摘要
【目的】探讨PD-1抗体联合替莫唑胺治疗晚期黑色素瘤患者的疗效与安全性。【方法】回顾性分析2017年8月至2019年4月在中山大学肿瘤防治中心接受PD-1抗体联合替莫唑胺方案治疗的晚期恶性黑色素瘤患者33例,具体方案为:PD-1抗体(Pembrolizumab 2 mg/kg,每3周为一个周期;或Nivolumab 3 mg/kg,每2周为一个周期;或Toripalimab 3 mg/kg,每2周为一个周期)联合替莫唑胺[200 mg/(m^2·d),连续口服5 d,每28 d为一个周期;或75 mg/(m^2·d),连续口服21 d,每28 d为一个周期],至少2个周期(以替莫唑胺周期为准,下同)后评价疗效。应用RECIST v1.1标准评价疗效,不良事件按照NCI-CTCAE 4.0分级。【结果】33例患者接受的中位疗程数为替莫唑胺6.0(1~12)个周期和PD-1抗体7.0(1~27)个周期,客观有效率(ORR)为24.2%(肢端型ORR为38.5%),疾病控制率(DCR)为60.6%,中位无进展生存期(mPFS)为4.3月(95%CI,1.3~7.3),中位疾病控制时间(mDDC)为7.5月(95%CI,2.3~12.7),中位缓解持续时间(mDOR)为11.1月(95%CI,5.5~16.6),中位总生存(mOS)尚未达到,1年生存率为86.1%。Kaplan-Meier法生存分析和COX多因素分析均显示影响PFS的因素有PD-L1表达和BARF V600E/K基因突变状态。PD-L1表达阳性患者比阴性患者有更长的PFS(P<0.05)。BARF V600E/K基因突变患者比野生型患者的PFS更短(P<0.05)。PFS在初治与复治、不同组织来源类型、不同给药方案以及不同性别、年龄、LDH等的患者之间差异均无统计学意义(P>0.05)。常见不良反应包括皮肤瘙痒(30.3%)、皮疹(21.2%)、疲劳(21.2%)、恶心(21.2%)、呕吐(15.2%)、转氨酶升高(15.2%)、胆红素升高(9.1%)等,绝大多数均为1~2级。【结论】PD-1抗体联合替莫唑胺治疗晚期黑色素瘤近期疗效优于单用,尤其是对于肢端型黑色素瘤,安全性高,可在临床进行更加深入的研究和应用。
【Objective】To evaluate the efficacy and safety of anti-PD-1 antibody combined with temozolomide in patients with advanced malignant melanoma.【Methods】Totally 33 patients who had histologically confirmed malignant melanoma with at least one measurable lesion,and received combined therapy of anti-PD-1 antibody and temozolomide,were enrolled from August 2017 to April 2019.Anti-PD-1 antibody was administered intravenously at a dose of 3 mg/kg every 2 weeks(Pembrolizumab)or 2 mg/kg every 3 weeks(Nivolumab or Toripalimab).Temozolomide was orally admin?istered at 200 mg/(m2·d)for 5 consecutive days or 75 mg/(m2·d)for 21 consecutive days,every 28 days for a cycle.Tumor response was evaluated by RECIST v1.1 criteria after every 2 cycles of temozolomide,and adverse events were graded according to NCI-CTCAE 4.0.【Results】The median number of temozolomide cycles was 6.0(1~12)and anti-PD-1 antibody cycles was 7.0(1~27).The objective response rate was 24.2%(38.5%in the Acral)and the disease con?trol rate was 60.6%.The median progression free survival,duration of disease control and duration of response were 4.3 months(95%CI,1.3~7.3),7.5 months(95%CI,2.3~12.7),and 11.1 months(95%CI,5.5~16.6),respectively.The median OS was not reached(95%CI,not estimable),but 12-month OS rates were 86.1%.Kaplan-Meier survival analy?sis and COX multivariate analysis showed that PFS was influenced by the expression of PD-L1 and the mutation status of BARF V600E/K gene.PFS of patients with positive expression of PD-L1 was longer than that of patients with negative expression(P<0.05).PFS of patients with BARF V600E/K gene mutation was shorter than that of patients with wild-type(P<0.05).There were no statistically significant differences in PFS between patients with drug therapy naive cohort and previously treated cohort,or with different histopathological type,drug regimen,gender,age and LDH group etc.(P>0.05).The common adverse events included pruritus(30.3%),rash(21.2%),fatigue(21.2%),nausea(21.2%),vomit?ing(15.2%),elevated transaminase(15.2%),and elevated bilirubin(9.1%),most of which were grade 1 or grade 2.【Con?clusion】The combination of anti-PD-1 antibody and temozolomide proves to be more efficient than being used alone and well tolerated in patients with advanced malignant melanoma,especially for acral melanoma,which can be worthy of fur?ther clinical research and application.
作者
刘巍
李婧婧
丁娅
李丹丹
文习之
祝保艳
张晓实
LIU Wei;LI Jing-jing;DING Ya;LI Dan-dan;WEN Xi-zhi;ZHU Bao-yan;ZHANG Xiao-shi(Biotherapy Center,Sun Yat-sen University Cancer Center//State Key Laboratory of Oncology in South China//Collaborative Innovation Center for Cancer Medicine,Guangzhou 510060,China)
出处
《中山大学学报（医学科学版）》
CAS
CSCD
北大核心
2020年第3期452-459,共8页
Journal of Sun Yat-Sen University:Medical Sciences
基金
国家自然科学基金(81772910)。
作者简介
刘巍,硕士,研究方向:肿瘤的免疫治疗及靶向治疗,E-mail:liuwei1@sysucc.org.cn;通信作者:张晓实,教授,E-mail:zhangxsh@sysucc.org.cn。
