Neoadjuvant toripalimab plus concurrent chemoradiotherapy for locally advanced adenocarcinoma of the esophagogastric junction: a phase II trial

Neoadjuvant chemoradiotherapy plus surgery is for the treatment of locally advanced adenocarcinoma of the esophagogastric junction (AEG), yet pathological response remains suboptimal. Given the potential synergy between PD-1 blockade and radiotherapy in modulating the tumor immune microenvironment, we hypothesized that adding toripalimab, a PD-1 inhibitor, to neoadjuvant chemoradiotherapy could improve tumor response. We enrolled cT3-T4/N + M0 AEG patients in this prospective, single-arm, phase II trial. Patients received neoadjuvant radiotherapy (50 Gy/45 Gy/25 f), with 5 cycles of weekly chemotherapy concurrently and 4 cycles of toripalimab, followed by radical surgery and adjuvant chemoimmunotherapy. The primary endpoint was the major pathological response (MPR) rate; the secondary endpoints included the pathological complete response (pCR) rate, R0 resection rate, disease-free survival (DFS), overall survival (OS), event-free survival (EFS) and safety, with exploratory analyses of immune correlates including the tertiary lymphoid structure (TLS). Between September 1, 2019, and April 30, 2024, 40 patients were enrolled. Thirty-one patients underwent radical surgery. In the surgery population, R0 resection rate was 100%, 24 patients (77.4%) achieved an MPR, and the pCR rate was 41.9%. In terms of safety, only one case of ≥ grade 4 treatment-related toxicity and one case of ≥ grade 3 surgical complication were reported. Notably, pCR patients were more likely to have detectable TLSs ( p = 0.047). During a median follow-up period of 54.4 months for OS and 51.6 months for DFS, the surgery set had 2-year and 4-year OS rates of 93.5% and 86.6%, versus 85.0% and 71.5% in the whole population. The 2-year and 4-year DFS rates of the surgery cohort were 83.9% and 80.4% respectively. Neoadjuvant toripalimab combined with chemoradiotherapy demonstrates promising efficacy and manageable toxicity in locally advanced AEG, with a notable association between TLS and pathological response. This study was registered at ClinicalTrials.gov as NCT04061928 in August 2019.