第一部分：血清乳酸脱氢酶和其他基线标志物用来预测抗PD-1抗体卡瑞利珠单抗治疗晚期食管鳞癌的疗效预测和预后价值

中文摘要

目的 研究显示仅有少数晚期食管鳞癌（esophageal squamous cell carcinoma，ESCC）患者能从免疫检查点抑制剂治疗中获益，目前尚未寻找到可靠的外周血标志物用于预测程序性死亡受体-1（programmed cell death-1，PD-1）治疗的疗效和预后。

方法 回顾性分析一项来自单中心、Ⅰ期研究的ESCC队列的43例患者。所有患者均接受静脉卡瑞利珠单抗，即一种新型的抗PD-1抗体的治疗，包含60mg、200mg或400mg共三个剂量组，给药频率为最初两次给药间隔为4周，之后每两周重复，直至疾病进展或不能耐受。我们探索了乳酸脱氢酶（lactate dehydrogenase，LDH）以及其他基线外周血标志物与卡瑞利珠单抗治疗晚期ESCC的疗效之间的关系。

结果 经过中位为19.6个月的随访时长，总体的客观缓解率（overall response rate，ORR）为25.6%（11/43），其中包括1例评估为完全缓解（complete response，CR）的患者。中位无进展生存时间（progression-free survival，PFS）为2个月，中位总生存时间（overall survival，OS）为8个月。与基线时LDH水平在正常范围内的患者相比，伴有基线LDH水平升高的患者具有更低的ORR（p=0.02）、更短的PFS（p=0.002）和更差的预后（p＜0.0001）。治疗过程中LDH程度的上升与疾病进展显著相关。多因素分析显示LDH水平（HR=0.18）、C-反应蛋白（C-reactive protein，CRP）（HR=0.27）、转移器官的数目（HR=0.31）、绝对单核细胞计数（absolute monocyte count， AMC）（HR=0.33）和东部协作肿瘤组织体力状况（eastern cooperative oncology group performance status，ECOG PS）（HR=0.36）为独立预后因素。

结论 血清LDH水平作为在临床实践中易于获得和成本较低的检测手段，对于抗PD-1抗体治疗晚期ESCC，是一个潜在的疗效预测因子和敏感的独立预后因素。

第二部分：UGT1A1基因多态性与伊立替康联合替吉奥治疗晚期食管鳞癌所致不良反应的关系：一项前瞻性随机对照研究（ESWN 01）的结果

中文摘要

目的 探索尿苷二磷酸葡萄糖醛酸转移酶 1A1（UDP glucuronosyltransferade 1 family，polypeptide A1，UGT1A1）基因多态性与伊立替康160mg/m²双周给药在晚期ESCC人群中所致不良事件的相关性。

方法 ESWN 01是一项前瞻性随机对照研究，旨在比较伊立替康（160mg/m² 静滴第一天）联合替吉奥（80-120mg口服，第1-10天）双周方案对比单药替吉奥（80-120mg口服，第1-14天）三周方案治疗既往化疗失败的晚期ESCC的有效性和安全性。本文报道ESWN 01研究的探索性研究终点的结果，即在伊立替康联合替吉奥人群中，探索UGT1A1基因多态性与不良反应的关系。留取患者基线时外周静脉血，提取基因组DNA，采用PCR方法检测UGT1A1*6和UGT1A1*28基因型，观察化疗期间出现的剂量限制性毒性（迟发型腹泻和中性粒细胞减少），并对UGT1A1基因多态性和伊立替康所致不良事件的相关性进行分析。

结果 共有46例病人获得了UGT1A1基因型检测结果，携带UGT1A1*6野生型（GG）、杂合突变型（GA）、纯合突变型（AA）分别为30、15和1例，携带UGT1A1*28野生型（TA6/6）、杂合突变型（TA6/7）、纯合突变型（TA7/7）分别为36、8和2例。不良反应方面，仅有的1例UGT1A1*6纯合突变型AA携有者出现3级迟发型腹泻，2例UGT1A1*28纯合突变型TA7/7携有者中有1例发生3级迟发型腹泻；仅有的1例UGT1A1*6纯合突变型AA携有者未出现骨髓抑制，而2例UGT1A1*28纯合突变型TA7/7携有者均发生3/4度中性粒细胞减少。另外在UGT1A1*28突变型（TA6/7和TA7/7）患者中，较野生型患者观察到更高的客观缓解率（55.6% vs. 26.5%）。

结论 中国ESCC人群中，UGT1A1*6和*28纯合突变均十分少见（＜5%），给予伊立替康160mg/m²联合替吉奥双周方案治疗后，携有纯合突变的患者并不都发生严重的剂量限制性毒性。但对携有UGT1A1*6和*28纯合突变的患者仍需密切监测严重迟发型腹泻和骨髓抑制的发生，并及时作出剂量调整。

Part Ⅰ: Lactate dehydrogenase and baseline markers associated with clinical outcomes of advance esophageal carcinoma patients treated with SHR-1210, a PD-1 antibody

Abstract

Background: A small proportion of patients with advanced esophageal squamous cell carcinoma (ESCC) could benefit from immune checkpoint inhibitors, and reliable peripheral blood biomarkers for outcomes of anti-PD-1 immunotherapy were not identified in ESCC.

Methods: A total of 43 patients were retrospectively reviewed in the ESCC cohort of a phase Ⅰ trial from our center. All patients received intravenous SHR-1210, a novel anti-PD-1 antibody, at a dose of 60 mg, 200 mg or 400 mg (4-week interval after first dose followed by a 2-week schedule) until disease progression or intolerable toxicity. The associations between lactate dehydrogenase (LDH) as well as other peripheral blood biomarkers at baseline and the efficacy of SHR-1210 were also investigated.

Results: With a median follow-up of 19.6 months, the overall response rate was 25.6% (11/43), including one complete response. Median progression-free survival (PFS) and overall survival were 2.0 months and 8.0 months, respectively. Patients with an elevated baseline LDH had lower tumor response rates (p=0.02) as well as shorter PFS (p=0.002) and overall survival (p<0.0001) compared with patients with normal levels. An increase of LDH level during treatment was significantly associated with disease progression. Multivariate Cox analysis identified LDH (HR=0.18), C-reactive protein (HR=0.27), number of involved organs (HR=0.31), absolute monocyte count (HR=0.33) and Eastern Cooperative Oncology Group performance status (HR=0.36) as independent prognostic factors.

Conclusions: Serum LDH, as is readily available and inexpensive in clinical practice, is a potential marker for response and a powerful independent factor for survival in advanced ESCC patients receiving anti-PD-1 treatment.

Part Ⅱ: Correlation between UGT1A1 gene polymorphisms and adverse events in patients with recurrent or metastatic esophageal squamous cell carcinoma treated with irinotecan plus S-1: results from a prospective, open-label, randomized controlled trial (ESWN 01)

Abstract

Background: To investigate the correlation between UGT1A1 polymorphisms and irinotecan-induced (160mg/m²) dose-limiting toxicities (DLT) in Chinese esophageal squamous cell carcinoma (ESCC) patients.

Methods: The ESWN 01 was a prospective randomized, open-label, trial to compare the efficacy and safety of irinotecan plus S-1 (intravenous infusion of irinotecan [160 mg/m²] on day 1 and oral S-1 [80–120 mg] on days 1–10, repeated every 14 days) with S-1 monotherapy (80–120 mg/day on days 1–14, repeated every 21 days) in recurrent or metastatic ESCC patients after failure of prior chemotherapy. This study reported the results of the exploratory endpoint, the relationship of irinotecan-induced DLT. Peripheral venous blood at baseline was collected and genomic DNA was extracted. The genetic polymorphisms of UGT1A1*6 and UGT1A1*28 were analyzed by PCR amplification. Irinotecan-induced DLT（delayed diarrhea and neutropenia）of patients with different UGT1A1 polymorphisms were observed. The correlation between UGT1A1 polymorphisms and irinotecan-induced adverse effects was analyzed.

Results: Forty-six patients were included in the analysis. The cases of UGT1A1*6 wild type genotype (GG), mutant heterozygote (GA) and mutant homozygote (AA) were 30, 15 and 1, while those with UGT1A1*28 wild type genotype (TA6/6), mutant heterozygote (TA6/7) and mutant homozygote (TA7/7) were 36, 8 and 2, respectively. The only one patient with UGT1A1*6 AA genotype occurred grade 3 diarrhea, while one of the 2 patients with UGT1A1*28 TA7/7 genotype occurred grade 4 diarrhea. No neutropenia was observed in the only one patient with UGT1A1*6 AA genotype, however, all two patients with UGT1A1*28 TA7/7 genotype occurred grade 3-4 neutropenia. Patients with UGT1A1*28 genetic polymorphism (TA 6/7 or TA7/7) had a higher response rate compared with wild-type TA6/6 carriers. (55.6% vs. 26.5%).

Conclusions The homozygous genotype of UGT1A1*6 AA and UGT1A1*28 TA7/7 were rare (<5%) in Chinese ESCC population. Not all homozygous AA and TA7/7 carriers occurred severe DLT when treated with irinotecan plus S-1. However, it’s still necessary to observe the occurrence of severe diarrhea and neutropenia frequently in patients with UGT1A1*6 AA and UGT1A1*28 TA7/7.