多塔利单抗治疗晚期或复发性 DNA 错配修复缺陷/微卫星不稳定高（dMMR/MSI-H）或 proficient/stable（MMRp/MSS）子宫内膜癌患者的安全性和抗肿瘤活性：GARNET 研究的初步结果，一项 I 期单臂研究。
Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study.
机构信息
Gynaecologic Cancer Programme, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
Department of Gynecologic Oncology, McGill University Health Centre Research Institute, Montreal, Quebec, Canada.
出版信息
J Immunother Cancer. 2022 Jan;10(1). doi: 10.1136/jitc-2021-003777.
BACKGROUND
Dostarlimab is a humanized monoclonal antibody that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L1 and PD-L2. We report interim data from patients with endometrial cancer (EC) participating in a phase I trial of single-agent dostarlimab.
METHODS
GARNET, an ongoing, single-arm, open-label, phase I trial of intravenous dostarlimab in advanced solid tumors, is being undertaken at 123 sites. Two cohorts of patients with EC were recruited: those with dMMR/MSI-H disease (cohort A1) and those with proficient/stable (MMRp/MSS) disease (cohort A2). Patients received dostarlimab 500 mg every 3 weeks for 4 cycles, then dostarlimab 1000 mg every 6 weeks until disease progression. The primary endpoints were objective response rate (ORR) and duration of response (DOR) per RECIST V.1.1, as assessed by blinded independent central review.
RESULTS
Screening began on April 10, 2017, and 129 and 161 patients with advanced EC were enrolled in cohorts A1 and A2, respectively. The median follow-up duration was 16.3 months (IQR 9.5-22.1) for cohort A1 and 11.5 months (IQR 11.0-25.1) for cohort A2. In cohort A1, ORR was 43.5% (95% CI 34.0% to 53.4%) with 11 complete responses and 36 partial responses. In cohort A2, ORR was 14.1% (95% CI 9.1% to 20.6%) with three complete responses and 19 partial responses. Median DOR was not reached in either cohort. In the combined cohorts, the majority of treatment-related adverse events (TRAEs) were grade 1-2 (75.5%), most commonly fatigue (17.6%), diarrhea (13.8%), and nausea (13.8%). Grade≥3 TRAEs occurred in 16.6% of patients, and 5.5% discontinued dostarlimab because of TRAEs. No deaths were attributable to dostarlimab.
CONCLUSION
Dostarlimab demonstrated durable antitumor activity in both dMMR/MSI-H (ORR 43.5%) and MMRp/MSS EC (ORR 14.1%) with a manageable safety profile.
TRIAL REGISTRATION NUMBER
NCT02715284.
背景
Dostarlimab 是一种与人源化的单克隆抗体，与 PD-1 具有高亲和力，导致与 PD-L1 和 PD-L2 的结合受到抑制。我们报告了参与单药 dostarlimab Ⅰ期试验的子宫内膜癌（EC）患者的中期数据。
方法
GARNET 是一项正在进行的、单臂、开放标签、Ⅰ期静脉 dostarlimab 治疗晚期实体瘤的试验，在 123 个地点进行。招募了两批 EC 患者：一组为 dMMR/MSI-H 疾病（A1 队列），另一组为 proficient/stable（MMRp/MSS）疾病（A2 队列）。患者每 3 周接受 dostarlimab 500mg 治疗 4 个周期，然后每 6 周接受 dostarlimab 1000mg 治疗，直到疾病进展。主要终点是根据 RECIST V.1.1 评估的盲法独立中心审查的客观缓解率（ORR）和缓解持续时间（DOR）。
结果
筛选于 2017 年 4 月 10 日开始，分别有 129 名和 161 名晚期 EC 患者入组 A1 队列和 A2 队列。A1 队列的中位随访时间为 16.3 个月（IQR 9.5-22.1），A2 队列为 11.5 个月（IQR 11.0-25.1）。A1 队列的 ORR 为 43.5%（95%CI 34.0%至 53.4%），其中 11 例完全缓解，36 例部分缓解。A2 队列的 ORR 为 14.1%（95%CI 9.1%至 20.6%），其中 3 例完全缓解，19 例部分缓解。在两个队列中，中位 DOR 均未达到。在联合队列中，大多数与治疗相关的不良事件（TRAEs）为 1-2 级（75.5%），最常见的是疲劳（17.6%）、腹泻（13.8%）和恶心（13.8%）。3 级及以上 TRAE 发生率为 16.6%，5.5%的患者因 TRAE 而停止 dostarlimab 治疗。无死亡与 dostarlimab 有关。
结论
Dostarlimab 在 dMMR/MSI-H（ORR 43.5%）和 MMRp/MSS EC（ORR 14.1%）中均表现出持久的抗肿瘤活性，安全性可管理。
试验注册号
NCT02715284。
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