BRAF V600突变型非小细胞肺癌的治疗进展  

Advances in the treatment of BRAF V600-mutant non-small cell lung cancer

作　　者：赵媛媛[1] 周建英[2] 范云 王佳蕾 黄鼎智 李峻岭[6] 史美祺[7] 刘基巍[8] 姚煜[9] 邬麟[10] 姚文秀[11] 张力[1] ZHAO Yuanyuan;ZHOU Jianying;FAN Yun;WANG Jialei;HUANG Dingzhi;LI Junling;SHI Meiqi;LIU Jiwei;YAO Yu;WU Lin;YAO Wenxiu;ZHANG Li(Department of Medical Oncology,Sun Yat-sen University Cancer Center,Guangzhou 510060,Guangdong Province,China;Department of Respiratory Medicine,The First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310003,Zhejiang Province,China;Department of Medical Oncology,Cancer Hospital of the University of Chinese Academy of Sciences,Zhejiang Cancer Hospital,Hangzhou 310022,Zhejiang Province,China;Department of Medical Oncology,Fudan University Shanghai Cancer Center,Department of Oncology,Shanghai Medical College,Fudan University,Shanghai 200032,China;Department of Pulmonary Medical Oncology,Tianjin Medical University Cancer Institute and Hospital,Tianjin 300181,China;Department of Medical Oncology,Cancer Hospital Chinese Academy of Medical Sciences,Beijing 100021,China;Department of Medical Oncology,Jiangsu Cancer Hospital,Nanjing 210009,Jiangsu Province,China;Department of Oncology,The First Affiliated Hospital of Dalian Medical University,Dalian 116011,Liaoning Province,China;Department of Medical Oncology,The First Affiliated Hospital of Xi'an Jiao Tong University,Xi'an 710061,Shaanxi Province,China;The Second Department of Thoracic Oncology,Hunan Cancer Hospital,Changsha 410031,Hunan Province,China;Department of Medical Oncology,Sichuan Cancer Hospital and Institute,Chengdu 610042,Sichuan Province,China)

机构地区：[1]中山大学附肿瘤防治中心肿瘤内科,广州广东510060 [2]浙江大学医学院附属第一医院呼吸内科,浙江杭州310003 [3]中国科学院大学附属肿瘤医院/浙江省肿瘤医院肿瘤内科,浙江杭州310022 [4]复旦大学附属肿瘤医院肿瘤内科,复旦大学医学院肿瘤学系,上海200032 [5]天津市肿瘤医院肺部肿瘤内科,天津300181 [6]中国医学科学院肿瘤医院内科,北京100021 [7]江苏省肿瘤医院肿瘤内科,江苏南京210009 [8]大连医科大学附属第一医院肿瘤科,辽宁大连116011 [9]西安交通大学第一附属医院肿瘤内科,陕西西安710061 [10]湖南省肿瘤医院胸部内二科,湖南长沙410031 [11]四川省肿瘤医院肿瘤内科,四川成都610042

出　　处：《中国癌症杂志》2021年第12期1145-1152,共8页China Oncology

摘　　要：肺癌是中国发病率和死亡率均排在第一位的恶性肿瘤,其中非小细胞肺癌(non-small cell lung cancer,NSCLC)约占肺癌的85%。鼠类肉瘤病毒癌基因同源物B1(V-Raf murine sarcoma viral oncogene homolog B1,BRAF)突变在NSCLC中的发生率为1.5%~3.5%,而BRAF V600约占所有BRAF突变的50%,其中V600E突变最为常见。国内外研究显示,NSCLC中的BRAF突变在男女比例和吸烟状态等方面的差异并不一致,而在病理学类型上,BRAF突变(尤其是BRAF V600E突变)的NSCLC患者均以腺癌为主。BRAF V600突变NSCLC患者的预后差,总生存期(overall survival,OS)较短。在此类患者的药物治疗方面,目前化疗和免疫治疗的临床获益并不理想,化疗的无进展生存期(progression-free survival,PFS)仅为1.5~4.2个月;免疫检查点抑制剂治疗BRAF突变NSCLC患者的PFS也只有2.5~5.3个月。而近年来靶向治疗的应用,为肺癌BRAF突变患者带来了新的希望。Ⅱ期临床试验VE-BASKET使用了BRAF抑制剂维莫非尼治疗BRAF V600E突变型NSCLC,最终结果显示,患者中位PFS和OS分别为6.5和15.4个月,初步证明了该药的有效性;但安全性仍需关注,约77%的患者发生了3/4级不良事件(adverse event,AE)。另一种BRAF抑制剂达拉非尼,对于BRAF V600E突变NSCLC患者,在Ⅱ期临床试验BRF113928的三个队列中,分别证明了该药作为单药治疗经治患者(队列A)、联合丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)激酶(MAPK kinases,MEK)抑制剂曲美替尼治疗经治患者(队列B)以及联合曲美替尼治疗初治患者(队列C)均具有显著疗效,客观缓解率(objective response rate,ORR)分别为33.0%、63.2%和64.0%,PFS分别为5.5、9.7和14.6个月。近期,该研究的5年长期生存随访数据还报告了队列B和C患者的5年OS率分别为19%和22%。BRF113928研究表明,无论作为一线治疗还是后线治疗,达拉非尼联合曲美替尼治疗BRAFV600突变NSCLC患者均具有良好的疗效,且优于BRAF单药靶向�Lung cancer has the highest morbidity and mortality among malignant tumors in China.Non-small cell lung cancer(NSCLC)represents approximately 85%of all new lung cancer diagnoses.V-Raf murine sarcoma viral oncogene homolog B1(BRAF)mutations emerge in about 1.5%-3.5% of the NSCLC cases.BRAF V600 accounts for about 50% of all BRAF mutations,among which V600E mutation is the most common.It has been reported that the proportion of men and women and smoking status in patients with BRAF-mutant NSCLC are still disputed.Pathological characteristics show that patients with BRAF-mutant NSCLC(especially BRAF V600E mutation)mainly have adenocarcinoma.Patients with BRAF V600-mutant NSCLC have poor prognosis and short overall survival(OS).The clinical benefits of chemotherapy or immunotherapy for BRAF-mutant NSCLC are not ideal as reported in the current studies.The progression-free survival(PFS)of patients with BRAF-mutant NSCLC treated with chemotherapy is only 1.5-4.2 months,while the PFS of those treated with immune checkpoint inhibitors is 2.5-5.3 months.In recent years,the application of targeted therapy has brought new breakthroughs to the treatment of BRAF V600-mutant NSCLC patients.VE-BASKET was a phase Ⅱ clinical trial,in which the BRAF inhibitor vemurafenib was used to treat BRAF V600E-mutant NSCLC.The final analysis results showed that the median PFS and OS of those patients were 6.5 months and 15.4 months respectively,which preliminarily proved the effectiveness of vemurafenib.However,about 77% of all patients had grade 3/4 adverse events(AEs)which need to be paid more attention.Dabrafenib,another BRAF inhibitor,has achieved significant efficacy in patients with BRAF V600E-mutant NSCLC in the phase Ⅱ clinical trial BRF113928.All patients were divided into three cohorts with dabrafenib monotherapy(cohort A),treated patients with combination therapy of dabrafenib plus mitogen-activated protein kinase(MAPK)kinase(MEK)inhibitor trametinib(cohort B)and untreated patients with combination therapy of dabrafenib plus t

关 键 词：非小细胞肺癌 鼠类肉瘤滤过性毒菌致癌基因同源体B1 突变 抑制剂 丝裂原活化蛋白激酶激酶抑制剂 

分 类 号：R734.2[医药卫生—肿瘤]