Nature Communications | SBAGA Study: Sintilimab Combined with IBI305 and Chemotherapy as First-Line Treatment for HER2-Negative Advanced Gastric or Gastroesophageal Junction Adenocarcinoma

This study provides critical clinical evidence for immunotherapy combined with anti-angiogenic therapy in HER2-negative gastric cancer. It suggests that future gastric cancer experimental designs should focus on efficacy differences in patients with low PD-L1 expression and specific Claudin-18.2 status to optimize patient stratification strategies.

 

Literature Overview

The article titled "Sintilimab plus Bevacizumab biosimilar IBI305 and chemotherapy as a first-line treatment in advanced gastric or gastroesophageal junction adenocarcinoma (SBAGA): a single-arm, phase Ib/II study," published in Nature Communications, systematically explores the efficacy and safety of sintilimab combined with the bevacizumab biosimilar IBI305 and chemotherapy as a first-line treatment regimen in patients with HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma.

Background Knowledge

Patients with advanced gastric cancer have a poor prognosis. Although the combination of immune checkpoint inhibitors and chemotherapy has improved survival for some patients, approximately 50% of patients exhibit low PD-L1 expression (CPS < 5), and traditional anti-angiogenic agents (such as bevacizumab) have not shown significant benefits in first-line therapy, constituting a major bottleneck in current targeted treatments. Furthermore, uncertainties regarding peritoneal metastasis and Claudin-18.2 expression status further limit therapeutic options. The focus of this study is to validate a "triple combination" strategy of anti-VEGF monoclonal antibody (IBI305), PD-1 inhibitor (Sintilimab), and chemotherapy. This aims to improve the tumor microenvironment through vascular normalization, enhance T-cell infiltration, and thereby overcome resistance mechanisms associated with single-agent immunotherapy or chemotherapy, particularly targeting the refractory subgroups with low PD-L1 expression and peritoneal metastasis.

 

 

Research Methods and Experiments

This study employed a single-arm, open-label phase Ib/II clinical trial design. The phase Ib portion utilized a 3+3 dose-escalation scheme to evaluate the safety of IBI305 and determine the recommended phase 2 dose (RP2D). The primary endpoint of phase II was the objective response rate (ORR). The study enrolled 57 treatment-naïve patients with HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma. The treatment regimen consisted of sintilimab combined with IBI305 and CapeOX chemotherapy (oxaliplatin + capecitabine). Key evidence included tumor response analysis in 54 evaluable patients, Kaplan-Meier curve assessments for progression-free survival (PFS) and overall survival (OS), and subgroup analyses based on biomarkers such as PD-L1 CPS, Claudin-18.2 expression, TMB, and CDH1.

Key Conclusions and Perspectives

• The triple combination regimen demonstrated exceptional anti-tumor activity in the first-line treatment of HER2-negative advanced gastric cancer, with an ORR of 87.0% and a median PFS of 12.2 months. The median OS was not yet reached, suggesting that this strategy significantly extends patient survival and provides data support for exploring its application in broader populations in future experimental directions.
• Efficacy benefits were not limited by PD-L1 expression levels; the median PFS in the low-expression subgroup (CPS < 1) still reached 14.5 months. This indicates that anti-VEGF therapy may compensate for the limitations of immunotherapy in low PD-L1 tumors, guiding future research to focus on the synergistic mechanisms between angiogenesis and the immune microenvironment.
• For the traditionally refractory subgroup with peritoneal metastasis (48% of patients), the regimen showed survival benefits comparable to those without peritoneal metastasis. This suggests that IBI305 may function by improving the peritoneal microenvironment barrier, offering a new strategy for the pharmacological treatment of peritoneal metastasis.
• In terms of safety, the incidence of grade 3 or higher treatment-related adverse events was 66%, primarily involving hematological toxicity and gastrointestinal bleeding. No fatal bleeding events occurred, indicating that the combination regimen has manageable toxicity characteristics under close monitoring, guiding clinical practice to focus on the management of bleeding risks.
• Biomarker analysis revealed that CCNE1 mutations were associated with longer PFS, while CDH1 mutations were associated with shorter PFS. Additionally, patients with MET amplification showed poor efficacy. These findings provide potential predictive biomarkers for patient selection in future drug development.

Research Significance and Prospects

From a research perspective, these findings confirm the synergistic potential of combining anti-VEGF monoclonal antibodies with PD-1 inhibitors and chemotherapy in the first-line treatment of gastric cancer, particularly for patients with low PD-L1 expression and peritoneal metastasis. This offers a new paradigm for combination therapy in drug development. Simultaneously, the study highlights the potential of CDH1 and CCNE1 as prognostic markers, suggesting that genomic testing should be incorporated into clinical monitoring to optimize treatment decisions. Furthermore, the breakthrough regarding the peritoneal metastasis barrier provides direction for constructing clinical-relevant peritoneal metastasis models in future disease modeling to screen anti-angiogenic drugs.

 

 

Conclusion

The SBAGA study is a landmark phase Ib/II clinical trial that powerfully demonstrates the feasibility and high efficacy of sintilimab combined with IBI305 and chemotherapy as a first-line treatment for HER2-negative advanced gastric cancer. This study not only overcomes the limitations of traditional anti-angiogenic drugs in first-line therapy but, more critically, observes significant survival benefits in refractory subgroups such as those with low PD-L1 expression and peritoneal metastasis, providing strong evidence-based medical evidence to improve the prognosis of gastric cancer patients. From a translational perspective from laboratory to clinic, this study establishes the cornerstone role of the "Immunotherapy + Anti-angiogenic + Chemotherapy" triple therapy in the gastric cancer care system. It also suggests that future research should focus on the validation of genomic biomarkers such as CDH1 and the development of precision treatment strategies targeting specific microenvironmental features, thereby driving gastric cancer treatment towards greater precision and efficiency.

 

Mo Cheng, Pengfei Zhang, Qiancheng Hu, Feng Bi, and Ming Liu. Sintilimab plus Bevacizumab biosimilar IBI305 and chemotherapy as a first-line treatment in advanced gastric or gastroesophageal junction adenocarcinoma (SBAGA): a single-arm, phase Ib/II study. Nature Communications.