Qiu Miao-Zhen, Bai Yuxian, Wang Jufeng, Gu Kangsheng, Yang Mudan, He Yifu, Yi Cheng, Jin Yongdong, Liu Bo, Wang Feng, Chen Yu-Kun, Dai Wei, Jiang Yingyi, Huang Chuanpei, Xu Rui-Hua, Luo Hui-Yan
Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China.
Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, PR China.
Signal Transduct Target Ther. 2024 Dec 16;9(1):349. doi: 10.1038/s41392-024-02063-0.
This phase 2/3 trial (NCT04856787) assessed the efficacy and safety of SHR-1701, a bifunctional protein targeting PD-L1 and TGF-β, in combination with BP102 (a bevacizumab biosimilar) and XELOX (capecitabine plus oxaliplatin) as a first-line treatment for unresectable metastatic colorectal cancer (mCRC). In this phase 2 study, a total of 62 patients with untreated, histologically confirmed colorectal adenocarcinoma and no prior systemic therapy for metastatic disease were enrolled. Patients received SHR-1701 (30 mg/kg), bevacizumab (7.5 mg/kg), and oxaliplatin (130 mg/m) intravenously on day 1, along with oral capecitabine (1 g/m twice daily) on days 1-14 of 21-day cycles. Up to eight induction cycles were administered, followed by maintenance therapy for responders or those with stable disease. The primary endpoints were safety and objective response rate (ORR) per RECIST v1.1. The combination achieved an ORR of 59.7% and a disease control rate (DCR) of 83.9%. Median progression-free survival (PFS) was 10.3 months (95% CI: 8.3-13.7), with 6- and 12-month PFS rates of 77.2% and 41.3%, respectively. The estimated 12-month overall survival (OS) rate was 67.7%. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 59.7% of patients, with anemia and neutropenia (8.1% each) being the most common. Retrospective DNA sequencing revealed that high tumor mutational burden, neo-antigens, and SBS15 enrichment correlated with better responses. Elevated baseline lactate dehydrogenase was linked to shorter PFS. SHR-1701 combined with XELOX and bevacizumab demonstrated a manageable safety profile and potent antitumor activity in unresectable mCRC.
这项2/3期试验（NCT04856787）评估了双功能蛋白SHR-1701（靶向程序性死亡受体配体1（PD-L1）和转化生长因子-β（TGF-β））联合BP102（贝伐珠单抗生物类似药）和XELOX（卡培他滨加奥沙利铂）作为不可切除转移性结直肠癌（mCRC）一线治疗的疗效和安全性。在这项2期研究中，总共纳入了62例未经治疗、经组织学确诊为结肠腺癌且既往未接受过转移性疾病全身治疗的患者。患者在第1天静脉注射SHR-1701（30mg/kg）、贝伐珠单抗（7.5mg/kg）和奥沙利铂（130mg/m²），并在21天周期的第1 - 14天口服卡培他滨（1g/m²，每日两次）。最多给予8个诱导周期，随后对缓解者或病情稳定者进行维持治疗。主要终点是根据实体瘤疗效评价标准（RECIST）v1.1的安全性和客观缓解率（ORR）。该联合方案的ORR为59.7%，疾病控制率（DCR）为83.9%。中位无进展生存期（PFS）为10.3个月（95%置信区间：8.3 - 13.7），6个月和12个月的PFS率分别为77.2%和41.3%。估计12个月总生存率（OS）为67.7%。59.7%的患者报告了≥3级治疗相关不良事件（TRAEs），最常见的是贫血和中性粒细胞减少（各8.1%）。回顾性DNA测序显示，高肿瘤突变负担、新抗原和SBS15富集与更好的反应相关。基线乳酸脱氢酶升高与较短的PFS相关。SHR-1701联合XELOX和贝伐珠单抗在不可切除的mCRC中显示出可控的安全性和强大的抗肿瘤活性。
