The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.
Clin Cancer Res. 2020 Feb 15;26(4):846-854. doi: 10.1158/1078-0432.CCR-19-2443. Epub 2019 Nov 1.
PURPOSE: This randomized, multicenter, open-label, phase Ib/II study assessed durvalumab and tremelimumab in combination or as monotherapy for chemotherapy-refractory gastric cancer or gastroesophageal junction (GEJ) cancer. PATIENTS AND METHODS: Second-line patients were randomized 2:2:1 to receive durvalumab plus tremelimumab (arm A), or durvalumab (arm B) or tremelimumab monotherapy (arm C), and third-line patients received durvalumab plus tremelimumab (arm D). A tumor-based IFNγ gene signature was prospectively evaluated as a potential predictive biomarker in second- and third-line patients receiving the combination (arm E). The coprimary endpoints were objective response rate and progression-free survival (PFS) rate at 6 months. RESULTS: A total of 113 patients were treated: 6 in phase Ib and 107 (arm A, 27; arm B, 24; arm C, 12; arm D, 25; arm E, 19) in phase II. Overall response rates were 7.4%, 0%, 8.3%, 4.0%, and 15.8% in the five arms, respectively. PFS rates at 6 months were 6.1%, 0%, 20%, 15%, and 0%, and 12-month overall survival rates were 37.0%, 4.6%, 22.9%, 38.8%, and NA, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 4%, 42%, 16%, and 11% of patients, respectively. CONCLUSIONS: Response rates were low regardless of monotherapy or combination strategies. No new safety signals were identified. Including use of a tumor-based IFNγ signature and change in baseline and on-treatment circulating tumor DNA are clinically feasible and may be novel strategies to improve treatment response in this difficult-to-treat population.
目的：本随机、多中心、开放性、Ib/II 期研究评估了度伐利尤单抗联合或单药治疗化疗耐药性胃癌或胃食管结合部（GEJ）癌的疗效。
方法：二线患者以 2:2:1 的比例随机分配接受度伐利尤单抗联合 Tremelimumab（A 组）、度伐利尤单抗（B 组）或 Tremelimumab 单药治疗（C 组），三线患者接受度伐利尤单抗联合 Tremelimumab（D 组）治疗。二线和三线接受联合治疗（E 组）的患者前瞻性评估了肿瘤 IFNγ 基因特征作为潜在的预测生物标志物。主要终点是 6 个月时的客观缓解率和无进展生存期（PFS）率。
结果：共治疗 113 例患者：Ib 期 6 例，II 期 107 例（A 组 27 例，B 组 24 例，C 组 12 例，D 组 25 例，E 组 19 例）。5 个治疗组的总缓解率分别为 7.4%、0%、8.3%、4.0%和 15.8%。6 个月时的 PFS 率分别为 6.1%、0%、20%、15%和 0%，12 个月的总生存率分别为 37.0%、4.6%、22.9%、38.8%和无法评估。分别有 17%、4%、42%、16%和 11%的患者发生与治疗相关的 3/4 级不良事件。
结论：无论采用单药还是联合治疗策略，缓解率均较低。未发现新的安全性信号。包括使用肿瘤 IFNγ 特征和基线及治疗中循环肿瘤 DNA 的变化是临床可行的，可能是改善这一难治性人群治疗反应的新策略。
Clin Pharmacol. 2025-7-23
Front Immunol. 2025-2-14
Zotero 插件