Efficacy and safety of sintilimab-based neoadjuvant regimens in patients with resectable gastric or gastroesophageal junction adenocarcinoma: a single-arm systematic review and meta-analysis

Introduction

Gastric and gastroesophageal junction (G/GEJ) tumors are among the most prevalent causes of cancer-related mortality worldwide, with both incidence and mortality burdens continuing to rise (1). Over 60% of cases are concentrated in East Asia (2). Within China, locally advanced gastric cancer accounts for approximately 70% of clinically treated cases (3). Although gastric and GEJ adenocarcinomas differ in terms of site of origin, tumor characteristics, and etiological factors, their clinical management strategies are generally similar (4). In cases of locally advanced stage, neoadjuvant therapy has become the standard strategy, aiming to achieve tumor downstaging, increase the R0 resection rate and ultimately improve long-term survival through preoperative systemic treatment. Several pivotal studies [such as MAGIC (5), FLOT4 (6), RESOLVE (7)] have confirmed that perioperative chemotherapy can significantly improve disease-free survival (DFS), overall survival (OS) and radical cure rate compared with surgery alone. However, the long-term prognosis of the patients still requires further improvement.

In recent years, the application of immune checkpoint inhibitors (ICIs) has brought a fundamental transformation to the treatment landscape of gastric cancer. Programmed death receptor-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors have demonstrated clear efficacy in metastatic gastric cancer and have been recommended as standard treatment options. With the widespread adoption of ICIs combined with chemotherapy in advanced G/GEJ cancer, their exploration in the neoadjuvant setting for locally advanced disease is also deepening (8). Meta-analysis have indicated that the combination of ICIs and neoadjuvant therapy can significantly improve the pathological complete response rate (9,10). It is noteworthy that the efficacy and safety profiles may vary among different PD-1/PD-L1 inhibitors. For instance, a meta-analysis (11) indicated that neoadjuvant regimens based on sintilimab or atezolizumab exhibited a comparatively higher major pathological response rate, and agents such as sintilimab appear to demonstrate a tendency towards a reduced incidence of grade 3–4 treatment-related adverse events (TRAEs).

Sintilimab is a recombinant fully human anti-PD-1 monoclonal antibody. Due to its high affinity for PD-1 and its fully humanised nature, it exhibits favourable antitumor activity and a well-tolerated safety profile. Currently, this agent has been approved in China for the first-line treatment of unresectable locally advanced or metastatic G/GEJ adenocarcinoma, with additional indications approved across multiple tumor types. Its favorable accessibility and cost-effectiveness make it a valuable agent in clinical practice (12). Recently, based on the positive outcomes from the NeoShot-1b (13) and NeoShot-III (14) studies, the dual-immunotherapy regimen combining sintilimab with the anti-CTLA-4 (anti-cytotoxic T lymphocyte-associated antigen 4) antibody (IBI310) has been approved by the National Medical Products Administration (NMPA) for the neoadjuvant treatment of microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) colon cancer. This also highlights its potential in the perioperative treatment.

Although several meta-analyses have investigated the role of neoadjuvant immunotherapy in resectable G/GEJ adenocarcinoma, these analyses typically combined different types of ICIs. Given the variations in drug characteristics and efficacy, such pooling may introduce considerable heterogeneity, potentially compromising the reliability of the conclusions. Currently, while there are multiple studies on sintilimab-based neoadjuvant regimen for locally advanced G/GEJ adenocarcinoma, most are small-scale clinical reports, and a systematic evaluation specifically focused on the efficacy and safety of this regimen is lacking. Therefore, to provide more precise guidance for clinical practice, this study aims to synthesise existing evidence through a single-arm meta-analysis to evaluate the efficacy and safety of sintilimab-based regimens in the neoadjuvant treatment of locally advanced G/GEJ adenocarcinoma. We present this article in accordance with the PRISMA reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0479/rc).

Methods

We have registered our review with PROSPERO (CRD420251145483). This meta-analysis is based on summary data, using the PICOTS system to formulate the research question (Table 1).

Data sources and searches

To identify relevant literature, a search was conducted on PubMed/MEDLINE, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials, covering the period from inception to August 19th, 2025. The following keywords were used: “sintilimab”, “IBI-308”, “Esophagogastric Junction”, “Stomach Neoplasms” and “Gastric Neoplasms” (detailed search strategies for all databases are provided in Tables S1-S4). No language restrictions were applied on searches. Reference lists from eligible studies and relevant reviews and guidelines were searched for additional studies. To ensure the reliability of the data synthesis, this study only included published original studies with complete outcome data. Grey literature and conference proceedings were excluded.

Study selection

Two authors (T.N. and S.L.) scanned the titles, abstracts, and full-texts of potentially eligible studies independently. They resolved any disagreements through discussion or by consulting a third investigator. The following inclusion standards were implemented: (I) both prospective and retrospective studies [e.g., randomized controlled trials (RCTs), cohort studies, cross-sectional studies, and single-arm trials] may be potentially included in our study; (II) adult patients (aged ≥18 years) were diagnosed with locally advanced, resectable G/GEJ adenocarcinoma. The staging system utilised in this study was based on the 8^th edition of the Union for International Cancer Control (UICC) or American Joint Committee on Cancer (AJCC) staging system. For studies that included stage IVA (cT4bNanyM0) patients, inclusion was limited to those in which the original articles clearly defined the disease as “resectable” or the treatment protocol followed a neoadjuvant therapy-to-radical surgery pathway; (III) sintilimab-based neoadjuvant regimen were administered before surgery; (IV) at least one of the following endpoints must be reported by studies: pathologic complete response (pCR), major pathologic response (MPR), R0 resection rate, surgical complication rates, objective response rate (ORR), disease control rate (DCR), DFS, OS, or TRAEs. We excluded the following studies: (I) non-human studies, case studies, conference abstracts, summaries, reviews and meta-analysis; (II) studies with fewer than ten patients; (III) studies from which usable data could not be extracted; (IV) conversion-therapy studies.

Data extraction and quality assessment

Two investigators (T.N. and S.L.) independently extracted the required data from all included studies, and then performed a quality assessment of the studies. The following information about the included studies was recorded: first author, publication year, country, trial type, combination therapy, sample size, median age, gender, tumor type, and reported endpoints. Clinical and safety outcomes included pCR, MPR, R0 resection rate, surgical complication rates, ORR, DCR, DFS, OS, and TRAEs. For surgically dependent outcomes (pCR, MPR, R0 resection rate, and postoperative complications), the denominator was defined as the number of patients who actually underwent surgery, consistent with the definitions used in the source studies. For other outcomes, the denominator was based on the intention-to-treat or full analysis set, as defined in each original study. The Methodological Index for Non-Randomized Studies (MINORS) was used to evaluate the quality of the prospective non-randomized studies (15). Retrospective single-arm studies were assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Series (16). The Newcastle-Ottawa Scale (NOS) was used to assess retrospective controlled studies (17).

Statistical analysis

The STATA 16.0 software was used to synthesize and analysis the data. Most of the included studies were single-arm clinical trials, and the outcome indicators were all ratio indicators calculated as binary variables. Therefore, we performed a single-arm meta-analysis of proportions with the metaprop/metan function in Stata. To avoid variance instability for proportions near 0 or 1, we applied the Freeman-Tukey double arcsine transformation as the primary method for pooling proportions, which handles zero-event and 100% event outcomes naturally without requiring continuity correction. The effect size (ES) of all pooled results was expressed as 95% confidence interval (CI) with upper and lower limits. In light of the anticipated substantial clinical heterogeneity across studies—arising from differences in study design, backbone chemotherapy regimens, concurrent targeted therapy/radiotherapy, and other factors—the random-effects model was prespecified as the default approach for all main analyses. The Q test combined with the I² statistic was used to determine if there was significant study heterogeneity existed in the included studies. If P<0.10 and I²>50%, then there was significant study heterogeneity. Further subgroup analyses were performed when sufficient subgroup data were available to assess potential sources of heterogeneity. Publication bias was evaluated using Begg’s and Egger’s test. P value <0.05 was considered statistically significant. To estimate and validate the impact of each study on the pooled results, sensitivity analyses were conducted.

Results

Study selection

The preliminary search yielded 844 relevant published studies, which were drawn from four databases (PubMed/MEDLINE =103, Embase =580, Cochrane Central Register of Controlled Trials =31, and Web of Science =130). After removing duplicates and screening titles and abstracts, about 39 studies remained. The remaining full-text articles were then subjected to a rigorous assessment. Twenty-six studies were excluded due to unavailability of the full text or non-alignment with the pre-defined criteria. Thirteen studies, comprising a total of 693 patients, ultimately met the inclusion criteria and were incorporated into this meta-analysis (18-30). Figure 1 illustrates the selection process.

Figure 1 PRISMA flow diagram of the study process.

All 13 of the eligible studies were conducted in China and included seven retrospective studies and six prospective studies. The studies included ten single-arm and three controlled trials, with publication dates ranging from 2022 to 2025. Four of the studies enrolled patients with human epidermal growth factor receptor 2 (HER2)-negative status, while one included HER2-positive patients. In 11 out of the 13 studies, the combined chemotherapy regimen consisted of fluorouracil-based agents plus oxaliplatin, and the remaining two studies employed S-1 combined with nab-paclitaxel. The primary characteristics and therapeutic modalities of the included articles are delineated in Table 2.

Quality assessment

Six prospective single-arm studies were evaluated using the MINORS index, achieving a score between 10 and 14 points, which was deemed suitable for the current meta-analysis (Table 3). All four retrospective single-arm studies met at least nine of the ten JBI Checklist items (Table 4). The three retrospective comparative studies were evaluated with the NOS and all received scores of ≥8 stars (out of 9) (Table 5).

Pathological response

A total of 11 studies reported data on pCR, involving 498 patients, of whom 117 achieved pCR. The reported pCR rates across these studies ranged from 13% to 55%. These studies showed significant heterogeneity (I²=52.36%, P=0.02). The pooled analysis revealed an overall pCR rate of 24% (95% CI: 18–30%) (Figure 2A).

Figure 2 Forest plot about the pooled results of pCR (A) and MPR (B). pCR and MPR were calculated based on the number of patients who underwent surgery. CI, confidence interval; ES, effect size; MPR, major pathological response; pCR, pathological complete response.

Furthermore, 12 studies reported data on MPR, encompassing 601 patients, with 291 achieving MPR. Significant heterogeneity was observed among these studies (I²=70.46%, P<0.001). The pooled analysis indicated an overall MPR rate of 50% (95% CI: 42–58%) (Figure 2B).

Imaging response

The ORR data were available from eight studies, involving 438 patients, of whom 325 achieved an objective response. The combined results showed an overall ORR of 75% (95% CI: 71–79%), with low between-study heterogeneity (I²=0.00%, P=0.50) (Figure 3A).

Figure 3 Forest plot about the pooled results of ORR (A) and DCR (B). CI, confidence interval; DCR, disease control rate; ES, effect size; ORR, objective response rate.

The DCR data were reported in seven studies, including 387 patients, with disease control achieved in 374 cases. Significant heterogeneity was observed among these studies (I²=60.61%, P=0.02). The pooled results indicated an overall DCR of 99% (95% CI: 96–100%) (Figure 3B).

Operative and postoperative complications

The R0 resection rate is another significant indicator of the efficacy of neoadjuvant therapy. In the subset of ten studies that reported R0 resection data, five achieved a 100% R0 resection rate. The pooled R0 resection rate was 99% (95% CI: 97–100%). There was low heterogeneity among the studies (I²=16.51%, P=0.29) (Figure 4).

Figure 4 Forest plot about the pooled results of R0 resection rate. R0 resection rate was calculated based on the number of patients who underwent surgery. CI, confidence interval; ES, effect size.

Postoperative complications were reported in 9 out of the 13 included studies. A pooled analysis was conducted for the complications commonly reported by at least three studies (Table 6). Anastomotic leakage and pneumonia were each reported in eight studies. The most prevalent complications were pleural effusion (13%; 95% CI: 6–22%) and pneumonia (12%; 95% CI: 5–21%).

Survival outcomes

Survival outcomes represent pivotal endpoints for the evaluation of long-term therapeutic efficacy. Data on survival rates were derived from multiple studies. The 1-year DFS rate and 1-year OS rate were each reported in four studies, while the 2-year event-free survival (EFS) rate and 2-year OS rate were reported in three and five studies, respectively. In investigations evaluating the efficacy of sintilimab-based neoadjuvant regimens, the pooled 1-year DFS and OS rates were 90% (95% CI: 84–97%, I²=23.3%, P=0.27) and 98% (95% CI: 97–100%, I²=0.00%, P=0.56), respectively. The pooled 2-year EFS and OS rates were 67% (95% CI: 57–77%, I²=23.3%, P=0.27) and 83% (95% CI: 72–95%, I²=85.5%, P<0.001), respectively (Figure 5).

Figure 5 Forest plot about the pooled results of 1-year DFS (A), 1-year OS (B), 2-year EFS (C), and 2-year OS (D). CI, confidence interval; DFS, disease-free survival; DL, DerSimonian-Laird; EFS, event-free survival; OS, overall survival.

Toxicities

The incidence rate of TRAEs (all grades and ≥ grade 3) was utilized to evaluate the safety of sintilimab-based neoadjuvant regimens, and the data from three or more studies were combined for analysis (Table 7). The most prevalent TRAE was nausea (70%; 95% CI: 34–96%), followed by alopecia (54%; 95% CI: 29–77%) and vomiting (41%; 95% CI: 24–61%). Hematological toxicity was also relatively common, including leukopenia (49%; 95% CI: 38–60%), neutropenia (45%; 95% CI: 37–54%), anemia (47%; 95% CI: 35–59%), and lymphopenia (47%; 95% CI: 9–86%). Potential immune-related adverse events (irAEs) included rash (13%; 95% CI: 5–22%), hyperthyroidism (4%; 95% CI: 2–7%), hypothyroidism(5%; 95% CI: 2–9%), and pneumonia(6%; 95% CI: 3–10%), all of which were reported at low rates. The incidence of TRAEs ≥ grade 3 was significantly reduced. Lymphopenia (18%; 95% CI: 8–32%) was the most common severe event among these, while the remaining severe adverse events occurring in less than 10% of cases. No instances of death due to drug toxicity were observed.

Exploratory subgroup analysis

Subgroup analyses of the primary outcome measures, pCR and MPR, were performed based on study design and patient biomarker profiles (Table 8). Analysis stratified by study type showed that both the pCR rate (31% vs. 19%, P=0.03) and the MPR rate (60% vs. 42%, P=0.009) were significantly higher in prospective studies than in retrospective studies. Among HER-2 status subgroups, a significant difference was observed in pCR rates (P=0.03), with a pooled pCR rate of 44% (95% CI: 25–64%) in the HER-2-positive subgroup; however, this result was based on only two studies. In contrast, no statistically significant difference in MPR rates was found across HER‑2 subgroups (P=0.28). Regarding PD-L1 expression, the difference in pCR rates between patients with combined positive score (CPS) ≥1 and those with CPS <1 did not reach statistical significance (P=0.16), whereas the MPR rate was significantly higher in patients with CPS ≥1 (55% vs. 36%, P=0.049). Further analysis revealed that patients with CPS ≥5 had significantly higher rates of both pCR (41% vs. 18%, P=0.02) and MPR (69% vs. 36%, P=0.002) compared to those with CPS <5. Additionally, patients with MSI-H/dMMR showed a significantly higher pCR rate than those with microsatellite stable/proficient mismatch repair (MSS/pMMR) (51% vs. 20%, P=0.01). However, no significant difference was observed in MPR rates between these two groups (P=0.12).

Sensitivity analysis and publication bias

Sensitivity analyses were conducted by removing each study individually to ascertain the stability of the combined results. The results demonstrated that none of the combined results were significantly influenced by any single study, indicating that the results of this study are relatively reliable.

Egger’s and Begg’s tests were employed in order to assess potential publication bias in this study. For pCR (Egger test: 0.187; Begg test: 0.161), MPR (Egger test: 0.115; Begg test: 0.373), DCR (Egger test: 0.362; Begg test: 0.133) and ORR (Egger test: 0.659; Begg test: 0.536), the tests did not suggest significant publication bias. For the R0 resection rate, Begg’s test yielded a P value of 0.012 (Egger test: 0.108). However, as reported above, five of the ten studies achieved a 100% R0 resection rate, creating a ceiling effect that can produce false-positive asymmetry in these tests. Given the extremely low between-study heterogeneity (I²=16.51%) and the consistently high R0 rates observed across the included studies, the significant Begg’s test result is more likely attributable to the statistical artifacts of rare negative events rather than genuine publication bias. Therefore, we consider the pooled R0 resection rate to be clinically robust.

Discussion

This meta-analysis included a total of 13 studies, comprising 6 clinical studies and 7 retrospective studies, to comprehensively evaluate the efficacy and safety of sintilimab-based regimen as neoadjuvant therapy for G/GEJ adenocarcinoma. Pathological response is considered a vital indicator of short-term treatment efficacy, in addition to its potential as a prognostic marker for survival outcomes in patients receiving neoadjuvant ICI therapy. Nevertheless, its definitive correlation with long-term survival benefits requires further validation (31,32). Previous meta-analysis focusing on neoadjuvant immunotherapy in this disease area have reported favorable pathological response outcomes. For instance, a meta-analysis conducted by Wu et al. involving 18 studies reported that the combined pCR rate was 26% (95% CI: 21–31%), and the MPR rate was 45% (95% CI: 36–54%) (33). Wang et al.’s analysis (including 33 studies and 1,074 patients) also reported a similar trend, with a combined pCR rate of 24% (95% CI: 19–28%), and 15 studies reported a combined MPR rate of 49% (95% CI: 38–61%) (34). The pooled analysis of this study indicates that the combination of sintilimab and chemotherapy regimens can also induce significant pathological response, with an overall pCR rate of 24% and an MPR rate of 50%, which is similar to the pooled results of previous similar studies. Among the studies reviewed, the highest pCR rate (55%) was observed in the study by Nie et al. (21). This study evaluated the neoadjuvant efficacy of anti-HER2 therapy combined with sintilimab and chemotherapy in patients with locally advanced gastric cancer exhibiting high HER2 expression. The remarkable pathological complete response may be related to the dual treatment mechanism of targeted therapy combined with immunotherapy for HER2-positive populations. It should be specifically noted that the pooled estimates of pCR and MPR in this study are based on patients who underwent surgery. This approach may overestimate the true benefit by excluding those who did not undergo surgery due to disease progression, toxicity, or other reasons. However, given the way data were reported in the primary studies, this bias could not be avoided in the present analysis. Therefore, caution is warranted when extrapolating these findings to the overall population of patients intended for surgery.

Subgroup analysis is a valuable tool that can provide significant insights into identifying sources of heterogeneity in efficacy and potential populations that may benefit more significantly. Considering the potential disparities between clinical trials conducted in ideal settings and real-world studies, as well as the potential impact of diversity in patients’ tumor microenvironment and immune status on clinical outcomes, we performed subgroup analyses for the two primary endpoints: pCR and MPR. The findings indicated that both the pCR rate (31% vs. 19%, P=0.03) and the MPR rate (60% vs. 42%, P=0.009) exhibited significantly higher values in prospective studies when compared to retrospective studies. This discrepancy may be attributed to the more rigorous design of prospective studies and the generally superior baseline conditions of patients. PD-L1, MSI, HER2, Epstein-Barr virus (EBV), etc. have been widely recognized as potential biomarkers in the treatment of gastroesophageal adenocarcinoma (35). Among these, PD-L1 expression is regarded as a relatively reliable predictor of the efficacy of ICIs. However, whether individuals with low PD-L1 expression can benefit from immunotherapy remains controversial (36). A meta-analysis aimed at determining the optimal threshold of PD-L1 CPS in HER2-negative gastric adenocarcinoma suggested that patients with PD-L1 CPS <5 or <10 may not obtain significant benefits from ICIs combined with chemotherapy (37). The study by Sun et al. also indicated that in patients with G/GEJ cancer treated with PD-1 inhibitors plus chemotherapy, PD-L1 CPS ≥5 was significantly associated with better treatment response and longer progression-free survival (38). Our subgroup analysis further validated these findings: patients with high PD-L1 expression (CPS ≥5) exhibited significantly superior rates of both pCR (41% vs. 18%, P=0.02) and MPR (69% vs. 36%, P=0.002) compared to those with low expression. Although the MPR rate was significantly higher in patients with CPS ≥1 than in those with CPS <1 (55% vs. 36%, P=0.049), the difference in pCR rates between these two groups did not reach statistical significance (P=0.16). MSI-H/dMMR tumors are typically characterized by high tumor mutational burden, increased neoantigen load, elevated PD-L1 expression, and an abundance of tumor-infiltrating lymphocytes. These features are associated with a high response rate to immune checkpoint blockade therapy (39,40). In metastatic gastric cancer, MSI-H status has been established as a predictive biomarker for response to immunotherapy, supported by multiple randomized clinical trials and meta-analyses (41,42). Furthermore, in the neoadjuvant treatment of MSI-H gastric cancer, combination with cytotoxic chemotherapy may be imperative to achieve optimal tumor regression (43). In this meta-analysis, the pCR rate was significantly higher in MSI-H/dMMR patients than in MSS/pMMR patients (51% vs. 20%, P=0.01). However, the difference in MPR rates between the two groups was not statistically significant (P=0.12). This study also conducted a subgroup analysis based on HER2 status. Despite the HER2-positive subgroup demonstrating a higher tendency for pCR, the stability of this conclusion remains uncertain due to the inclusion of only two studies and the absence of a significant disparity in MPR rates across varying HER2 statuses. Further verification is necessary to substantiate this conclusion, ideally through the utilisation of a more substantial sample size. In addition, although three included studies reported the subgroup results of the EBV status, the corresponding analysis was not performed in this study due to the limited sample size. This issue merits further exploration in future research.

Neoadjuvant therapy aims to reduce tumor burden and minimise involvement of regional lymph nodes, thereby downstaging the disease, limiting surgical scope, and improving the feasibility of radical resection as well as perioperative safety. Imaging efficacy evaluation can directly reflect tumor regression caused by treatment; however, further exploration is required to ascertain its correlation with long-term survival of patients undergoing neoadjuvant therapy (44,45). The results of this study demonstrate that the sintilimab-based neoadjuvant regimen exhibited promising efficacy in imaging evaluations, with an ORR of 75% and a DCR as high as 99%, indicating substantial tumor-regressive capability of this regimen. Regarding surgical outcomes, the R0 resection rate reached 99%, postoperative complications were generally manageable, with pleural effusion (13%) and pneumonia (12%) had a relatively high incidence rate. Short-term survival data also showed encouraging trends: the 1-year DFS and OS rates recorded at 90% and 98%, respectively. The 2-year EFS rate was 67%, while the 2-year OS rate reached 83%. The DANTE/IKF-s633 trial showed that perioperative treatment with atezolizumab plus FLOT improved postoperative tumor staging (46). The MATTERHORN trial demonstrated that perioperative durvalumab plus FLOT significantly improved EFS outcomes compared with FLOT alone (47). In this context, our findings further support the therapeutic activity of immunochemotherapy in locally advanced G/GEJ adenocarcinoma, potentially offering more favourable conditions for surgery and near-term survival benefits for patients.

Current evidence indicates that in the neoadjuvant or perioperative treatment of locally advanced G/GEJ cancer, the combination of ICIs with chemotherapy significantly enhances efficacy without correspondingly increasing treatment-related safety risks. The safety profile has been validated in multiple key large-scale randomised controlled trials. For example, the MATTERHORN study (47) demonstrated similar rates of grade 3–4 adverse events between the durvalumab plus chemotherapy group and the placebo plus chemotherapy group (71.6% vs. 71.2%). Similarly, in the KEYNOTE-585 study (48), no significant difference was observed in the incidence of grade ≥3 adverse events between the pembrolizumab group and the placebo group (78% vs. 74%). The most common adverse events included nausea, anemia, and anorexia, and the rates of treatment-related serious adverse events were comparable (26% vs. 24%). This safety conclusion has been further supported by multiple meta-analyses. A meta-analysis of RCTs in this field indicated that the addition of ICIs to chemotherapy did not significantly increase the incidence of TRAEs of any grade (95.0% vs. 94.9%, P=0.77) or grade 3–4 AEs (49.1% vs. 41.4%, P=0.13) (9). Another meta-analysis encompassing four phase II/III randomised trials also showed that combination immunotherapy did not significantly increase the overall risk of grade 3–5 TRAEs, although the risk of grade 3–5 irAEs was heightened. The adverse event profiles of all grades were similar between the two groups, with the most common events including nausea, diarrhea and neutropenia. Immune-related toxicities primarily consisted of stomatitis, rash, pruritus, hypothyroidism, and colitis (49). The safety results of this study are basically consistent with those of the aforementioned studies. Among all levels of adverse events, nausea, alopecia, vomiting, and hematologic toxicities (such as leukopenia and anemia) were relatively common. The overall incidence of grade ≥3 serious adverse events was low, with all except lymphopenia (18%) occurring at rates below 10%. Notably, the incidence of potential irAEs (such as rash, thyroid dysfunction, and pneumonitis) was also at a relatively low level. The findings indicate suggest that, with standardized monitoring and management, the safety profile of the sintilimab-based neoadjuvant regimen is generally manageable, and its risk-benefit ratio is deemed acceptable.

This study has several limitations. Firstly, there was considerable heterogeneity among the included studies. Although subgroup analyses were performed based on study design and patient biomarker profiles, other factors—such as the type of combined chemotherapy regimens, the cycle and frequency of neoadjuvant therapy, and follow-up duration—may also have contributed to heterogeneity. Secondly, the evidence base consisted predominantly of uncontrolled single-arm studies, with only three retrospective comparative trials included, thus limiting the overall quality of evidence. Consequently, we pooled the single-arm data for sintilimab-based neoadjuvant therapy from all included studies to evaluate the efficacy and safety of this regimen in resectable G/GEJ adenocarcinoma. However, due to insufficient comparator data, this study could not directly assess the relative superiority of this regimen over other treatment strategies. Thirdly, all trials included in this analysis enrolled Chinese patients, and the sample size was relatively limited. Consequently, the generalizability of these findings to other populations necessitates further validation.

Conclusions

In conclusion, the pooled results indicate that the sintilimab-based neoadjuvant regimen demonstrates promising efficacy and an acceptable safety profile in G/GEJ adenocarcinoma. Subgroup analyses suggest that patients with high PD-L1 expression or MSI-H/dMMR status may demonstrate a higher pathological response. However, the conclusions of this study are limited by the predominance of single-arm designs, relatively small sample sizes, and short follow-up durations, particularly with regard to the insufficiency of long-term survival data. Future large-scale, prospective RCTs are required to further validate the survival benefits of this regimen and to continue exploring biomarkers capable of accurately predicting therapeutic response, thereby advancing the goal of individualized treatment.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0479/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0479/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0479/prf

Funding: This work was financially supported by Joint Funds for the Innovation of Science and Technology, Fujian province (No. 2024Y9731).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0479/coif). T.N. reports that this study was supported by Joint Funds for the Innovation of Science and Technology, Fujian province (No. 2024Y9731). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Zhang T, Zhang Y, Leng X. Global, regional, and national trends in gastric cancer burden: 1990-2021 and projections to 2040. Front Oncol 2024;14:1468488. [Crossref] [PubMed]
2. Sekiguchi M, Oda I, Matsuda T, et al. Epidemiological Trends and Future Perspectives of Gastric Cancer in Eastern Asia. Digestion 2022;103:22-8. [Crossref] [PubMed]
3. Han L. Recent advances of neoadjuvant and conversion therapies for locally advanced and stage IV gastric or esophagogastric junction adenocarcinoma. Abdominal Surg 2023;36:79-82+7.
4. Fong A, Castillo D, Shah P, et al. Right place right time: the role of immunotherapy in patients with locally advanced gastric/gastroesophageal junction adenocarcinoma. J Gastrointest Oncol 2025;16:2895-9. [Crossref] [PubMed]
5. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:11-20. [Crossref] [PubMed]
6. Al-Batran SE, Homann N, Pauligk C, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet 2019;393:1948-57. [Crossref] [PubMed]
7. Zhang X, Liang H, Li Z, et al. Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial. Lancet Oncol 2021;22:1081-92. [Crossref] [PubMed]
8. Liu J, Zhang R, Zhou W, et al. Neoadjuvant adebrelimab combined with triplet chemotherapy for locally advanced resectable adenocarcinoma of esophagogastric junction: a prospective, single-arm, phase II feasibility and safety study. J Gastrointest Oncol 2026;17:46. [Crossref] [PubMed]
9. Huang D, Sun F, Ke L, et al. Perioperative immune checkpoint inhibitors combined with chemotherapy versus chemotherapy for locally advanced, resectable gastric or gastroesophageal junction adenocarcinoma: A systematic review and meta-analysis of randomized controlled trials. Int Immunopharmacol 2024;138:112576. [Crossref] [PubMed]
10. Liang C, Yu Z, Hou S, et al. Therapeutic efficacy of multiple neoadjuvant regimens involving targeted therapy, immunotherapy and chemotherapy in gastric cancer: a systematic review and meta-analysis. BMC Cancer 2025;25:1694. [Crossref] [PubMed]
11. Yuan Z, Cui H, Wang S, et al. Combining neoadjuvant chemotherapy with PD-1/PD-L1 inhibitors for locally advanced, resectable gastric or gastroesophageal junction adenocarcinoma: A systematic review and meta-analysis. Front Oncol 2023;13:1103320. [Crossref] [PubMed]
12. Wu YY, Shao H. Research progress of sintilimab in the treatment of cancer Oncol Lett 2025;29:240. (Review). [Crossref] [PubMed]
13. Wang F, Chen G, Qiu M, et al. Neoadjuvant treatment of IBI310 plus sintilimab in locally advanced MSI-H/dMMR colon cancer: A randomized phase 1b study. Cancer Cell 2025;43:1958-1967.e2. [Crossref] [PubMed]
14. Xu RH, Wang F, Chen G, et al. 127P Neoadjuvant IBI310 plus sintilimab in locally advanced MSI-H/dMMR colon cancer: Interim results of the phase III neoshot study. Immuno-Oncology and Technology 2025;28:101211.
15. Slim K, Nini E, Forestier D, et al. Methodological index for non-randomized studies (minors): development and validation of a new instrument. ANZ J Surg 2003;73:712-6. [Crossref] [PubMed]
16. Munn Z, Barker TH, Moola S, et al. Methodological quality of case series studies: an introduction to the JBI critical appraisal tool. JBI Evid Synth 2020;18:2127-33. [Crossref] [PubMed]
17. Zhang Y, Huang L, Wang D, et al. The ROBINS-I and the NOS had similar reliability but differed in applicability: A random sampling observational studies of systematic reviews/meta-analysis. J Evid Based Med 2021;14:112-22. [Crossref] [PubMed]
18. Che S, Gao Z, Qing H, et al. Real-world effectiveness of an immunosuppressant combined with different chemotherapy regimens in the neoadjuvant treatment of advanced gastric cancer. Chinese Journal of Clinical Oncology 2025;52:447-53.
19. Chen QX, Zhang YB, Zeng WM, et al. Efficacy and safety of sintilimab combined with nab-paclitaxel plus S-1 for neoadjuvant treatment of locally advanced gastric cancer. World J Gastrointest Surg 2025;17:106361. [Crossref] [PubMed]
20. Chen L, Zhang S, Ma H, et al. The short-term efficacy and safety of neoadjuvant Sintilimab combined with chemotherapy for resectable gastroesophageal junction adenocarcinoma. Langenbecks Arch Surg 2024;410:5. [Crossref] [PubMed]
21. Nie RC, Chen XJ, Liang CC, et al. Safety and efficacy of perioperative dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Cell Rep Med 2025;6:102190. [Crossref] [PubMed]
22. Cao B, Zhang P, Shi Z. Association of Body Composition Parameters with the Short- and Long-Term Efficacy of Neoadjuvant Immunotherapy Combined with Chemotherapy in Advanced Gastric Cancer. Nutr Cancer 2025;77:455-64. [Crossref] [PubMed]
23. Xu M, Zhang Y, Zhao K, et al. Prediction of pathological response to neoadjuvant immunochemotherapy with baseline and post-treatment 18F-FDG PET imaging biomarkers in patients with locally advanced gastric cancer. BMC Cancer 2025;25:378. [Crossref] [PubMed]
24. Wang YC, Zhang CG, Wang YW, et al. SOX plus sintilimab vs P-SOX vs SOX as neoadjuvant therapy in advanced gastric cancer: Efficacy and safety. World J Gastrointest Oncol 2025;17:109646. [Crossref] [PubMed]
25. Zhou H, Long B, Yu Z, et al. Neoadjuvant sintilimab and apatinib combined with perioperative FLOT chemotherapy for locally advanced gastric cancer: A prospective, single-arm, phase II study. Chin Med J (Engl) 2024;137:2615-7. [Crossref] [PubMed]
26. Li N, Li Z, Fu Q, et al. Efficacy and safety of neoadjuvant sintilimab in combination with FLOT chemotherapy in patients with HER2-negative locally advanced gastric or gastroesophageal junction adenocarcinoma: an investigator-initiated, single-arm, open-label, phase II study. Int J Surg 2024;110:2071-84. [Crossref] [PubMed]
27. Wei J, Lu X, Liu Q, et al. Neoadjuvant sintilimab in combination with concurrent chemoradiotherapy for locally advanced gastric or gastroesophageal junction adenocarcinoma: a single-arm phase 2 trial. Nat Commun 2023;14:4904. [Crossref] [PubMed]
28. Huang X, Fang J, Huang L, et al. SOX combined with sintilimab versus SOX alone in the perioperative management of locally advanced gastric cancer: a propensity score-matched analysis. Gastric Cancer 2023;26:1040-50. [Crossref] [PubMed]
29. Jiang H, Yu X, Li N, et al. Efficacy and safety of neoadjuvant sintilimab, oxaliplatin and capecitabine in patients with locally advanced, resectable gastric or gastroesophageal junction adenocarcinoma: early results of a phase 2 study. J Immunother Cancer 2022;10:e003635. [Crossref] [PubMed]
30. Guo H, Ding P, Sun C, et al. Efficacy and safety of sintilimab plus XELOX as a neoadjuvant regimen in patients with locally advanced gastric cancer: A single-arm, open-label, phase II trial. Front Oncol 2022;12:927781. [Crossref] [PubMed]
31. Sugiyama K, Gordon A, Popat S, et al. Is pathological response an adequate surrogate marker for survival in neoadjuvant therapy with immune checkpoint inhibitors? ESMO Open 2025;10:104122. [Crossref] [PubMed]
32. Saltalamacchia G, Bernardo A, Quaquarini E. Prognostic Role of Pathological Complete Response in Early Stage Epithelial Solid Tumors. Cancer Control 2023;30:10732748231161466. [Crossref] [PubMed]
33. Wu D, Yang L, Yan Y, et al. Neoadjuvant immunotherapy improves outcomes for resectable gastroesophageal junction cancer: A systematic review and meta-analysis. Cancer Med 2024;13:e7176. [Crossref] [PubMed]
34. Wang J, Tong T, Zhang G, et al. Evaluation of neoadjuvant immunotherapy in resectable gastric/gastroesophageal junction tumors: a meta-analysis and systematic review. Front Immunol 2024;15:1339757. [Crossref] [PubMed]
35. Svrcek M, Voron T, André T, et al. Improving individualised therapies in localised gastro-oesophageal adenocarcinoma. Lancet Oncol 2024;25:e452-63. [Crossref] [PubMed]
36. Zhao JJ, Yap DWT, Chan YH, et al. Low Programmed Death-Ligand 1-Expressing Subgroup Outcomes of First-Line Immune Checkpoint Inhibitors in Gastric or Esophageal Adenocarcinoma. J Clin Oncol 2022;40:392-402. [Crossref] [PubMed]
37. Li JB, Lai MY, Lin ZC, et al. The optimal threshold of PD-L1 combined positive score to predict the benefit of PD-1 antibody plus chemotherapy for patients with HER2-negative gastric adenocarcinoma: a meta-analysis. Cancer Immunol Immunother 2024;73:132. [Crossref] [PubMed]
38. Sun YT, Lu SX, Lai MY, et al. Clinical outcomes and biomarker exploration of first-line PD-1 inhibitors plus chemotherapy in patients with low PD-L1-expressing of gastric or gastroesophageal junction adenocarcinoma. Cancer Immunol Immunother 2024;73:144. [Crossref] [PubMed]
39. Ratti M, Lampis A, Hahne JC, et al. Microsatellite instability in gastric cancer: molecular bases, clinical perspectives, and new treatment approaches. Cell Mol Life Sci 2018;75:4151-62. [Crossref] [PubMed]
40. Ozer M, Vegivinti CTR, Syed M, et al. Neoadjuvant Immunotherapy for Patients with dMMR/MSI-High Gastrointestinal Cancers: A Changing Paradigm. Cancers (Basel) 2023;15:3833. [Crossref] [PubMed]
41. Park YG, Kim HD, Hyung J, et al. Factors associated with the efficacy of first-line nivolumab plus chemotherapy in advanced gastric cancer patients with deficient mismatch repair. Gastric Cancer 2024;27:840-9. [Crossref] [PubMed]
42. Pietrantonio F, Randon G, Di Bartolomeo M, et al. Predictive role of microsatellite instability for PD-1 blockade in patients with advanced gastric cancer: a meta-analysis of randomized clinical trials. ESMO Open 2021;6:100036. [Crossref] [PubMed]
43. Kim YJ, Kim HD, Hyung J, et al. Neoadjuvant Chemotherapy for Gastric Cancer: Evolving Approaches and Supporting Evidence. J Gastric Cancer 2026;26:106-26. [Crossref] [PubMed]
44. Chen X, Ma K. Neoadjuvant Therapy in Lung Cancer: What Is Most Important: Objective Response Rate or Major Pathological Response? Curr Oncol 2021;28:4129-38. [Crossref] [PubMed]
45. Ye J, Ji X, Dennis PA, et al. Relationship Between Progression-Free Survival, Objective Response Rate, and Overall Survival in Clinical Trials of PD-1/PD-L1 Immune Checkpoint Blockade: A Meta-Analysis. Clin Pharmacol Ther 2020;108:1274-88. [Crossref] [PubMed]
46. Lorenzen S, Götze TO, Thuss-Patience P, et al. Perioperative Atezolizumab Plus Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel for Resectable Esophagogastric Cancer: Interim Results From the Randomized, Multicenter, Phase II/III DANTE/IKF-s633 Trial. J Clin Oncol 2024;42:410-20. [Crossref] [PubMed]
47. Janjigian YY, Al-Batran SE, Wainberg ZA, et al. Perioperative Durvalumab in Gastric and Gastroesophageal Junction Cancer. N Engl J Med 2025;393:217-30. [Crossref] [PubMed]
48. Shitara K, Rha SY, Wyrwicz LS, et al. Neoadjuvant and adjuvant pembrolizumab plus chemotherapy in locally advanced gastric or gastro-oesophageal cancer (KEYNOTE-585): an interim analysis of the multicentre, double-blind, randomised phase 3 study. Lancet Oncol 2024;25:212-24. [Crossref] [PubMed]
49. Lin Y, Liao Y, Shen J. Addition of immunotherapy to perioperative chemotherapy for resectable gastric and gastroesophageal junction cancer: a meta-analysis of phase 2/3 trials. Front Immunol 2025;16:1692336. [Crossref] [PubMed]