A prospective study of neoadjuvant pembrolizumab plus chemotherapy for resectable esophageal squamous cell carcinoma: The Keystone-001 trial

In this phase II study, 47 patients with locally advanced, resectable esophageal squamous cell carcinoma (ESCC) received three cycles of pembrolizumab plus chemotherapy, followed by Da Vinci robot-assisted surgery. The primary endpoints were safety and major pathological response (MPR). Key secondary endpoints included complete pathological response (pCR) and survival. No grade ≥3 adverse events or surgical delays occurred during neoadjuvant therapy. Among 46 patients studied for efficacy, the MPR and pCR rates were 72% and 41%, respectively. After a median follow-up of 27.2 months, the 2-year overall survival (OS) and disease-free survival (DFS) rates were 91% and 89%, respectively. Expansion of TRGC2+ NKT cells in peripheral blood correlated with neoadjuvant treatment effectiveness, which was validated by in vitro organoid experiments and external cancer datasets, and its functional classification and mechanism of action were further explored. These findings show preoperative pembrolizumab plus chemotherapy is a promising therapeutic strategy for resectable ESCC. [Display omitted] •Neoadjuvant pembrolizumab + chemotherapy was explored in resectable stage III ESCC•Quality of life and nutritional status improved following neoadjuvant therapy•After a median follow-up of 27.2 months, the 2-year overall survival rate was 91%•TRGC2+ NKT cells in peripheral blood are a potential response biomarker Shang et al. demonstrate the efficacy and safety of neoadjuvant pembrolizumab plus chemotherapy for patients with locally advanced, resectable esophageal squamous cell carcinoma in a phase II clinical trial. They identify TRGC2+ NKT cells as potential biomarkers of response using single-cell RNA-seq in peripheral blood.