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)

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. Methods: 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. TABLE TIS + CT vs PBO + CT Population Subpopulation N OS HR (95% CI) P value Interaction P value GES evaluable 507 CTL high 254 0.69 (0.52, 0.91) 0.009 0.063 CTL low 253 1.00 (0.76, 1.32) 0.999 Neutrophil high 254 1.01 (0.76, 1.33) 0.970 0.044 Neutrophil low 253 0.67 (0.50, 0.89) 0.005 WES evaluable 235 High cTMB (90 th percentile) 24 0.37 (0.14, 0.95) 0.038 0.125 Low cTMB (90 th percentile) 211 0.80 (0.59, 1.08) 0.144 HLA B27 52 1.30 (0.70, 2.41) 0.401 0.045 HLA non-B27 183 0.64 (0.46, 0.89) 0.007 TP53 mutation a 148 0.96 (0.67, 1.38) 0.825 0.025 TP53 wildtype 84 0.48 (0.29, 0.78) 0.003 20q13.13 non-amp 205 0.64 (0.47, 0.88) 0.005 0.002 20q13.13 amp 30 2.58 (1.15, 5.79) 0.021 a Pts with TP53 amplification not included