皮下注射恩沃利单抗治疗中国晚期实体瘤的Ⅰ期临床研究

A phase I study of subcutaneous envafolimab(KN035)monotherapy in Chinese patients with advanced solid tumors

目的评估恩沃利单抗单药治疗中国晚期实体瘤患者的初步疗效及安全性。方法研究为一项开放、多中心、剂量递增和剂量扩展的前瞻性Ⅰ期临床研究,剂量递增阶段采用改良的"3+3"设计在6个剂量组(0.1~10.0 mg/kg)中进行,皮下注射每周给药1次。剂量扩展阶段分别在2.5和5.0 mg/kg剂量组进行。结果截至2019年9月2日,共287例实体瘤患者入组并接受恩沃利单抗治疗。在剂量递增阶段未观察到剂量限制性不良反应。所有级别和3~4级药物相关治疗期间不良事件发生率分别为75.3%(216/287)和20.6%(59/287)。所有级别的免疫相关不良反应发生率为24.0%(69/287),常见免疫相关不良反应(发生率≥2%)包括甲状腺功能减退、甲状腺功能亢进、免疫相关性肝炎和皮疹。3.8%(11/287)的患者发生注射部位反应,均为1~2级。在216例疗效可评估的患者中,客观缓解率和疾病控制率分别为11.6%和43.1%,中位缓解持续时间为49.1周(95%CI:24.0~49.3周)。药代动力学结果显示,恩沃利单抗的体内暴露量与剂量成正比,达到血药峰浓度的时间为72~120 h。结论皮下注射恩沃利单抗显示出良好的安全性和初步抗肿瘤活性。

ObjectiveTo evaluate the safety and antitumor activity of envafolimab monotherapy in Chinese patients with advanced solid tumors.MethodsThis open-label,multicenter phase I trial included dose escalation and dose expansion phases.In the dose escalation phase,patients received subcutaneous 0.1,0.3,1.0,2.5,5.0 or 10.0 mg/kg envafolimab once weekly(QW)following a modified"3+3"design.The dose expansion phase was performed in the 2.5 mg/kg and 5.0 mg/kg(QW)dose cohorts.ResultsAt November 25,2019,a total of 287 patients received envafolimab treatment.During the dose escalation phase,no dose-limiting toxicities(DLT)was observed.In all dose cohorts,drug-related treatment-emergent adverse events(TEAEs)for all grades occurred in 75.3%of patients,and grade 3 or 4 occurred in 20.6% of patients.The incidence of immune-related adverse reactions(irAE)was 24.0%for all grades,the most common irAEs(≥2%)included hypothyroidism,hyperthyroidism,immune-associated hepatitis and rash.The incidence of injection site reactions was low(3.8%),all of which were grades 1-2.Among the 216 efficacy evaluable patients,the objective response rate(ORR)and disease control rate(DCR)were 11.6%and 43.1%,respectively.Median duration of response was 49.1 weeks(95%CI:24.0,49.3).Pharmacokinetic(PK)exposure to envafolimab is proportional to dose and median time to maximum plasma concentration is 72-120 hours based on the PK results from the dose escalation phase of the study.ConclusionSubcutaneous envafolimab has a favorable safety and promising preliminary anti-tumor activity in Chinese patients with advanced solid tumors.