背景：目前标准的晚期或转移性食管鳞癌的一线治疗是双重化疗，预后仍然很差。Camrelizumab是一种人源化抗 D-1 单克隆抗体，在先前治疗的晚期或转移性 ESCC 中显示出良好的抗肿瘤活性（Huang et al。柳叶刀 Oncol 2019）。免疫治疗可能与化疗有协同作用，但对 ESCC 缺乏临床证据。在此，我们报告了第 3-1 期研究的结果，该研究评估了卡美瑞珠单抗联合化疗与化疗对未经治疗的晚期或转移性食管鳞癌患者的疗效和安全性。

Background: The current standard first-line therapy for advanced or metastatic ESCC is doublet chemotherapy, and prognosis remains poor. Camrelizumab, a humanized anti-PD-1 monoclonal antibody, has shown promising antitumor activity in previously treated advanced or metastatic ESCC (Huang et al. Lancet Oncol 2019). Immunotherapy may work synergistically with chemotherapy, but lacking clinical evidences in ESCC. Here, we report the findings of the phase 3 ESCORT-1st study which evaluated the efficacy and safety of camrelizumab plus chemotherapy vs chemotherapy in patients with untreated advanced or metastatic ESCC.

方法：符合条件的患者按 1:1 随机分为 Camrelizumab 200mg 组和安慰剂组，两组均联合紫杉醇（175mg/m）和顺铂（75mg/m）6 个疗程，均给予 Q3W 静脉注射。根据 RECIST v1.1 每 6 周评估一次肿瘤反应。联合主 要终点：在所有随机患者中评估 OS 和独立审查委员会（IRC）评估的 PFS 疗效，在所有治疗患者中评估安全性。预先指定的中期 OS 和最终 PFS 分析的数据截止日期为 2020 年 10 月 30 日。

Methods: Eligible patients were randomized 1:1 to receive camrelizumab 200 mg or placebo, both combined with up to 6 cycles of paclitaxel (175 mg/m2) and cisplatin (75 mg/m2). All were given intravenously Q3W. Tumor response was assessed every 6 weeks according to RECIST v1.1. Co-primary endpoints were OS and independent review committee (IRC)-assessed PFS. Efficacy was assessed in all randomized patients and safety was assessed in all treated patients. Data cutoff date for the prespecified interim OS and final PFS analysis was Oct 30, 2020.

结果：2018年12月3日至2020年5月12日，共随机抽取596例患者。298例接受camrelizumb化疗，297例接受安慰剂化疗。中位随访时间为10.8个月，与安慰剂加化疗相比，卡美瑞珠单抗加化疗显著改善OS（中位，15.3个月[95%CI 12.8-17.3]vs 12.0个月[11.0-13.3]；心率，0.70[95%CI，0.56-0.88]；单侧P=0.0010）。Camrelizumab加化疗对PFS（每个IRC）和安慰剂加化疗也有优势（中位数，6.9个月[95%CI，5.8-7.4]和5.6个月[95%CI，5.5-5.7]；心率，0.56[95%CI，0.46-0.68]；单侧P<0.0001）。卡美瑞珠单抗化疗组每位研究者的ORR为72.1%，安慰剂化疗组为62.1%，DoR中位数为7.0 vs 4.6个月。等级发生率≥两组中有3例治疗相关不良事件具有可比性（63.4%对67.7%），其中中性粒细胞计数减少（39.9%对43.4%）是最常见的不良事件。严重治疗相关不良事件发生率分别为30.2%和23.2%，治疗相关死亡发生率分别为3.0%和3.7%。

Results: From Dec 3, 2018 to May 12, 2020, 596 patients were randomized. 298 patients were treated with camrelizumb-chemotherapy and 297 patients with placebo-chemotherapy. With a median follow-up of 10.8 months, camrelizumab plus chemotherapy significantly improved OS compared with placebo plus chemotherapy (median, 15.3 month [95% CI 12.8-17.3] vs 12.0 months [11.0-13.3]; HR, 0.70 [95% CI, 0.56-0.88]; one-sided P = 0.0010). Camrelizumab plus chemotherapy was also superior for PFS (per IRC) vs placebo plus chemotherapy (median, 6.9 months [95% CI, 5.8-7.4] vs 5.6 months [95% CI, 5.5-5.7]; HR, 0.56 [95% CI, 0.46-0.68]; one-sided P < 0.0001). ORR per investigator was 72.1% in camrelizumab-chemotherapy group vs 62.1% in placebo-chemotherapy group, and median DoR was 7.0 vs 4.6 months. Incidences of grade ≥3 treatment-related AEs were comparable between the two groups (63.4% vs 67.7%), with decreased neutrophil count (39.9% vs 43.4%) as the most common one. Serious treatment-related AEs occurred in 30.2% vs 23.2% of patients, and treatment-related deaths occurred in 3.0% vs 3.7% of patients, respectively.

结论：与安慰剂加化疗相比，在化疗中加入 Camrelizumab 可提供更好的 OS 和 PFS，安全性可控。Camrelizumab 联合紫杉醇和顺铂有可能成为晚期或转移性 ESCC 患者的新标准一线治疗。基于这项试验，我们正在提交 NDA 以寻求中国国家药品监督管理局批准 camrelizumabplus 化疗治疗未经治疗的晚期或转移性 ESCC。

Conclusions: Addition of camrelizumab to chemotherapy provided superior OS and PFS vs placebo plus chemotherapy, with a manageable safety profile. Camrelizumab in combination with paclitaxel and cisplatin has the potential to become a new standard first-line therapy in patients with advanced or metastatic ESCC. Based on this trial, we are submitting NDA to seek the approval from China National Medical Products Administration for camrelizumab plus chemotherapy in the treatment of untreated advanced or metastatic ESCC.