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.

Tumor mutation load better predicts the prognosis of patients treated with immune checkpoint inhibitors in upper gastrointestinal cancers: A systematic review and meta‐analysis

“…Subsequently, 268 eligible studies were subjected to a full‐text review for further screening. Finally, 11 publications between 2018 and 2022 were included in the analysis 20,24–33 . The flowchart depicting the process of search and identification of studies is shown in Figure 1.…”

“…Finally, 11 publications between 2018 and 2022 were included in the analysis. 20 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 The flowchart depicting the process of search and identification of studies is shown in Figure 1 .…”

Association of the CD4+ /CD8+ ratio with response to PD-1 inhibitor-based combination therapy and dermatologic toxicities in patients with advanced gastric and esophageal cancer

“…For example, the KEYNOTE-059 trial showed that, in metastatic GC or gastroesophageal junction cancer, the e cacy (ORR: 15.5% vs.6.4%) and the median duration of response (16.3 vs. 8.4 months) of patients with positive PD-L1 expression was far better than that of patients with negative PD-L1 expression [41]. Likewise, several studies have demonstrated that PD-L1 expression alone, or with other factors, is positively associated with the clinical bene ts of PD-1/PD-L1 inhibitors [42][43][44].…”

Complete remission in a patient with metastatic gastric cancer receiving tislelizumab combined with chemotherapy: a case report

“…Despite a positive correlation between TMB-H and GC incidence has been reported in meta-analyses, evidence also suggests that patients with high PD-L1 expression and TMB-H derive favorable survival benefits from ICIs ( 26 ). Meanwhile, it was reported in a study that PD-L1 positivity, Interferon-gamma (IFN-γ)-related gene signature, and TMB-H were positively associated with the clinical benefit of tislelizumab in advanced GEAC ( 27 ). It is uncertain whether this is a coincidence, but it is reasonable to speculate that patients with MSI-H/dMMR, TMB-H, and positive PD-L1 expression have better sensitivity to tislelizumab.…”

“…benefits from ICIs (26). Meanwhile, it was reported in a study that PD-L1 positivity, Interferon-gamma (IFN-g)-related gene signature, and TMB-H were positively associated with the clinical benefit of tislelizumab in advanced GEAC (27).…”