The combination of gene hyperamplification and PD-L1 expression as a biomarker for the clinical benefit of tislelizumab in gastric/gastroesophageal junction adenocarcinoma

Abstract

Background: In solid tumor Phase 1/2 trials (NCT02407990; NCT04068519), tislelizumab demonstrated clinical benefit, including in advanced gastroesophageal adenocarcinoma (GEA). However, the majority of patients with GEA did not respond, highlighting the need to understand mechanisms of resistance and identify predictive biomarkers for response.

Methods: All tislelizumab-treated patients with GEA from the Phase 1/2 trials were included (N = 105). Programmed death-ligand 1 (PD-L1) expression (Tumor Area Positivity [TAP] ≥ 5%), interferon gamma (IFNγ)-related gene signature, gene expression profile, tumor mutational burden (TMB), and gene hyperamplification (HA) were analyzed for correlation with tislelizumab.

Results: A moderate association was observed between PD-L1 TAP ≥ 5%, IFNγ gene signature, TMB-high and efficacy. A potential correlation between hyperamplification (HA +) and worse outcomes with programmed cell death protein 1 (PD-1) inhibition was identified. Hyperamplified genes were mainly enriched in cancer progression pathways, including cell cycle and RTK-RAS-PI3K pathways. Joint PD-L1 TAP ≥ 5% and lack of hyperamplification showed the most favorable benefit with an objective response rate of 29.4%, and median progression-free survival and overall survival of 4.1 and 14.7 months, respectively. Tumors with TAP ≥ 5% and HA - had inflamed immune signatures with increased immune cell infiltration, enhanced anti-tumor cytotoxic activity and antigen presentation signatures. Findings were validated in two independent gastric and gastrointestinal cancer cohorts treated with immune checkpoint inhibitors.

Conclusions: In GEA, PD-L1 positivity, IFNγ-related gene signature and TMB-high status were positively associated with tislelizumab clinical benefit, whereas HA was associated with worse clinical outcomes. Combining PD-L1 positivity and HA - may help identify patients more likely to benefit from PD-1 blockade.

Keywords: Gastroesophageal adenocarcinoma; Hyperamplification; Immuno-oncology; PD-(L)1 inhibitor; PD-L1.

Fig. 1

Association of PD-L1 TAP and IFNγ-related gene signature expression with clinical outcome of tislelizumab monotherapy in the tislelizumab-treated GEA cohort. a Objective response rates according to PD-L1 status, b Kaplan–Meier plot for PFS according to PD-L1 status, c Kaplan–Meier plot for OS according to PD-L1 status, d objective response rates according to IFNγ-related gene signature expression, e Kaplan–Meier plot for PFS according to IFNγ-related gene signature expression, f Kaplan–Meier plot for OS according to IFNγ-related gene signature expression. BMK biomarker, CI confidence interval, GEA gastroesophageal adenocarcinoma, IFNγ interferon gamma, mOS median OS, mPFS median PFS, NR non-responder, OS overall survival, PD-L1 programmed death-ligand 1, PFS progression-free survival, R responder, TAP Tumor Area Positivity

Fig. 2

Association of somatic alteration with clinical outcome of tislelizumab monotherapy in the tislelizumab-treated GEA cohort. a Objective response rates according to TMB status, b Kaplan–Meier plot for PFS according to TMB status, c Kaplan–Meier plot for OS according to TMB status, d Objective response rates according to HA status, e Kaplan–Meier plot for PFS according to HA status, f Kaplan–Meier plot for OS according to HA status. BMK biomarker, CI confidence interval, GEA gastroesophageal adenocarcinoma, HA hyperamplification, mOS median OS, mPFS median PFS, NR non-responder, OS overall survival, PFS progression-free survival, R responder, TMB tumor mutational burden

Fig. 3

Characterization of genes with high amplification frequency in the tislelizumab-treated GEA cohort. a Genes with amplification frequency ≥ 4% of patients, b Gene HA landscape per patient categorized by response to tislelizumab monotherapy and ranked by PFS. GEA gastroesophageal adenocarcinoma, HA hyperamplification, NA not applicable, NR non-responder, OS overall survival, PD-L1 programmed death-ligand 1, PFS progression-free survival, R responder

Fig. 4

Association of joint PD-L1 status and HA with clinical outcome of tislelizumab monotherapy, and immune and tumor gene expression contexture in the tislelizumab-treated GEA cohort and pembrolizumab-treated independent GC validation cohort. a Kaplan–Meier plot for PFS by joint biomarker subgroup in the tislelizumab-treated GEA cohort, b Kaplan–Meier plot for OS by joint biomarker subgroup in the tislelizumab-treated GEA cohort, c Top rank gene expression signatures identified from TAP ≥ 5%, HA + versus TAP ≥ 5%, HA − subgroups in the tislelizumab-treated GEA cohort, d Top rank gene expression signatures identified from CPS ≥ 1, HA + versus CPS ≥ 1, HA − in the pembrolizumab-treated GC independent validation cohort. CPS combined positive score, DC dendritic cell, DCR disease control rate, ECM extracellular matrix, FDR false discovery rate, GC gastric cancer, GEA gastroesophageal adenocarcinoma, GSEA gene set enrichment analysis, HA hyperamplification, IL interleukin, JAK Janus kinase, MHC major histocompatibility complex, NK natural killer, ORR objective response rate, OS overall survival, PD-L1 programmed death-ligand 1, PFS progression-free survival, STAT, signal transducer and activator of transcription, TAP Tumor Area Positivity, TH T helper, TLR toll-like receptor