Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Department of Hematology-Oncology, Ajou University, Suwon, Republic of Korea.
J Immunother Cancer. 2022 Jul;10(7). doi: 10.1136/jitc-2022-005041.
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.
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.
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.
Ceralasertib plus durvalumab has promising antitumor activity, with durable responses in patients with refractory AGC. Thus, a biomarker-driven trial is required.
NCT03780608.
靶向 DNA 损伤修复 (DDR) 途径是提高癌症免疫疗法疗效的一种有吸引力的策略。Ceralasertib (AZD6738) 是一种口服的共济失调毛细血管扩张症和 Rad3 相关蛋白激酶抑制剂，是 DDR 的主要调节剂。我们进行了一项 ceralasertib 联合 durvalumab 治疗既往治疗过的晚期胃癌 (AGC) 患者的 II 期试验，以证明该联合的安全性、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 治疗 AGC 患者的疗效和安全性。研究药物方案为 ceralasertib（每天两次，每次 240mg），每 28 天为一个周期，联合 durvalumab（1500mg），每 4 周一次。主要终点是根据实体瘤反应评价标准（V.1.1）评估的总缓解率（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 名患者中，ORR、疾病控制率、中位无进展生存期（PFS）和总生存期分别为 22.6%（95%CI 9.6%至 41.1%）、58.1%（95%CI 39.1%至 75.5%）、3.0（95%CI 2.1 至 3.9）个月和 6.7（95%CI 3.8 至 9.6）个月。常见的不良反应可通过剂量调整来控制。与 ATM 表达完整且 sig.HRD 低的患者相比，ATR 缺失（ATM）表达缺失和/或同源重组修复缺陷（sig.HRD）归因的高比例突变特征的患者 PFS 明显更长（5.60 个月 vs. 1.65 个月；HR 0.13，95%CI 0.045 至 0.39；长秩 p<0.001）。在研究治疗期间，在应答者中鉴定到细胞质 DNA 引发的固有免疫反应的上调、肿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。肿瘤血管生成特征的富集与治疗耐药相关。
Ceralasertib 联合 durvalumab 具有有前途的抗肿瘤活性，可使难治性 AGC 患者获得持久缓解。因此，需要进行基于生物标志物的试验。
NCT03780608。
