Phase 3 STAR-221 Study of First-Line Domvanalimab/Zimberelimab Plus Chemo in Upper GI Cancers to Be Discontinued

The phase 3 STAR-221 study (NCT05568095) evaluating the anti-TIGIT antibody domvanalimab in combination with the anti–PD-1 antibody zimberelimab and chemotherapy as a first-line treatment for patients with advanced gastric and esophageal cancers is being discontinued due to futility, following a recommendation from the study’s independent data monitoring committee.¹

The committee’s recommendation followed a review of data from a prespecified interim analysis of overall survival (OS) of STAR-221, at which time the domvanalimab-based combination did not improve OS compared with nivolumab (Opdivo) plus chemotherapy. The regimen’s safety profile was comparable to that of nivolumab plus chemotherapy, and no new safety data were identified.

“Patients in the domvanalimab-containing arm derived the same benefit as patients treated in the control arm, and there were no new safety concerns,” Richard Markus, MD, chief medical officer of Arcus Biosciences, stated in a news release. “We are disappointed with this outcome and sincerely thank all those who participated in the study and made this research possible. We remain committed to advancing research for people living with cancer and immune-related diseases.”

In addition to STAR-221, the ongoing, multi-arm, global phase 2 EDGE-Gastric study (NCT05329766) evaluating the safety and efficacy of various domvanalimab-based and zimberelimab-based combinations in locally advanced unresectable or metastatic gastric, gastroesophageal junction (GEJ), or esophageal adenocarcinoma, will also be discontinued.^1,2

Arcus Biosciences and Gilead Sciences, the co-developers of domvanalimab, are currently in communication with study investigators to determine appropriate next steps for patients in the study. A detailed analysis will be conducted to further clarify these results.

“The results from STAR-221 are not what we had hoped for, and we have important work ahead to meet the needs of patients on our domvanalimab studies and also accelerate the casdatifan [AB521] and inflammation and immunology programs,” Terry Rosen, chief executive officer of Arcus, added in a news release.¹ “We are fortunate to be well capitalized and plan to focus our resources on casdatifan, including studying new early-line combinations in kidney cancer, broadening its development into new tumor types, and extending our capabilities beyond oncology.”

What prior data were reported with domvanalimab plus zimberelimab and chemotherapy in EDGE-Gastric?

Arm A1 of EDGE-Gastric enrolled treatment-naive patients with locally advanced unresectable or metastatic gastric, GEJ, or esophageal adenocarcinoma.^2,3 All patients received 1600 mg of domvanalimab and 480 mg of zimberelimab intravenously every 4 weeks, plus chemotherapy every 2 weeks, until disease progression or unacceptable toxicity.

The study’s coprimary end points were investigator-assessed overall response rate (ORR) and safety.³ Secondary end points included OS, progression-free survival (PFS), disease control rate, and duration of response (DOR) in both the overall patient population and in PD-L1 expression subgroups.

First OS results and updated efficacy findings from arm 1 of EDGE-Gastric were presented during the 2025 ESMO Congress.² At the data cutoff of March 3, 2025, and a median follow-up of 26.4 months, domvanalimab plus zimberelimab and chemotherapy produced a median OS of 26.7 months (90% CI, 18.4-not evaluable) and a median PFS of 12.9 months (90% CI, 9.8-14.6) in the overall patient population (n = 41). The confirmed ORR per RECIST 1.1 criteria was 59% (90% CI, 45%-72%). No unexpected safety signals were observed at the time of data cutoff, and the regimen was generally well tolerated.

Results from EDGE-Gastric supported the ongoing development of this regimen in STAR-221.

What was the design of STAR-221?

STAR-221 was a global, randomized, open-label, phase 3 trial evaluating domvanalimab plus zimberelimab and chemotherapy vs nivolumab plus chemotherapy as frontline therapy for patients with locally advanced, unresectable or metastatic HER2-negative gastric, GEJ, and esophageal adenocarcinomas.² The study enrolled 1,040 patients from approximately 30 countries.

Patients were randomly assigned 1:1 to one of 2 treatment arms: 1600 mg of IV domvanalimab plus 480mg of zimberelimab IV every 4 weeks and FOLFOX (oxaliplatin, leucovorin, fluorouracil) every 2 weeks, or 1200 mg of domvanalimab plus 360 mg of zimberelimab every 3 weeks and CAPOX (capecitabine and oxaliplatin) every 3 weeks; vs 240mg of nivolumab IV and FOLFOX every 2 weeks, or 360 mg of nivolumab plus CAPOX every 3 weeks.

The study’s primary end points were OS in PD-L1–high tumors, PD-L1–positive tumors, and in the intention-to-treat population. PFS, ORR, DOR, safety, and patient-reported outcomes all served as secondary end points.

References

1. Arcus provides update on phase 3 STAR-221 study and concentrates its R&D investment on casdatifan and emerging inflammation and immunology portfolio. News release. Coherus. December 12, 2025. Accessed December 12, 2025. https://investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2025/Arcus-Provides-Update-on-Phase-3-STAR-221-Study-and-Concentrates-Its-RD-Investment-on-Casdatifan-and-Emerging-Inflammation-and-Immunology-Portfolio/default.aspx
2. Anti-TIGIT domvanalimab plus anti-PD-1 zimberelimab and chemotherapy showed 26.7 months of median overall survival as first-line treatment of unresectable or advanced gastroesophageal adenocarcinomas in the phase 2 EDGE-Gastric study. News Release. Arcus Biosciences. October 12, 2025. December 12, 2025. https://investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2025/Anti-TIGIT-Domvanalimab-Plus-Anti-PD-1-Zimberelimab-and-Chemotherapy-Showed-26-7-Months-of-Median-Overall-Survival-as-First-Line-Treatment-of-Unresectable-or-Advanced-Gastroesophageal-Adenocarcinomas-in-the-Phase-2-EDGE-Gastric-Study/default.aspx
3. Janjigian YY, Oh DY, Pelster M, Wainberg ZA, Prusty S, Nelson S, DuPage A, Thompson A, Koralek DO, Sison EAR, Rha SY. Domvanalimab and zimberelimab in advanced gastric, gastroesophageal junction or esophageal cancer: a phase 2 trial. Nat Med.(2025). doi: 10.1038/s41591-025-04022-w.