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.

Comprehensive multi‐omics analysis of resectable locally advanced gastric cancer: Assessing response to neoadjuvant camrelizumab and chemotherapy in a single‐center, open‐label, single‐arm phase II trial

“…Comparable observations regarding TMB were made in a neoadjuvant trial involving camrelizumab combined with chemoradiotherapy for GC 36 . Additionally, the presence of CD8+ T cells and a higher ratio of M1 to M2 macrophages were associated with better pathological responses, 37,38 findings that align with our research.…”

“…Recently clinical trials have shown promising results for neoadjuvant treatment in GC using various therapeutic approaches and ICIs. These studies, often exploratory with small sample sizes, have utilized multi‐omics to discover novel biomarkers 36–38 . Gene mutations, specifically RREB1 and SSPO, along with TMB, have been linked to positive outcomes in patients treated with a PD‐1 inhibitor, apatinib, and chemotherapy 37 .…”

“…These studies, often exploratory with small sample sizes, have utilized multi‐omics to discover novel biomarkers. 36 , 37 , 38 Gene mutations, specifically RREB1 and SSPO, along with TMB, have been linked to positive outcomes in patients treated with a PD‐1 inhibitor, apatinib, and chemotherapy. 37 Comparable observations regarding TMB were made in a neoadjuvant trial involving camrelizumab combined with chemoradiotherapy for GC.…”

Evaluation of neoadjuvant immunotherapy in resectable gastric/gastroesophageal junction tumors: a meta-analysis and systematic review

“…Furthermore, it was found that microsatellite instability (MSI)/ mismatch repair (MMR) levels and tumor mutation burden (TMB) may be effective markers for screening patients for potential benefit from immunotherapy (64,65). Ten (28,35,36,38,44,47,(50)(51)(52)58) of the 33 included studies were found to indicate a higher incidence of PCR with MPR after neoadjuvant immunotherapy in patients with detectable CPS ≥ 1 or dMMR than in patients with CPS < 1 or pMMR. This result indicates that CPS ≥ 1 or dMMR may serve as a biomarker of prognosis in patients with resectable G/ GEJ.…”

Analysis of Patient Outcomes following Curative R0 Multiorgan Resections for Locally Advanced Gastric Cancer: A Systematic Review and Meta-Analysis

“…The prognosis of locally advanced gastric cancer (LAGC) remains a formidable challenge in the field of oncological surgery [1,2]. Despite advancements in preoperative chemotherapy and radiation therapy, the survival rates post-surgery have shown only modest improvements over the past decades, with approximately 40% overall survival 2 of 20 in all gastric cancers, and from 0% to 15% in disseminated and LAGC [3][4][5]. A critical determinant of long-term survival in patients with LAGC is the achievement of R0 resection, defined as the complete removal of the tumor with no microscopic residual disease [6].…”