2023年CSCO指南更新解读：驱动基因阳性非小细胞肺癌诊疗.pdf

427实用肿瘤杂志 2023 年 第 38 卷 第 5 期 指南解读DOI:10.13267/ki.syzlzz.2023.0672023 年 CSCO 指南更新解读：驱动基因阳性非小细胞肺癌诊疗 邹宜丰1，段建春1,21.国家癌症中心/国家肿瘤临床医学研究中心/中国医学科学院北京协和医学院肿瘤医院肿瘤内科，分子肿瘤学国家重点实验室，中国医学科学院肺癌转化研究重点实验室，北京 100021；2.山西省肿瘤医院/中国医学科学院肿瘤医院山西医院/山西医科大学附属肿瘤医院肿瘤内科，山西 太原 030013通信作者：段建春，E-mail：摘要：靶向治疗为驱动基因阳性的非小细胞肺癌（non-small-cell lung cancer，NSCLC）患者带来显著生存获益。伴随新药研发、临床试验的开展及阳性结果的获得，驱动基因阳性的 NSCLC 也迎来了更多的治疗选择、更优的疗效及安全性。中国临床肿瘤学会（Chinese Society of Clinical Oncology，CSCO）基于过去 1 年的研究进展更新指南为中国临床肿瘤学会(CSCO)非小细胞肺癌诊疗指南2023。本版针对驱动基因阳性的NSCLC的更新包括：伏美替尼和莫博赛替尼在表皮生长因子受体（epidermal growth factor receptor，EGFR）突变晚期 NSCLC 治疗中的相关更新，布格替尼、洛拉替尼和恩沙替尼在间变性淋巴瘤激酶（anaplastic lymphoma kinase，ALK）融合晚期 NSCLC 治疗中的相关更新以及其他靶向药物的更新。本文将对 2023 年 CSCO NSCLC 诊疗指南中驱动基因阳性的 NSCLC 的诊疗更新进行详细解读。关键词：非小细胞肺癌；中国临床肿瘤学会；靶向治疗；表皮生长因子受体；间变性淋巴瘤激酶Interpretation of updates of 2023 CSCO guidelines for non-small-cell lung cancer with oncogenic driver mutations Chau Yi Fung1,Duan Jianchun1,21.CAMS Key Laboratory of Translational Research on Lung Cancer,State Key Laboratory of Molecular Oncology,Department of Medical Oncology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences Peking Union Medical College,Beijing 100021,China;2.Department of Medical Oncology,Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital,Chinese Academy of Medical Sciences/Cancer Hospital Affi liated to Shanxi Medical University,Taiyuan 030013,ChinaCorresponding to:Duan Jianchun,E-mail:Abstract:Targeted therapies have provided a substantial survival benefit for non-small-cell lung cancer(NSCLC)patients with onco-genic driver mutations.With the development of new drugs and progress of clinical trials,more targeted treatments with better efficacy and safety have become available.Chinese Society of Clinical Oncology(CSCO)has updated the CSCO guidelines for NSCLC based on the ad-vances of the past year.Its updated points include updated recommendation of furmonertinib and mobocertinib in epidermal growth factor receptor mutated NSCLC,brigatinib and lorlatinib and ensartinib in anaplastic lymphoma kinase fusion NSCLC,and other targeted ther-apies.This article provides a profound and detailed interpretation of updates of the 2023 CSCO guidelines in the treatment of NSCLC with oncogenic driver mutations.Key words:non-small-cell lung cancer;Chinese Society of Clinical Oncology;targeted therapy;epidermal growth factor receptor;ana-plastic lymphoma kinase 基金项目：中国医学科学院医学与健康科技创新工程重大协同创新项目（2022-I2M-1-009）；希思科-豪森肿瘤研究基金（2021-070-ZZ）428Journal of Practical Oncology Vol.38No.5 肺癌是我国发病率和死亡率位居前列的恶性肿瘤之一，2016 年发病例数达 82.8 万1。近年来针对表皮生长因子受体（epidermal growth factor receptor，EGFR）等基因突变的靶向治疗改善了非小细胞肺癌（non-small-cell lung cancer，NSCLC）的预后2-3。随着驱动基因阳性 NSCLC 治疗的进一步探索、新型药物上市和国家医保药品目录更新，治疗的选择更多，药物的可及性更强；中国临床肿瘤学会(CSCO)非小细胞肺癌诊疗指南2023（下称指南）基于这些改变进行更新4。本文对指南中关于驱动基因阳性的 NSCLC 内容进行详细解读。1EGFR 突变阳性的晚期 NSCLC 的治疗EGFR 是 NSCLC 中最常见的驱动癌症基因之一，在中国患者中可检出率可高达 50.2%5。奥希替尼（osimertinib）和阿美替尼（aumolertinib）等EGFR-酪氨酸激酶抑制剂（EGFR-tyrosine kinase inhibitor，EGFR-TKI）在 EGFR 常见突变阳性的NSCLC 的一线治疗中已获得 CSCO 指南的级推荐。本版指南依据 FURLONG 研究结果新增伏美替尼（furmonertinib，AST2818）为 EGFR 敏感突变NSCLC 一线治疗的级推荐，依据荟萃分析将莫博赛替尼（mobocertinib，TAK-788）在 EGFR 20 号外显子插入（EGFR ex20ins）突变的后线治疗中上升至级推荐。1.1期 EGFR 敏感突变 NSCLC 一线治疗：新增“伏美替尼”作为级推荐伏美替尼是不可逆和选择性的第三代 EGFR-TKI。伏 美 替 尼 推 荐 基 于 期 FURLONG 研 究（n=358）6-7。FURLONG 研究纳入 EGFR 敏感突变阳性的晚期初治 NSCLC 患者，发现和吉非替尼（gefitinib）比较，伏美替尼提升中位无进展生存时间（median progression-free survival，mPFS；20.8个月 vs 11.1 个月，HR=0.44，P0.01）。亚组分析中，两类 EGFR 敏感突变（ex19del 和 L858R）和脑转移人群中伏美替尼的 mPFS 均优于吉非替尼；两组安全性可控，各有 1 例出现间质性肺病。基于以上证据，国家药品监督管理局（National Medical Products Administration，NMPA）批准伏美替尼用于 EGFR 敏感突变的晚期 NSCLC 一线治疗，指南将伏美替尼作为期 EGFR 敏感突变 NSCLC 一线治疗中的级推荐。1.2期 EGFR ex20ins 突变后线治疗：“莫博赛替尼”由级推荐上升至级推荐莫博赛替尼是针对 EGFR ex20ins 突变设计的强效且不可逆的 EGFR-TKI。本更新基于莫博赛替尼应用于 EGFR ex20ins 突变阳性 NSCLC 患者的期、期及 EXCLAIM 扩展队列非随机化研究8-9。在既往接受铂类治疗的队列（n=114）中，客 观 缓 解 率（objective response rate，ORR）为28%，mPFS 和中位总体生存时间（median overall survival，mOS）分别为 7.3 个月和 20.2 个月。基于该研究，莫博赛替尼获 NMPA 批准用于治疗含铂化疗期间或之后出现进展的 EGFR ex20ins 突变阳性的局部晚期或转移性 NSCLC 患者。本版指南将其推荐级别上升为级。2 间 变 性 淋 巴 瘤 激 酶（anaplastic lymphoma kinase，ALK）融合阳性的晚期 NSCLC 的治疗：上调“布格替尼、洛拉替尼和恩沙替尼”为级推荐ALK 融 合 在 NSCLC 中 约 占 3%5%。克 唑替尼是首个获批的 ALK-TKI，与传统化疗比较，显著改善该类患者的疗效和预后。二代及三代ALK 抑制剂 布格替尼（brigatinib）、恩沙替尼（ensartinib）和洛拉替尼（lorlatinib）因其广谱的抑制效果和更强的血-脑脊液屏障穿透力，在临床中展示出更佳的疗效。基于 ALTA-1L、eXalt3和 CROWN 研究，在期 ALK 融合 NSCLC 中，指南在一线治疗中上调“布格替尼、恩沙替尼和洛拉替尼”为级推荐；在后线治疗中，上调“布格替尼和洛拉替尼”为级推荐。以下对 3 个 ALK-TKI 分别进行解读。2.1在一线和后线治疗中上调“布格替尼”为级推荐布格替尼对 ALK 融合突变有较强的抑制效果，指南中布格替尼在期 ALK 融合 NSCLC 的一线和后线治疗中都获得了线推荐。布格替尼在一线治疗中的推荐基于 ALTA-1L10试验结果，该B/期研究比较布格替尼和克唑替尼疗效和安全性，主要入组未经 ALK-TKI 治疗的 ALK 融合阳性的局部晚期或转移性NSCLC。与克唑替尼比较，布格替尼延长了 PFS（24.0 个 月 vs 11.1 个 月，HR=0.48，P0.01），特429实用肿瘤杂志 2023 年 第 38 卷 第 5 期 别是基线脑转移患者的颅内 PFS（24.0 个月 vs 5.5个月，HR=0.29，P0.01）。该研究中克唑替尼组65 例（47%）在克唑替尼治疗期间出现疾病进展后交叉至布格替尼组，校正后的 OS 的 HR 为 0.54（P=0.023）。布格替尼于 2022 年 3 月 24 日获得NMPA 批准，用于 ALK 融合阳性的局部晚期或转移性 NSCLC 患者的一线治疗。布格替尼在晚期患者中的推荐基于期的ALTA 试验11。该研究纳入 222 例克唑替尼治疗后进展的 ALK 融合阳性 NSCLC 患者，对比布格替尼 90 mg 每天 1 次和 180 mg 每天 1 次（有先导剂量）的疗效，两组的 ORR 分别为 45%和 54%，mPFS为 9.2 个月和 15.6 个月。结果显示，2 个剂量组的布格替尼在 ALK 融合阳性的晚期 NSCLC 的后线治疗中均有可观的疗效，安全性可控。期、随机对照的 ATLA-3 研究显示，布格替尼和阿来替尼在克唑替尼耐药的 ALK 融合阳性晚期 NSCLC 中的疗效相仿（HR=0.97，P=0.867 2）12。基于上述证据和国内适应证，本版 CSCO 指南上调布格替尼作为一代 TKI 一线治疗失败后的级推荐。2.2在一线治疗中新增“恩沙替尼”为级推荐恩沙替尼是国产的二代小分子的高选择性ALK-TKI。B/期的 eXalt3 研究对比了恩沙替尼和克唑替尼在 ALK 融合阳性 NSCLC 患者一线治疗中疗效13。结果显示，意向治疗（intent-to-treat,ITT）人群的恩沙替尼组 mPFS 较克唑替尼组延长（31.3 个 月 vs 12.7 个 月，HR=0.50，P2线治疗后且基线伴中枢神经系统转移的亚组中展现出一致的抗肿瘤疗效。双盲随机期非比较性研究 DESTINY-Lung02将 79 例受试者按 21 比例随机纳入德喜曲妥珠单抗 5.4 mg/kg 或 6.4 mg/kg 每 3 周 1 次治疗组40。5.4 mg/kg 组 ORR 为 57.7%，在疗效和安全性方面均优于 6.4 mg/kg 组。基于以上证据，FDA 加速批准德喜曲妥珠单抗用于治疗不可切除或转移性且HER2 阳性 NSCLC 患者的后线治疗；德喜曲妥珠单抗在中国的上市申请获得 NMPA 受理。因德喜曲妥珠单抗尚未在中国上市，本版指南对德喜曲妥珠单抗在期 HER2 突变 NSCLC 的后线治疗中进行级推荐。过去的 1 年中，晚期 NSCLC 的靶向治疗在常见突变和罕见突变以及一线和后线治疗方案中均有进展，各种新药及方案百花齐放。除了基于临床研究的期别和数据成熟程度，CSCO 指南的更新也基于药品是否获批 NMPA 和国家医疗保险适应证，使其更符合中国国情和更具临床指导意义。CSCO指南的更新像里程碑，见证了国内外诊疗的接轨，国内诊治水平不断进步，NSCLC 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