Domvanalimab Combo Shows Enriched First-Line Efficacy in Advanced GI Cancers

In the phase 2 EDGE-Gastric trial (NCT05329766), the combination of monoclonal antibodies domvanalimab and zimberelimab (YuTuo in China) plus chemotherapy demonstrated durable efficacy and manageable toxicity in treatment-naive patients with advanced HER2-negative gastroesophageal cancer.¹

As of the data cutoff on March 3, 2025, the confirmed objective response rate (ORR) among 41 previously untreated patients was 59% (90% CI, 44.5%–71.6%), including 3 complete responses and 21 partial responses, with a 12.4-month median duration of response (90% CI, 10.2–15.4). Further, the median progression-free survival (PFS) and median overall survival (OS) were 12.9 months (90% CI, 9.8–14.6) and 26.7 months (90% CI, 18.4–not estimable), respectively.

The safety profile was also reported to be consistent with prior reports for anti–PD-1 plus platinum-based chemotherapy. More than half (73%) of patients experienced a grade ≥3 treatment-emergent adverse event (TEAE), with the most common being neutrophil count decrease (37%), anemia (17%), and neutropenia (15%). In addition, 27% of patients experienced immune-related TEAEs. These updated results are similar to safety trends previously reported in this cohort by Yelena Y. Janjigian, MD, Memorial Sloan Kettering Cancer Center, in November 2023 at an American Society of Clinical Oncology (ASCO) Plenary Series session.

Mechanistic Rationale for Domvanalimab/Zimberelimab

Domvanalimab, an Fc-silent anti-TIGIT antibody, and zimberelimab, an anti–PD-1 antibody, have demonstrated antitumor responses in the preclinical setting,¹ which set the rationale for investigating this duo as treatment for this indication. These findings suggest that their mechanistic features, enabling a dual TIGIT and PD-1 blockade, may play a role in delivering enhanced and durable antitumor activity, according to the authors.

“The Fc-silent design of domvanalimab may further optimize the therapeutic window by balancing efficacy with safety in the context of PD-1 blockade and chemotherapy,” explained Janjigian et al, authors of the study published in Nature Medicine.¹

Overview of the EDGE-Gastric Trial

The phase 2 EDGE-Gastric trial is an ongoing, multicenter, randomized, open-label trial designed to assess the safety and efficacy of domvanalimab plus zimberelimab with or without oxaliplatin, leucovorin, and fluorouracil (FOLFOX) chemotherapy in patients with locally advanced unresectable or metastatic gastric cancer (GC), gastroesophageal junction (GEJ) or esophageal adenocarcinoma (EAC).²

The trial has enrolled 332 adult patients across 3 cohorts receiving varying lines of treatment: cohort A in the first-line setting, and cohorts B and C in the second-line or greater setting. Cohort A comprises 2 nonrandomized arms (A1 and A2) and 2 randomized arms (A3 and A4); this paper reported the results of arm A1.

The study treatment regimen consisted of 1600 mg of intravenous (IV) domvanalimab plus 480 mg of IV zimberelimab every 4 weeks, as well as chemotherapy administered every 2 weeks.

Additional Studies of Domvanalimab/Zimberelimab

In parallel to the EDGE-Gastric study, the combination is also being evaluated in the randomized phase 3 STAR-221 trial (NCT05568095), bolstered by the positive findings from phase 2. Specifically, the trial is comparing the efficacy of the domvanalimab and zimberelimab plus chemotherapy against nivolumab (Opdivo) and chemotherapy in 1040 patients with locally advanced unresectable or metastatic GC/GEJ/EAC.³ The trial is estimated to complete in 2026.

REFERENCES

1. Janjigian YY, Oh DY, Pelster M, et al. Domvanalimab and zimberelimab in advanced gastric, gastroesophageal junction or esophageal cancer: a phase 2 trial. Nat Med. Published online October 18, 2025. doi:10.1038/s41591-025-04022-w

2. A safety and efficacy study of treatment combinations with and without chemotherapy in adult participants with advanced upper gastrointestinal tract malignancies (EDGE-Gastric). ClinicalTrials.gov. Updated October 30, 2025. Accessed November 4, 2025. https://clinicaltrials.gov/study/NCT05329766

3. A clinical trial of a new combination treatment, domvanalimab and zimberelimab, plus chemotherapy, for people with an upper gastrointestinal tract cancer that cannot be removed With Surgery that has spread to other parts of the body (STAR-221). ClinicalTrials.gov. Updated November 3, 2025. Accessed November 4, 2025. https://www.clinicaltrials.gov/study/NCT05568095