Neoadjuvant sintilimab in combination with concurrent chemoradiotherapy for locally advanced gastric or gastroesophageal junction adenocarcinoma: a single-arm phase 2 trial

Abstract

In this multicenter, single-arm phase 2 trial (ChiCTR1900024428), patients with locally advanced gastric/gastroesophageal junction cancers receive one cycle of sintilimab (anti-PD1) and chemotherapy (S-1 and nab-paclitaxel), followed by 5 weeks of concurrent chemoradiotherapy and sintilimab, and another cycle of sintilimab and chemotherapy thereafter. Surgery is preferably scheduled within one to three weeks, and three cycles of adjuvant sintilimab and chemotherapy are administrated. The primary endpoint is the pathological complete response. Our results meet the pre-specified primary endpoint. Thirteen of 34 (38.2%) enrolled patients achieve pathological complete response (95% CI: 22.2-56.4). The secondary objectives include disease-free survival (DFS), major pathological response, R0 resection rate, overall survival (OS), event-free survival (EFS), and safety profile. The median DFS and EFS were 17.0 (95%CI: 11.1-20.9) and 21.1 (95%CI: 14.7-26.1) months, respectively, while the median OS was not reached, and the 1-year OS rate was 92.6% (95%CI: 50.1-99.5%). Seventeen patients (50.0%) have grade ≥3 adverse events during preoperative therapy. In prespecified exploratory biomarker analysis, CD3⁺ T cells, CD56⁺ NK cells, and the M1/M1 + M2-like macrophage infiltration at baseline are associated with pathological complete response. Here, we show the promising efficacy and manageable safety profile of sintilimab in combination with concurrent chemoradiotherapy for the perioperative treatment of locally advanced gastric/gastroesophageal junction adenocarcinoma.

Fig. 1. Treatment response (n = 34).

Tumor shrinkage from baseline (A) and duration of disease response (B). All patients had R0 resection. The duration of response was censored at the time of the procedure.

Fig. 2. Survival outcomes of all patients.

(A) Disease-free survival, (B) event-free survival and (C) overall survival. Source data are provided as a Source Data file.

Fig. 3. Immune cell infiltration levels in the tumor tissue before neoadjuvant sintilimab and concurrent chemoradiotherapy between patients achieving pCR (n = 9) and those not achieving pCR (non-pCR; n = 14) assessed by multiplex immunofluorescence (mIF).

A–L The comparison of immune cell infiltration levels was performed using Friedman’s non-parametric test and the adjusted P-value using Bonferroni methods were presented in Supplementary Table 4. The error bars represented the standard deviation. Indicators marked with red dashed boxes represent p < 0.05. Source data are provided as a Source Data file.

Fig. 4. Representative multiplex immunofluorescence (mIF) of tumor immune microenvironment (TiME).

A, B Typical mIF images showing elevated CD56^bright, CD56^dim and CD3 cell infiltration in a patient achieving pCR (A) than another patient not achieving pCR (B). C, D Typical mIF images in a patient achieving pCR with relatively high levels of CD20⁺ B and CD3⁺ T cell infiltration at baseline (C) and developed tertiary lymphoid structure after therapy (D). The images are representative of three patients, bar = 50 um.