Division of Hematology-Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea.
Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
Clin Cancer Res. 2021 Sep 1;27(17):4700-4709. doi: 10.1158/1078-0432.CCR-21-0251. Epub 2021 May 11.
Ceralasertib is a potent and selective oral inhibitor of the serine/threonine protein kinase ataxia telangiectasia and Rad3-related (ATR) protein.
Eligible patients with solid tumors, enriched for melanoma, received ceralasertib in combination with a fixed dose of paclitaxel (80 mg/m on D1, D8, D15) in 28-day cycles. The dose of ceralasertib was escalated to reach an MTD in a rolling 6 design. The starting dose of ceralasertib was 40 mg QD. Fifty-seven patients (33 patients with melanoma who failed prior PD1/L1 treatment) were enrolled in 7 dose cohorts ranging from 40 mg QD to 240 mg BD plus weekly paclitaxel.
The RP2D was established as ceralasertib 240 mg BD days 1-14 plus paclitaxel 80 mg/m on D1, D8, D15 every 28 days. The most common toxicities were neutropenia ( = 39, 68%), anemia ( = 25, 44%), and thrombocytopenia ( = 21, 37%). In the full analysis set of 57 patients, the overall response rate (ORR) was 22.6% (95% CI, 12.5-35.3). In 33 patients with melanoma, resistant to prior anti-PD1 therapy, the ORR was 33.3% (95% CI, 18.0-51.8). In the melanoma subset, the mPFS was 3.6 months (95% CI, 2.0-5.8), the median duration of response was 9.9 months (95% CI, 3.7-23.2), and the mOS was 7.4 months (95% CI, 5.7-11.9).
Ceralasertib in combination with paclitaxel was well tolerated in patients with advanced malignancies and showed evidence of antitumor activity. Durable responses were observed in patients with advanced cutaneous, acral, and mucosal melanoma resistant to anti-PD1/L1 treatment..
Ceralasertib 是一种有效的、选择性的丝氨酸/苏氨酸蛋白激酶共济失调毛细血管扩张症和 Rad3 相关蛋白（ATR）的口服抑制剂。
入选标准为患有实体瘤的患者，包括黑色素瘤，在 28 天的周期内接受 ceralasertib 联合固定剂量紫杉醇（第 1、8、15 天 80mg/m）治疗。ceralasertib 的剂量以滚动 6 设计递增至达到最大耐受剂量（MTD）。ceralasertib 的起始剂量为 40mg QD。7 个剂量组共招募了 57 名患者（33 名接受过 PD1/L1 治疗失败的黑色素瘤患者），剂量范围为 40mg QD 至 240mg BD 加每周紫杉醇。
确定 ceralasertib 240mg BD 每天 1-14 天加紫杉醇 80mg/m 于第 1、8、15 天，每 28 天 1 次为 RP2D。最常见的毒性反应为中性粒细胞减少症（ = 39，68%）、贫血（ = 25，44%）和血小板减少症（ = 21，37%）。在 57 例患者的全分析集（FAS）中，总缓解率（ORR）为 22.6%（95%CI，12.5-35.3）。在 33 名对先前抗 PD1 治疗耐药的黑色素瘤患者中，ORR 为 33.3%（95%CI，18.0-51.8）。在黑色素瘤亚组中，中位无进展生存期（mPFS）为 3.6 个月（95%CI，2.0-5.8），中位缓解持续时间为 9.9 个月（95%CI，3.7-23.2），中位总生存期（mOS）为 7.4 个月（95%CI，5.7-11.9）。
Ceralasertib 联合紫杉醇在晚期恶性肿瘤患者中耐受性良好，表现出抗肿瘤活性。在对 PD1/L1 治疗耐药的晚期皮肤、肢端和粘膜黑色素瘤患者中观察到持久的反应。
