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.

• Authors: Zhihao Lu, Silu Yang, Xuerui Luo, Yang Shi, Jong-Seok Lee, Sanjeev Deva, Tianshu Liu, Yee Chao, Yun Zhang, Ruiqi Huang, Yaling Xu, Zhirong Shen, Lin Shen
• Journal: Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association (Gastric Cancer) Vol. 25 Issue 5 Pg. 943-955 (09 2022) ISSN: 1436-3305 [Electronic] Japan
• PMID: 35778636 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• Antibodies, Monoclonal, Humanized
• B7-H1 Antigen
• Biomarkers, Tumor
• CD274 protein, human
• Programmed Cell Death 1 Receptor
• tislelizumab

Topics

• Adenocarcinoma (drug therapy, genetics)
• Antibodies, Monoclonal, Humanized
• B7-H1 Antigen
• Biomarkers, Tumor (genetics)
• Clinical Trials, Phase I as Topic
• Clinical Trials, Phase II as Topic
• Esophageal Neoplasms
• Esophagogastric Junction (pathology)
• Humans
• Lung Neoplasms (drug therapy)
• Mutation
• Phosphatidylinositol 3-Kinases (genetics)
• Programmed Cell Death 1 Receptor (genetics)
• Stomach Neoplasms (drug therapy, genetics)