Mutation and Survival Analysis of Tislelizumab in Advanced or Metastatic Esophageal Squamous Cell Carcinoma: A Biomarker Analysis From the Randomized, Phase III, RATIONALE-302 Trial.
Journal
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Start Page
論文號碼 JCO-24-01818
ISSN
1527-7755
Date Issued
2025-04-03
Author(s)
Lu, Zhihao
Du, Wenting
Jiao, Xi
Wang, Yanni
Shi, Jingwen
Shi, Yang
Shu, Yongqian
Niu, Zuoxing
Hara, Hiroki
Wu, Jun
Van Cutsem, Eric
Brock, Malcolm V
Zhang, Zhang
Ding, Ningning
Zhang, Yun
Shen, Zhirong
Shen, Lin
Abstract
Although multiple agents targeting PD-1 have been approved as second-line treatment for esophageal squamous cell carcinoma (ESCC), only a fraction of patients derive long-term survival. Hence, reliable predictive biomarkers are urgently needed.
Comprehensive tumor genomic profiling and transcriptome sequencing were performed on samples from the RATIONALE-302 study. We also conducted single-cell RNA sequencing analysis on knockdown ESCC murine models to further explore the potential molecular mechanisms underlying anti-PD-1 benefit.
We identified mutation as a potential predictive biomarker for longer overall survival (OS) with tislelizumab versus chemotherapy (18.4 months 5.3 months; hazard ratio, 0.35 [95% CI, 0.17 to 0.71]). At the transcriptional level, type I IFN (IFN-I)/toll-like receptor expression signatures were positively associated with OS benefit of tislelizumab, whereas B-cell and neutrophil signatures predicted unfavorable OS. Exploratory analyses showed that the presence of mutation correlated with enrichment of IFN-I signatures and reduced infiltration of B cells and neutrophils. In murine models, comparative single-cell transcriptome analyses further revealed that deficiency facilitated a more immunologically activated tumor microenvironment which potentiated anti-PD-1 treatment.
Our data provide novel insights for anti-PD-1 treatment selection using mutations and may provide a rationale for combination therapy in ESCC.
SDGs
Type
journal article