NOTCH1-Mutant Esophageal Squamous Cell Carcinoma (ESCC) AchievesGets 18.4 month OS on Tislelizumab—HR 0.35 vs Chemo

Tislelizumab, an anti-PD-1 antibody, was pitted against investigator-choice paclitaxel/docetaxel/irinotecan in the Phase III RATIONALE-302 trial (second-line advanced/metastatic ESCC; NCT03430843). Comprehensive profiling of 209 tumors showed NOTCH1 mutations in ≈22% of cases; in this subgroup, median overall survival was 18.4 months on tislelizumab versus 5.3 months with chemotherapy (HR 0.35, 95% CI 0.17-0.71). Transcriptomic data linked the mutation to type-I IFN/TLR activation and reduced B-cell/neutrophil signatures, hinting at a more immune-inflamed micro-environment, while sSafety mirrored the parent study’s low grade ≥3 TRAE rate (≈19%). By contrast, the unselected intent-to-treat population in RATIONALE-302 logged an mOS of 8.6 in the Tislelizumab cohort vs 6.3 months in the chemotherapy cohort OS (HR 0.70), and other PD-1 inhibitors typically yield ≤10 months OS—highlighting a roughly three-fold survival gain when NOTCH1 is altered.