Domvanalimab and zimberelimab in advanced gastric, gastroesophageal junction or esophageal cancer: a phase 2 trial.

IF 50 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Nature Medicine Pub Date : 2025-10-18 DOI:10.1038/s41591-025-04022-w

Yelena Y Janjigian, Do-Youn Oh, Meredith Pelster, Zev A Wainberg, Subhransu Prusty, Sandahl Nelson, Amy DuPage, Amy Thompson, Daniel O Koralek, Edward Allan R Sison, Sun Young Rha

{"title":"Domvanalimab and zimberelimab in advanced gastric, gastroesophageal junction or esophageal cancer: a phase 2 trial.","authors":"Yelena Y Janjigian, Do-Youn Oh, Meredith Pelster, Zev A Wainberg, Subhransu Prusty, Sandahl Nelson, Amy DuPage, Amy Thompson, Daniel O Koralek, Edward Allan R Sison, Sun Young Rha","doi":"10.1038/s41591-025-04022-w","DOIUrl":null,"url":null,"abstract":"<p><p>Dual inhibition of T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and programmed cell death protein 1 (PD-1) may enhance antitumor immunity in advanced gastroesophageal cancers. Here we report the EDGE-Gastric study, an ongoing, multicenter, international, phase 2 study with three cohorts, one in the first-line setting (cohort A) and two in the second-line or greater setting (cohorts B and C). Cohort A comprises four arms: two nonrandomized (A1 and A2) and two randomized (A3 and A4). In arm A1, presented here, dual blockade of TIGIT and PD-1 with domvanalimab (Fc-silent anti-TIGIT) and zimberelimab (anti-PD-1) plus oxaliplatin, leucovorin, fluorouracil (FOLFOX) was evaluated in patients with previously untreated advanced HER2-negative gastric, gastroesophageal junction or esophageal adenocarcinoma. Among 41 treated patients, the confirmed objective response rate was 59% (90% confidence interval (CI) 44.5-71.6%), median progression-free survival was 12.9 months (90% CI 9.8-14.6 months) and median overall survival was 26.7 months (90% CI 18.4 months to not estimable (NE)). In patients with tumor area positivity ≥1% (PD-L1 positive) and tumor area positivity ≥5% (PD-L1 high), respectively, the objective response rate was 62% (90% CI 45.1-77.1%) and 69% (90% CI 45.2-86.8%), median progression-free survival was 13.2 months (90% CI 11.3-15.2 months) and 14.5 months (90% CI 11.3 months-NE), and median overall survival was 26.7 months (90% CI 19.5 months-NE) and not reached (90% CI 17.4 months-NE). Immune-related adverse events were reported in 27% of patients; the safety profile was consistent with that reported for anti-PD-1 plus platinum-based chemotherapy. Dual TIGIT and PD-1 blockade with domvanalimab and zimberelimab plus chemotherapy demonstrated encouraging efficacy, and the regimen is being evaluated in the phase 3 STAR-221 trial. ClinicalTrials.gov identifier: NCT05329766 .</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0000,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41591-025-04022-w","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Dual inhibition of T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and programmed cell death protein 1 (PD-1) may enhance antitumor immunity in advanced gastroesophageal cancers. Here we report the EDGE-Gastric study, an ongoing, multicenter, international, phase 2 study with three cohorts, one in the first-line setting (cohort A) and two in the second-line or greater setting (cohorts B and C). Cohort A comprises four arms: two nonrandomized (A1 and A2) and two randomized (A3 and A4). In arm A1, presented here, dual blockade of TIGIT and PD-1 with domvanalimab (Fc-silent anti-TIGIT) and zimberelimab (anti-PD-1) plus oxaliplatin, leucovorin, fluorouracil (FOLFOX) was evaluated in patients with previously untreated advanced HER2-negative gastric, gastroesophageal junction or esophageal adenocarcinoma. Among 41 treated patients, the confirmed objective response rate was 59% (90% confidence interval (CI) 44.5-71.6%), median progression-free survival was 12.9 months (90% CI 9.8-14.6 months) and median overall survival was 26.7 months (90% CI 18.4 months to not estimable (NE)). In patients with tumor area positivity ≥1% (PD-L1 positive) and tumor area positivity ≥5% (PD-L1 high), respectively, the objective response rate was 62% (90% CI 45.1-77.1%) and 69% (90% CI 45.2-86.8%), median progression-free survival was 13.2 months (90% CI 11.3-15.2 months) and 14.5 months (90% CI 11.3 months-NE), and median overall survival was 26.7 months (90% CI 19.5 months-NE) and not reached (90% CI 17.4 months-NE). Immune-related adverse events were reported in 27% of patients; the safety profile was consistent with that reported for anti-PD-1 plus platinum-based chemotherapy. Dual TIGIT and PD-1 blockade with domvanalimab and zimberelimab plus chemotherapy demonstrated encouraging efficacy, and the regimen is being evaluated in the phase 3 STAR-221 trial. ClinicalTrials.gov identifier: NCT05329766 .

查看原文本刊更多论文

Domvanalimab和zimberelimab治疗晚期胃癌、胃食管交界处或食管癌：2期临床试验

免疫球蛋白和ITIM结构域（TIGIT）和程序性细胞死亡蛋白1 （PD-1）双重抑制T细胞免疫受体可能增强晚期胃食管癌的抗肿瘤免疫。在这里，我们报告了EDGE-Gastric研究，这是一项正在进行的多中心国际2期研究，有三个队列，一个在一线（队列A），两个在二线或更大的环境（队列B和C）。队列A包括四个组：两个非随机组（A1和A2）和两个随机组（A3和A4）。在A1组中，在先前未经治疗的晚期her2阴性胃、胃食管交界处或食管腺癌患者中，评估了domvanalimab （fc沉默抗TIGIT）和zimberelimab（抗PD-1）联合奥沙利铂、亚叶酸钙、氟尿嘧啶（FOLFOX）双重阻断TIGIT和PD-1的效果。在41名接受治疗的患者中，证实的客观缓解率为59%(90%置信区间（CI） 44.5-71.6%)，中位无进展生存期为12.9个月（90% CI 9.8-14.6个月），中位总生存期为26.7个月（90% CI 18.4个月至不可估计（NE））。在肿瘤区域阳性≥1% （PD-L1阳性）和肿瘤区域阳性≥5% （PD-L1高）的患者中，客观缓解率分别为62% （90% CI 45.1-77.1%）和69% (90% CI 45.2-86.8%)，中位无进展生存期为13.2个月（90% CI 11.3-15.2个月）和14.5个月（90% CI 11.3个月- ne），中位总生存期为26.7个月（90% CI 19.5个月- ne），未达到（90% CI 17.4个月- ne）。27%的患者报告了免疫相关不良事件；安全性与报道的抗pd -1加铂基化疗一致。domvanalimab和zimberelimab联合化疗的双重TIGIT和PD-1阻断显示出令人鼓舞的疗效，该方案正在STAR-221期临床试验中进行评估。ClinicalTrials.gov识别码：NCT05329766。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Nature Medicine 医学-生化与分子生物学

CiteScore

100.90

自引率

0.70%

发文量

525

审稿时长

1 months

期刊介绍： Nature Medicine is a monthly journal publishing original peer-reviewed research in all areas of medicine. The publication focuses on originality, timeliness, interdisciplinary interest, and the impact on improving human health. In addition to research articles, Nature Medicine also publishes commissioned content such as News, Reviews, and Perspectives. This content aims to provide context for the latest advances in translational and clinical research, reaching a wide audience of M.D. and Ph.D. readers. All editorial decisions for the journal are made by a team of full-time professional editors. Nature Medicine consider all types of clinical research, including: -Case-reports and small case series -Clinical trials, whether phase 1, 2, 3 or 4 -Observational studies -Meta-analyses -Biomarker studies -Public and global health studies Nature Medicine is also committed to facilitating communication between translational and clinical researchers. As such, we consider “hybrid” studies with preclinical and translational findings reported alongside data from clinical studies.