In an analysis from the phase III RATIONALE-302 trial reported in the Journal of Clinical Oncology, Lu et al found that the presence of NOTCH1 mutation was associated with improved overall survival in patients receiving second-line tislelizumab vs investigator’s choice of chemotherapy for advanced or metastatic esophageal squamous cell carcinoma.
Study Details
In this international open-label trial, 512 patients with disease progression after first-line systemic treatment were randomly assigned to receive tislelizumab at 200 mg every 3 weeks (n = 256) or investigator’s choice of chemotherapy of paclitaxel, docetaxel, or irinotecan (n = 256). The primary endpoint of the trial was overall survival. To investigate potential biomarkers, baseline samples underwent comprehensive tumor genomic profiling and transcriptome sequencing. Approximately 69% of patients were from Asia (excluding Japan), 10% were from Japan, and 21% were from Europe or the United States.
Key Findings
NOTCH1 mutation, identified in 22% of patients, was found to be a potential predictive biomarker of longer overall survival (median = 18.4 months vs 5.3 months in chemotherapy group; hazard ratio [HR] = 0.35, 95% confidence interval [CI] = 0.17–0.71). At the transcriptional level, type I IFN (IFN-I)/Toll-like receptor expression signatures were positively associated with the overall survival benefit of tislelizumab; B-cell and neutrophil signatures were associated with poorer survival.
In exploratory analyses, 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 indicated that NOTCH1 protein deficiency was associated with a more immunologically activated tumor microenvironment, potentiating activity of anti–PD-1 treatment.
The investigators concluded: “Our data provide novel insights for anti–PD-1 treatment selection using NOTCH1 mutations and may provide a rationale for combination therapy in esophageal squamous cell carcinoma.”
Zhihao Lu, MD, of the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, is the corresponding author of the Journal of Clinical Oncology article.
Disclosure: The study was supported by BeiGene. For full disclosures of the study authors, visit ascopubs.org.
