Nature Medicine | Dual TIGIT and PD-1 Inhibitor Combined with FOLFOX in Patients with Advanced Gastric, Gastroesophageal Junction, or Esophageal Adenocarcinoma

This study demonstrates the antitumor efficacy and safety of dual TIGIT and PD-1 inhibitors combined with chemotherapy in advanced gastric, gastroesophageal junction, or esophageal adenocarcinoma, providing important evidence for future immune combination therapeutic strategies.

 

Literature Overview

This article, titled 'Domvanalimab and Zimberelimab Combined with FOLFOX in Advanced Gastric, Gastroesophageal Junction, or Esophageal Cancer,' published in the journal Nature Medicine, reviews and summarizes the treatment regimen from Cohort A1 of the EDGE-Gastric study. The study evaluates the efficacy and safety of Domvanalimab (anti-TIGIT) and Zimberelimab (anti-PD-1) combined with FOLFOX in first-line treatment of HER2-negative advanced gastrointestinal adenocarcinoma. The results show that this combination therapy provides a high objective response rate, along with prolonged progression-free survival and overall survival, offering new clinical evidence for combination immunotherapy in advanced gastric cancer.

Background Knowledge

Gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma are malignant tumors with high incidence and mortality rates globally. Although PD-1 inhibitors combined with chemotherapy have shown efficacy in first-line treatment, the overall survival for patients remains limited. TIGIT is another immune checkpoint receptor whose inhibitors can enhance antitumor immune responses when combined with PD-1 inhibitors. Domvanalimab is an Fc-silent anti-TIGIT antibody designed to avoid antibody-dependent cellular cytotoxicity (ADCC) and the depletion of regulatory T cells (Tregs), thereby maintaining immune homeostasis and reducing immune-related toxicities. This study builds on preclinical data of Domvanalimab and Zimberelimab combined with FOLFOX to explore their potential in first-line treatment. Survival curves were estimated using the Kaplan-Meier method, and PD-L1 expression was assessed using the VENTANA PD-L1 (SP263) assay. The study also explores how different PD-L1 expression levels (TAP≥1% and TAP≥5%) influence treatment response. The findings support further validation of this regimen in the STAR-221 phase III clinical trial.

 

 

Research Methods and Experiments

The study is a multicenter, international, phase 2 clinical trial named the EDGE-Gastric study (NCT05329766), which includes three cohorts. Cohort A1 assesses the efficacy of Domvanalimab and Zimberelimab combined with FOLFOX in first-line treatment of HER2-negative advanced gastric, gastroesophageal junction, or esophageal adenocarcinoma. A total of 41 patients were enrolled, including 26 with gastric adenocarcinoma, 29 who were PD-L1 positive (TAP≥1%), and 16 with high PD-L1 expression (TAP≥5%). The primary endpoints were safety and the investigator-assessed objective response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), and duration of response (DOR). PD-L1 expression was evaluated using the VENTANA PD-L1 (SP263) assay and cross-validated with the Dako 28-8 assay. Patients received Domvanalimab, Zimberelimab, and FOLFOX, and the endpoints were analyzed using the Kaplan-Meier method.

Key Conclusions and Perspectives

• Among 41 treated patients, the confirmed objective response rate was 59% (90% CI: 44.5–71.6%), with a complete response rate of 7% and a partial response rate of 51%.
• In PD-L1 positive (TAP≥1%) and PD-L1 high-expressing (TAP≥5%) patients, the objective response rates were 62% and 69%, respectively, with progression-free survival durations of 13.2 months and 14.5 months, and overall survival durations of 26.7 months and not reached, respectively.
• The rate of immune-related adverse events was 27%, consistent with previous studies of PD-1 inhibitors combined with platinum-based chemotherapy, with no ≥3-grade immune-related toxicities observed.
• The Fc-silent design of Domvanalimab reduces depletion of regulatory T cells, thereby decreasing autoimmune toxicity and improving treatment tolerability.
• This study supports the further investigation of this regimen in the phase 3 STAR-221 clinical trial, which will compare the efficacy of Domvanalimab and Zimberelimab combined with chemotherapy versus Nivolumab combined with chemotherapy.

Research Significance and Prospects

The findings of this study offer a novel immune combination strategy for first-line treatment of advanced gastric, gastroesophageal junction, or esophageal adenocarcinoma, suggesting that dual TIGIT and PD-1 blockade may further enhance antitumor immune responses. The results indicate that patients with higher PD-L1 expression may derive greater clinical benefit from this combination, suggesting that future studies should focus on PD-L1 expression as a predictive biomarker. Additionally, the Fc-silent property of Domvanalimab may optimize the therapeutic window, improving efficacy while reducing immune-related adverse events. The STAR-221 phase 3 trial will further validate the clinical utility of this regimen in a larger patient population and explore potential differences in efficacy across gastric cancer subtypes.

 

 

Conclusion

In summary, Domvanalimab and Zimberelimab combined with FOLFOX demonstrate favorable antitumor activity and long-term survival benefits in the first-line treatment of HER2-negative advanced gastric, gastroesophageal junction, or esophageal adenocarcinoma. These findings support further validation in the STAR-221 phase 3 clinical trial and offer a new direction for combination immunotherapy in gastrointestinal cancers. This study highlights the importance of TIGIT as a synergistic target alongside PD-1 inhibitors in antitumor immunity and lays the foundation for future clinical applications of dual checkpoint inhibitors. Moreover, the study suggests that PD-L1 expression levels may serve as a predictive biomarker for therapeutic response, although further standardization is required across different testing platforms. Overall, this research introduces a new treatment option for patients with advanced gastric cancer and advances the field of immunotherapy based on dual TIGIT and PD-1 blockade.

 

Yelena Y Janjigian, Do-Youn Oh, Meredith Pelster, Edward Allan R Sison, and Sun Young Rha. Domvanalimab and zimberelimab in advanced gastric, gastroesophageal junction or esophageal cancer: a phase 2 trial. Nature Medicine.