要点
01
Ⅱ期EDGE-Gastric试验正在评估晚期胃食管癌患者的几种新型免疫治疗方案，其中一些方案同时抑制PD-1和TIGIT。
02
初步数据显示，接受PD-1*制剂抑**zimberelimab联合TIGIT*制剂抑**domvanalimab和FOLFOX一线治疗的晚期胃食管癌患者的客观缓解率（ORR）为59%和6个月无进展生存率（PFS）为77%，在PD-L1高表达的患者中，疗效更佳。
03
zimberelimab联合domvanalimab和化疗的Ⅲ期试验正在进行，可能成为胃食管癌的新标准治疗。
正在进行的Ⅱ期EDGE-Gastric试验的最新数据表明，在局部晚期不可切除或转移性胃食管癌患者一线治疗中，同时抑制PD-1和TIGIT联合化疗可在相当大比例的患者中产生抗肿瘤活性。41例可评估患者的数据显示，zimberelimab（PD-1单抗）联合domvanalimab（TIGIT单抗）和FOLFOX组的ORR为59%，6个月PFS率为77%。
目前，PD-1*制剂抑**联合化疗是胃食管癌一线标准治疗。这项研究探索了PD-1*制剂抑**联合TIGIT*制剂抑**和化疗的疗效，并显示出有希望的PFS和ORR，耶鲁大学医学博士Pamela Kunz评论道。与低表达（定义为肿瘤面积阳性＜5%）的患者相比，PD-L1高表达（≥5%）的患者的结果似乎更有利。PD-L1高组和PD-L1低组的ORR分别为80%和46%，6个月PFS分别为93%和68%。
“这项Ⅱ期研究的初步结果表明，与历史对照组相比，早期疗效令人鼓舞，特别是在PD-L1高表达的患者中。然而，进一步随访将评估长期疗效，如PFS和总生存期（OS），”纪念斯隆凯特琳癌症中心的首席研究员Yelena Y. Janjigian医学博士说，他在11月ASCO全体系列会议上汇报了EDGE-Gastric数据。将domvanalimab加入zimberelimab和FOLFOX似乎耐受性相对较好，缓解了对同时使用这两种免疫疗法的潜在担忧。“这种新组合的安全性与PD-1单抗联合化疗相似，”Janjigian博士说。总之，最常见的治疗不良事件（TEAEs）包括中性粒细胞减少症（59%）、恶心（54%）和贫血（27%）。68%的患者发生≥3级TEAEs, 24%的患者发生严重TEAEs。无TEAEs相关死亡。
EDGE-Gastric试验原理
EDGE-Gastric试验（NCT05329766）正在评估几种以zimberelimab联合或不联合domvanalimab治疗局部晚期不可切除或转移性胃、胃食管交界处和食管腺癌患者的新治疗组合。Janjigian博士目前公布的结果代表了该试验A1组的结果，患者一线治疗时每4周接受一次zimberelimab和domvanalimab，每2周接受一次FOLFOX。
“在一线化疗中加入PD -1*制剂抑**改变了这一领域的治疗格局，成为转移性胃食管癌患者的标准治疗。尽管患者最初对治疗敏感，但会逐渐出现耐药，大多数患者仍然将死于胃食管癌。我们正在努力进一步改善这些患者的预后，”Janjigian博士解释说。
同时抑制TIGIT和PD-1有可能比单独抑制PD-1进一步加强免疫系统攻击胃食管肿瘤细胞。与PD-1一样，TIGIT也是一种免疫抑制检查点受体，在多种淋巴细胞上表达，包括肿瘤浸润性细胞毒性T细胞、调节性T细胞和自然*伤杀**细胞。然而，PD-1和TIGIT通过不重叠的机制独立抑制抗肿瘤免疫反应，成为两个有吸引力的治疗靶点。事实上，先前的研究表明，同时阻断PD-1和TIGIT会增加肿瘤抗原特异性CD8+T细胞的扩增，从而产生有效的抗肿瘤活性[1]。
展望未来
EDGE-Gastric试验的结果虽然令人鼓舞，但目前还不足以改变临床实践。一项正在进行的随机、开放标签的Ⅲ期STAR-221 （NCT05568095）临床试验，比较了zimberelimab联合domvanalimab和化疗与nivolumab联合化疗一线治疗局部晚期不可切除或转移性胃、胃食管交界处和食管腺癌患者的有效性和安全性。
而且，还有多项研究正在探索抗PD-1联合抗TIGIT治疗胃食管癌的有效性和安全性。最值得注意的是，正在探索atezolizumab、tiragolumab和XELOX一线治疗HER2阴性、不可切除、复发或转移性胃癌或胃食管交界腺癌的有效性和安全性的Ⅱ期试验（NCT04933227）。另一项Ⅱ期试验正在评估AZD2936（PD-1和TIGIT双特异性抗体）联合FOLFOX或XELOX一线治疗HER2阴性不可切除或转移性胃或胃食管交界腺癌（NCT05702229）患者的有效性和安全性。
摘要原文
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EDGE-Gastric Arm A1: Phase 2 study of domvanalimab, zimberelimab, and FOLFOX in first-line (1L) advanced gastroesophageal cancer
Background
The addition of programmed cell death protein 1 (PD-1) inhibitors to chemotherapy (chemo) confers a survival advantage in 1L gastroesophageal cancers. However, long term outcomes remain poor. Dual PD-1 and anti-T-cell immunoglobulin and ITM domain (TIGIT) blockade increases tumor antigen-specific CD8+ T cell expansion, resulting in potent antitumor activity.
The ongoing, multi-arm, global EDGE-Gastric trial (NCT05329766) is evaluating the safety and efficacy of various combinations of the anti-TIGIT Fc-silent monoclonal antibody (mAb) domvanalimab (D) and the anti-PD-1 mAb zimberelimab (Z) in patients (pts) with locally advanced unresectable or metastatic gastric (G)/gastroesophageal junction (GEJ)/esophageal (E) adenocarcinoma. Arm A1 is fully enrolled and results from this 1L arm are presented here.
Methods
Patients with previously untreated G/GEJ/E adenocarcinoma received D 1600 mg intravenously (IV) every 4 weeks (Q4W) + Z 480 mg IV Q4W + FOLFOX (oxaliplatin 85 mg/m2 IV, leucovorin 400 mg/m2 IV, fluorouracil 400 mg/m2 IV bolus + 2400 mg/m2 continuous 46-48-hour IV infusion) Q2W. Primary endpoints are safety and objective response rate (ORR) per RECIST 1.1. Secondary endpoints include ORR by PD-L1 expression and PFS.
Results
As of the data cutoff (5 June 2023), 41 pts were enrolled and had the opportunity to have ≥2 imaging assessments. There was an even distribution of pts accrued in Asia vs. rest of world and 63% of pts had gastric cancer. Median time on treatment was 23 weeks (1 to 40), 31 pts (76%) continue on protocol therapy, and there were no deaths on study. Intent-to-treat ORR was 59% (95% CI 42 to 74). Clinical outcomes by PD-L1 status are in the Table. The most common treatment-emergent adverse events (TEAE) were neutropenia (56% of pts), nausea (54%), and anemia (27%).
Infusion related reactions were observed in 10% and none were deemed related to D/Z. Grade ≥3 TEAEs occurred in 66% pts, with 54% and 12% having grade ≥3 TEAEs related to FOLFOX and D/Z, respectively. Serious TEAEs occurred in 24% pts: 7% had serious TEAEs related to FOLFOX and no pts had serious TEAEs related to D/Z. TEAE related FOLFOX discontinuation occurred in 13 pts (32%), and in 1 pt due to D/Z.
Conclusions
Addition of DZ to FOLFOX showed encouraging ORR and early PFS, particularly in pts with PD-L1-high tumors. The regimen is well tolerated, with a similar AE profile to anti-PD-1+FOLFOX. Updated safety and efficacy will be presented. The randomized phase 3 1L STAR-221 trial of DZ+chemo vs. SOC is underway. Clinical trial information: NCT05329766.
参考文献
[1] CHU X, TIAN W, WANG Z, et al. Co-inhibition of TIGIT and PD-1/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials [J]. Mol Cancer, 2023, 22(1): 93.