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PURPOSE: Adding pembrolizumab to first-line fluoropyrimidine (5-FU)/platinum chemotherapy plus trastuzumab improves outcomes in advanced HER2+ gastroesophageal adenocarcinomas, but the benefit is largely confined to dual HER2+ and PD-L1+ patients. To assess the contributions of components, we conducted a phase II trial evaluating 5-FU/platinum/trastuzumab and added pembrolizumab in cycle 2 in patients with metastatic HER2+ disease.PATIENTS AND METHODS: Treatment-naïve patients with advanced HER2+ gastroesophageal cancer underwent a baseline biopsy and received a single dose of 5-FU/platinum with trastuzumab followed by repeat biopsy. Pembrolizumab was added, and a third biopsy was performed after six cycles. The primary endpoint was the objective response rate. Secondary endpoints included progression-free and overall survival. Exploratory biomarker analysis and dynamic changes in HER2 and PD-L1 were prespecified.RESULTS: Sixteen patients were enrolled. The objective response rate was 69%, and the median progression-free survival was 11.9 months. Serial whole-exome, single-cell RNA, T-cell receptor sequencing, and spatial transcriptomics from pretreatment and on-treatment samples revealed early trastuzumab-induced NK cell infiltration in HER2+ tumor beds and an increase in Fc receptor gamma III expression in macrophages, suggesting that trastuzumab directs Fc receptor-mediated antibody-dependent cytotoxicity. This favorable remodeling was enhanced by the addition of pembrolizumab, primarily in PD-L1+ samples. We observed TGF-β signaling in HER2-negative tumor regions, which was associated with nonresponder status.CONCLUSIONS: These data highlight the biology of intratumoral heterogeneity and the impact of tumor and immune cell features on clinical outcomes and may partly explain the lesser magnitude of pembrolizumab benefit in HER2+ and PD-L1-negative subgroups.