Abstract 496: Clinical, biologic, and immunogenic characteristics of gastro-esophageal cancers (GEC) harboring <i>CLDN18::ARHGAP</i> fusions

Abstract Background: Claudin 18.2 (CLDN18.2) overexpression has recently emerged as a therapeutic target in advanced gastro-esophageal cancer (GEC). CLDN18::ARHGAP fusions are pathognomonic for GEC, but their biologic relevance in this malignancy is poorly understood. We analyzed the correlation of CLDN18::ARHGAP fusions with other molecular parameters, tumor microenvironment (TME) parameters, patient characteristics, and outcomes data in a large clinico-genomic database. Methods: DNA and RNA (whole transcriptome) sequencing was performed for patient tumor samples submitted to Caris Life Sciences. CLDN18::ARHGAP fusions were identified from RNA transcripts. PD-L1 (28-8) and CLDN18 (43-14A) protein levels were determined by immunohistochemistry (IHC). TMB-High (TMB-H) was defined as ≥10 mutations/Mb. Significance was tested using Mann-Whitney, Fisher’s Exact, or Chi-squared tests with multiple comparisons correction applied as appropriate. TME cell fractions were estimated by RNA deconvolution using quanTIseq. Real-world overall survival (OS) and nivolumab time on treatment (ToT) were obtained from insurance claims data and calculated from collection date to time of last contact and first of nivolumab to last of nivolumab, respectively; associated hazard ratios (HR) and p-values were calculated using the Cox proportional hazard model. Results: Among 4430 GEC tumors, 262 tumors (6.1%) harbored a CLDN18::ARHGAP fusion, primarily CLDN18::ARHGAP26 (N=226). Patients with fusion+ tumors were younger (median age: 58 vs 66 years, p&amp;lt;0.0001) and more frequently female (64.1% vs 41.1%, p&amp;lt;0.0001). Fusion+ tumors had more frequent HER2 (9.7% vs 3.4%, p&amp;lt;0.0001) and HER3 (10.5% vs 3.8% p&amp;lt;0.0001) mutations and less frequent RHOA (0% vs 7.5%, p=0.0009), CDH1(3.9% vs 20.4%, p&amp;lt;0.0001), and KRAS (2.7% vs 10.0%, p=0.0033) mutations. Fusion+ tumors had a lower prevalence of the IO-related biomarkers TMB-H (4.8% vs 13.9%, p=0.0030), dMMR/MSI-H (3.9% vs 9.5%, p=0.0416), and PD-L1+ (12.5% vs 32.5%, p=0.0001), lower infiltration of CD8+ T cells (0% vs 0.2%, p=0.0016) and M1 macrophages (3.0% vs 3.9%, p&amp;lt;0.0001), and higher infiltration of M2 macrophages (5.4% vs 3.9%, p&amp;lt;0.0001). Using either standard (≥2+, ≥75%) or reduced (≥2+, ≥40%) IHC cut-offs, fusion+ tumors were more frequently CLDN18 IHC+ than fusion- tumors (79.5% vs 47.9%, p&amp;lt;0.0001 and 86.4% vs 54.5%, p&amp;lt;0.0001, respectively). Comparing fusion+ vs fusion- cancers, there was no significant difference in median OS (15.6 vs 13.6 months; HR=0.892, p=0.1986) or nivolumab ToT (7.4 vs 4.8 months, HR=0.751, p=0.1359). Conclusions: CLDN18::ARHGAP fusions characterize GECs with distinct clinical and biologic features that suggest lower immunogenicity. Fusions were positively correlated with a higher CLDN18 protein expression Citation Format: Axel Grothey, Amber Fifield, Kieran Sweeney, Heinz-Josef Lenz, Matthew Oberley, Sanjay Goel, Shuanzeng Wei, Andrew Elliott, Bradley Somer. Clinical, biologic, and immunogenic characteristics of gastro-esophageal cancers (GEC) harboring CLDN18::ARHGAP fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 496.