) was 70% (21/30) overall, 78% (18/23) and 50% (3/6) in pts with HER2 IHC 3+ and IHC 2+/ISH+ tumors, and 82% (9/11) and 50% (3/6) in pts with PD-L1 CPS ≥1 and CPS <1 tumors, respectively. Safety data are shown in the Table. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 2 pts (7%; both Grade 2); there were no reports of drug-related left ventricular dysfunction. Conclusions: Early results showed promising antitumor activity with 1L T-DXd + rilve + FP in HER2+ GCs; safety findings were generally consistent with the known profiles of each agent as monotherapy, with no new safety signals observed. Data support further study of this 1L triplet regimen in HER2+ GCs. Citation Format: Yelena Y. Janjigian, Hanneke van Laarhoven, Hirokazu Shoji, Lucjan Wyrwicz, Sara Lonardi, Boguslawa Karaszewska, Xinjun Liang, Aitana Calvo Ferrándiz, Mariusz Kwiatkowski, Keun-Wook Lee, Tianshu Liu, Kohei Shitara, Sun Young Rha, Salvatore Siena, Roy Rabbie, Caron Lloyd, Megan Scott, Arthur W. Lambert, Jeeyun Lee. First-line (1L) trastuzumab deruxtecan (T-DXd) + rilvegostomig (rilve) + fluoropyrimidine (FP) in HER2-positive (HER2+) gastric cancer (GC), gastroesophageal junction adenocarcinoma (GEJA), or esophageal adenocarcinoma (EA): DESTINY-Gastric03 (DG-03) Part 4 arm A results [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB331.