NOTCH1 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
Menée à l'aide de modèles murins de carcinome épidermoïde de l'oesophage, cette étude met en évidence une corrélation entre la présence de mutations au niveau du gène du récepteur transmembranaire NOTCH1 et des signatures moléculaires associées au bénéfice clinique du tislélizumab
Purpose : 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.
Methods : 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 Notch1 knockdown ESCC murine models to further explore the potential molecular mechanisms underlying anti–PD-1 benefit.
Results : We identified NOTCH1 mutation as a potential predictive biomarker for longer overall survival (OS) with tislelizumab versus chemotherapy (18.4 months v 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 NOTCH1 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 Notch1 deficiency facilitated a more immunologically activated tumor microenvironment which potentiated anti–PD-1 treatment.
Conclusion : Our data provide novel insights for anti–PD-1 treatment selection using NOTCH1 mutations and may provide a rationale for combination therapy in ESCC.
Journal of Clinical Oncology , article en libre accès, 2025