Abstract LB010: First-line (1L) trastuzumab deruxtecan (T-DXd) regimens in advanced HER2-positive (HER2+) gastric cancer (GC), gastroesophageal junction adenocarcinoma (GEJA), or esophageal adenocarcinoma (EA): Exploratory analysis of baseline HER2-related biomarkers in DESTINY-Gastric03 (DG-03) Part 2

Abstract Background: DG-03 Part 2 showed promising antitumor activity for 1L T-DXd regimens in advanced HER2+ GCs. We report concordance rates between local and central HER2 IHC results, and ORRs according to baseline HER2-related biomarkers, in DG-03 Part 2. Methods: DG-03 (NCT04379596) is a Phase 1b/2, open-label, multipart trial. In Part 2, patients (pts) with previously untreated advanced HER2+ (IHC 3+ or IHC 2+/ISH+; local test) GC/GEJA/EA were enrolled across six arms and received either trastuzumab + chemotherapy (CT; fluoropyrimidine FP; 5-fluorouracil or capecitabine + cisplatin/oxaliplatin), T-DXd 6. 4 mg/kg, T-DXd 6. 4 mg/kg + FP, T-DXd 6. 4 mg/kg + FP + pembrolizumab (pembro), T-DXd 6. 4 mg/kg + pembro, or T-DXd 5. 4 mg/kg + FP + pembro. Confirmed investigator-assessed ORRs were reported by local and central HER2 IHC/ISH status (HercepTest for central IHC) and by plasma (GuardantOMNI) and tumoral (FoundationOne CDx) HER2 (ERBB2) amplification (amp). Results: As of Feb 28, 2025, 230 pts were enrolled; 229 received treatment. Overall (n/N), 80% (160/199) of HER2+ (IHC 3+ or IHC 2+/ISH+) GCs by local test were centrally scored as HER2+; 86% (143/166) and 52% (17/33) of IHC 3+ and IHC 2+/ISH+ GCs by local test were centrally scored as HER2+, respectively (missing/unknown data for n=2 local IHC, n=1 local ISH, n=3 central ISH, and n=24 central IHC results). Baseline HER2-related biomarker analyses are in the Table. Conclusions: Concordance results were broadly consistent with prior studies in GC. Elevated baseline HER2 IHC expression and HER2 amp were generally associated with higher ORRs for pts with HER2+ GCs treated with 1L T-DXd regimens, versus those with lower HER2 expression and/or without amplified HER2. Data provide further evidence of antitumor activity for 1L T-DXd combinations in HER2+ GCs. Citation Format: Yelena Y. Janjigian, Hanneke van Laarhoven, Sun Young Rha, Vadim Kozlov, Keun-Wook Lee, Do-Youn Oh, Adriano Gravina, Min-Hee Ryu, Liane Rapatoni, Luís Antunes, Filippo Pietrantonio, Hirokazu Shoji, Ralf-Dieter Hofheinz, Maxime Chénard-Poirier, Li-Tzong Chen, Aleksandr Vasiliev, Svetlana Kutukova, Arthur W. Lambert, Kun Yu, Megan Scott, Roy Rabbie, Jeeyun Lee. First-line (1L) trastuzumab deruxtecan (T-DXd) regimens in advanced HER2-positive (HER2+) gastric cancer (GC), gastroesophageal junction adenocarcinoma (GEJA), or esophageal adenocarcinoma (EA): Exploratory analysis of baseline HER2-related biomarkers in DESTINY-Gastric03 (DG-03) Part 2 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 (8Suppl): Abstract nr LB010.