<i>NOTCH1</i> 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
Abstract
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.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (18)
Zhihao Lu
Key Laboratory of Life‐Organic Analysis of Shandong Province School of Chemistry and Chemical Engineering Qufu Normal University Qufu 273165 P.R. China
Wenting Du
Zhihao Lu, MD, Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China; Wenting Du, PhD, Clinical Biomarker, BeOne Medicines, Ltd, Shanghai, China; Xi Jiao, MD, and Yanni Wang, PhD, Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China; Zhang Zhang, PhD, Statistics, BeOne Medicines, Ltd, Beijing, China; and Lin Shen, MD, Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital &a...
Xi Jiao
Zhihao Lu, MD, Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China; Wenting Du, PhD, Clinical Biomarker, BeOne Medicines, Ltd, Shanghai, China; Xi Jiao, MD, and Yanni Wang, PhD, Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China; Zhang Zhang, PhD, Statistics, BeOne Medicines, Ltd, Beijing, China; and Lin Shen, MD, Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital &a...
Yanni Wang
Jingwen Shi
Yang Shi
Yongqian Shu
Jiangsu Province Hospital, Nanjing, China
Zuoxing Niu
Hiroki Hara
Saitama Cancer Center, Ina, Japan
Jun Wu
Chih-Hung Hsu
National Taiwan University Cancer Center, Taipei City, Taiwan
Eric Van Cutsem
University Hospitals Gasthuisberg, Leuven, Belgium
Malcolm V. Brock
Zhang Zhang
State Key Laboratory of Bioactive Molecules and Druggability Assessment, and School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
Ningning Ding
Clinical Development, BeiGene (Beijing) Co, Ltd, Beijing, China
Yun Zhang
Zhirong Shen
20BeOne Medicines Ltd, Shanghai, China
Lin Shen