背景：目前標準的晚期或轉移性食管鱗癌的一線治療是雙重化療，預後仍然很差。Camrelizumab是一種人源化抗 D-1 單克隆抗體，在先前治療的晚期或轉移性 ESCC 中顯示出良好的抗腫瘤活性（Huang et al。柳葉刀 Oncol 2019）。免疫治療可能與化療有協同作用，但對 ESCC 缺乏臨床證據。在此，我們報告了第 3-1 期研究的結果，該研究評估了卡美瑞珠單抗聯合化療與化療對未經治療的晚期或轉移性食管鱗癌患者的療效和安全性。
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：符合條件的患者按 1:1 隨機分為 Camrelizumab 200mg 組和安慰劑組，兩組均聯合紫杉醇（175mg/m）和順鉑（75mg/m）6 個療程，均給予 Q3W 靜脈注射。根據 RECIST v1.1 每 6 周評估一次腫瘤反應。聯合主 要終點：在所有隨機患者中評估 OS 和獨立審查委員會（IRC）評估的 PFS 療效，在所有治療患者中評估安全性。預先指定的中期 OS 和最終 PFS 分析的數據截止日期為 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.
結果：2018年12月3日至2020年5月12日，共隨機抽取596例患者。298例接受camrelizumb化療，297例接受安慰劑化療。中位隨訪時間為10.8個月，與安慰劑加化療相比，卡美瑞珠單抗加化療顯著改善OS（中位，15.3個月[95%CI 12.8-17.3]vs 12.0個月[11.0-13.3]；心率，0.70[95%CI，0.56-0.88]；單側P=0.0010）。Camrelizumab加化療對PFS（每個IRC）和安慰劑加化療也有優勢（中位數，6.9個月[95%CI，5.8-7.4]和5.6個月[95%CI，5.5-5.7]；心率，0.56[95%CI，0.46-0.68]；單側P<0.0001）。卡美瑞珠單抗化療組每位研究者的ORR為72.1%，安慰劑化療組為62.1%，DoR中位數為7.0 vs 4.6個月。等級發生率≥兩組中有3例治療相關不良事件具有可比性（63.4%對67.7%），其中中性粒細胞計數減少（39.9%對43.4%）是最常見的不良事件。嚴重治療相關不良事件發生率分別為30.2%和23.2%，治療相關死亡發生率分別為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.
結論：與安慰劑加化療相比，在化療中加入 Camrelizumab 可提供更好的 OS 和 PFS，安全性可控。Camrelizumab 聯合紫杉醇和順鉑有可能成為晚期或轉移性 ESCC 患者的新標準一線治療。基於這項試驗，我們正在提交 NDA 以尋求中國國家藥品監督管理局批準 camrelizumabplus 化療治療未經治療的晚期或轉移性 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.
