肿瘤细胞治疗研究
英文原题：Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced gastric cancer.
Ceralasertib联合durvalumab具有前景良好的抗肿瘤活性，在难治性AGC患者中产生了持久缓解。因此，需要进行生物标志物驱动的试验。
靶向DNA损伤修复（DDR）通路是增强癌症免疫治疗的一种有吸引力的策略。Ceralasertib（AZD6738）是一种口服激酶抑制剂，靶向共济失调毛细血管扩张症和Rad3相关蛋白，后者是DDR的主要调控因子。我们开展了一项ceralasertib联合durvalumab在既往接受过治疗的晚期胃癌（AGC）患者中的II期试验，以证明该联合方案的安全性、耐受性和临床活性。
这项II期、开放标签、单中心、非随机研究旨在评估ceralasertib联合durvalumab在AGC患者中的疗效和安全性。研究药物方案为ceralasertib（240 mg，每日两次）在28天周期的第15-28天联合durvalumab（1500 mg）每4周第1天给药。主要终点为根据实体瘤疗效评价标准（V.1.1）评估的客观缓解率（ORR）。对所有入组患者的新鲜肿瘤活检进行了探索性生物标志物分析。
在31例患者中，ORR为22.6%（95% CI 9.6%至41.1%），疾病控制率为58.1%（95% CI 39.1%至75.5%），中位无进展生存期（PFS）为3.0（95% CI 2.1至3.9）个月，总生存期为6.7（95% CI 3.8至9.6）个月。常见不良事件可通过剂量调整进行管理。在共济失调毛细血管扩张突变（ATM）表达缺失和/或归因于同源重组修复缺陷的突变特征比例较高（sig. HRD）的亚组患者中，其PFS显著长于ATM完整且sig. HRD低的患者（5.60 vs 1.65个月；HR 0.13，95% CI 0.045至0.39；long-rank p<0.001）。在研究治疗期间，在应答者中发现了胞质DNA对先天免疫应答的上调、瘤内淋巴细胞的激活以及循环肿瘤反应性CD8 +T细胞克隆的扩增。肿瘤血管系统特征的富集与治疗耐药相关。
BACKGROUND: Targeting the DNA damage repair (DDR) pathways is an attractive strategy for boosting cancer immunotherapy. Ceralasertib (AZD6738) is an oral kinase inhibitor of ataxia telangiectasia and Rad3 related protein, which is a master regulator of DDR. We conducted a phase II trial of ceralasertib plus durvalumab in patients with previously treated advanced gastric cancer (AGC) to demonstrate the safety, tolerability, and clinical activity of the combination. METHODS: This phase II, open-label, single-center, non-randomized study was designed to evaluate the efficacy and safety of ceralasertib in combination with durvalumab in patients with AGC. The study drug regimen was ceralasertib (240 mg two times a day) days 15-28 in a 28-day cycle in combination with durvalumab (1500 mg) at day 1 every 4 weeks. The primary end point was overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (V.1.1). Exploratory biomarker analysis was performed using fresh tumor biopsies in all enrolled patients. RESULTS: Among 31 patients, the ORR, disease control rate, median progression-free survival (PFS), and overall survival were 22.6% (95% CI 9.6% to 41.1%), 58.1% (95% CI 39.1% to 75.5%), 3.0 (95% CI 2.1 to 3.9) months, and 6.7 (95% CI 3.8 to 9.6) months, respectively. Common adverse events were manageable with dose modification. A subgroup of patients with a loss of ataxia telangiectasia mutated (ATM) expression and/or high proportion of mutational signature attributable to homologous repair deficiency (sig. HRD) demonstrated a significantly longer PFS than those with intact ATM and low sig. HRD (5.60 vs 1.65 months; HR 0.13, 95% CI 0.045 to 0.39; long-rank p<0.001). During the study treatment, upregulation of the innate immune response by cytosolic DNA, activation of intratumoral lymphocytes, and expansion of circulating tumor-reactive CD8 +T cell clones were identified in responders. Enrichment of the tumor vasculature signature was associated with treatment resistance. CONCLUSIONS: Ceralasertib plus durvalumab has promising antitumor activity, with durable responses in patients with refractory AGC. Thus, a biomarker-driven trial is required. TRIAL REGISTRATION: NCT03780608.
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