Abstract LB011: Exploratory biomarker analysis of the phase 3 RATIONALE 305 trial: First-line (1L) tislelizumab (TIS) + chemotherapy (CT) vs placebo (PBO) + CT for advanced gastric cancer/gastro-oesophageal junction adenocarcinoma (GC/GEJC)

Abstract Background: In the randomised phase 3 RATIONALE 305 trial (NCT03777657), patients (pts) with advanced GC/GEJC treated with 1L TIS + CT had significantly improved overall survival (OS) vs PBO + CT. We present exploratory biomarker and molecular subtyping results from RATIONALE 305 derived using RNA sequencing (RNAseq) and whole exome sequencing (WES) data. Results: RNAseq (507/997, 50.9%) of baseline (BL) tumor tissue was used to assess gene expression signatures (GES). GES subgroups were defined by median cutoff. WES (235/997, 23.6%) of BL tumor tissue and matching blood samples was performed to assess tumor mutational burden (TMB), human leukocyte antigen (HLA) genotyping, significantly mutated genes, and cytoband amplifications (amp). Associations between biomarker status and OS were evaluated. All P values are descriptive. Results: BL characteristics in the GES- or WES-evaluable pts were similar to the ITT population. High inflammation (e.g. cytotoxic T cells [CTL]) and low immunosuppression (e.g. neutrophils) GES were associated with improved OS for TIS + CT vs PBO + CT (Table). High clonal TMB was linked to improved OS with TIS + CT vs PBO + CT (Table) while total TMB showed no clear association. Non-HLA B27 supertype or TP53 wildtype or 20q13.13 non-amp were associated with improved OS benefit with TIS + CT vs PBO + CT (Table). Additional biomarker analyses including immunohistochemistry and molecular subtyping results will be presented. Conclusion: This exploratory biomarker analysis found that high CTL GES and low neutrophil GES, as well as clonal TMB, certain HLA genotypes, TP53 wildtype, and cytoband non-amp were all associated with OS benefit in 1L TIS + CT vs PBO + CT treated pts with advanced GC/GEJC. Citation Format: Miaozhen Qiu, Kai Wang, Jingwen Shi, Yang Shi, Mingyu Lai, Jing Yang, Do-Youn Oh, Yuxian Bai, Ruiqi Huang, David Shames, Rui-Hua Xu. Exploratory biomarker analysis of the phase 3 RATIONALE 305 trial: First-line (1L) tislelizumab (TIS) + chemotherapy (CT) vs placebo (PBO) + CT for advanced gastric cancer/gastro-oesophageal junction adenocarcinoma (GC/GEJC) [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 LB011.