Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
Front Immunol. 2024 Oct 9;15:1450533. doi: 10.3389/fimmu.2024.1450533. eCollection 2024.
The third-line treatment for refractory colorectal cancer (CRC) has limited efficacy. This study aimed to evaluate the safety and efficacy of SHR-8068 (an anti-CTLA-4 antibody), combined with adebrelimab (an anti-PD-L1 antibody), and bevacizumab in refractory non-microsatellite instability-high (MSI-H) or proficient mismatch repair (pMMR) CRC.
This study is a prospective, open-label, single-center phase Ib/II clinical trial. Patients with pathologically confirmed pMMR/non-MSI-H metastatic colorectal adenocarcinoma who have failed ≥2 lines prior standard systemic treatments will be enrolled (n=36). The Ib phase will evaluate two dosing regimens of SHR-8068 in combination therapy (n=9 each dosage): SHR-8068 (1 mg per kilogram, every six weeks, intravenously) or SHR-8068 (4 mg per kilogram, every twelve weeks, intravenously) combined with adebrelimab (1200 mg, every three weeks, intravenously) and bevacizumab (7.5 mg per kilogram, every three weeks, intravenously). The efficacy and adverse events (AEs) of these regimens will be assessed to determine the recommended phase II dose (RP2D) of SHR-8068. Those of RP2D group from the phase Ib will be included in the phase II. The study will go to include 18 additional patients according to the one-sample log-rank test design in the phase II. The primary endpoint of the Ib phase is safety, with secondary endpoints including the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and quality of life (QOL). The primary endpoint for phase II was PFS, with secondary endpoints including ORR, OS, DCR, safety, and QOL. Identifying biomarkers to predict the efficacy of this regimen is the exploratory study endpoint.
This proof-of-concept study would provide safety and efficacy signals of this novel combination treatment for the MSS CRCs in the late-line setting. And it may offer new insights on the clinical application of dual immunotherapy combined with anti-angiogenic therapy in the MSS CRC.
难治性结直肠癌（CRC）的三线治疗疗效有限。本研究旨在评估 SHR-8068（一种抗 CTLA-4 抗体）联合 adebrelimab（一种抗 PD-L1 抗体）和贝伐珠单抗治疗难治性非微卫星不稳定高（MSI-H）或 proficient mismatch repair（pMMR）CRC 的安全性和疗效。
这是一项前瞻性、开放标签、单中心的 Ib/II 期临床研究。招募经病理证实为 pMMR/非 MSI-H 转移性结直肠腺癌且既往标准系统治疗失败≥2 线的患者（n=36）。Ib 期将评估 SHR-8068 联合治疗的两种剂量方案（n=9 例/剂量）：SHR-8068（1 毫克/千克，每六周静脉注射一次）或 SHR-8068（4 毫克/千克，每 12 周静脉注射一次）联合 adebrelimab（1200 毫克，每三周静脉注射一次）和贝伐珠单抗（7.5 毫克/千克，每三周静脉注射一次）。评估这些方案的疗效和不良事件（AE），以确定 SHR-8068 的推荐 II 期剂量（RP2D）。Ib 期 RP2D 组的患者将纳入 II 期。根据 II 期的单样本对数秩检验设计，将额外纳入 18 名患者。Ib 期的主要终点是安全性，次要终点包括客观缓解率（ORR）、无进展生存期（PFS）、总生存期（OS）、疾病控制率（DCR）和生活质量（QOL）。II 期的主要终点是 PFS，次要终点包括 ORR、OS、DCR、安全性和 QOL。确定预测该方案疗效的生物标志物是探索性研究终点。
这项概念验证研究将为晚期 MSS CRC 患者提供这种新型联合治疗的安全性和疗效信号，并可能为 MSS CRC 中双重免疫治疗联合抗血管生成治疗的临床应用提供新的见解。
