可切除非小细胞肺癌围手术期免疫治疗热点问题中国专家共识

前言

肺癌是我国乃至全球发病率与死亡率最高的恶性肿瘤,根据中国国家癌症中心最新数据显示,我国肺癌新发与死亡病例数分别达106.06万例与73.33万例,其中非小细胞肺癌(non-small cell lung

cancer, NSCLC)为最常见的病理类型,约占全部肺癌的80%~85%[1,2]。临床中,约35%的NSCLC患者初次确诊时属于早期(I/II期),约30%的患者属于局部晚期(III期),约35%的患者属于晚期(IV期)[3]。目前,手术切除是早期及部分局部晚期NSCLC最主要的根治性治疗手段[3]。然而,所有NSCLC患者术后均存在肿瘤复发、转移的风险,且相关研究数据显示,随着肿瘤分期的增加,患者5年总生存(overall survival, OS)率逐渐下降,为进一步改善患者长期生存,围手术期治疗应运而生[4]。

[基金项目] 中国胸部肿瘤协作组 (CTONG) 基金 (CTONG-YC20220106); 广东省肺癌转化医学重点实验室项目 (2017B030314120)。

[通讯作者] 吴一龙, E-mail: syylwu@live.cn。

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近年来,基于多项大型Ⅲ期临床研究所展现的数据结果,以程序性死亡受体-1/程序性死亡受体配体-1(programmed death-1/programmed death-ligand 1, PD-1/PD-L1)抑制剂为代表的免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)不仅颠覆了晚期NSCLC临床诊疗格局,更在可切除NSCLC围手术期治疗中确立了标准治疗地位。但临床实践过程中,NSCLC围手术期治疗仍存在诸多待完善的关键问题,如生物标志物探索、优势人群筛选、不同治疗模式的选择等。为协助临床医生优化可切除NSCLC患者的围手术期诊疗决策,围手术期免疫治疗热点问题共识专家组基于现有临床研究证据,系统梳理当前实践中的关键热点问题,通过深入研讨、针对性循证检索与草案撰写,初步形成《可切除非小细胞肺癌围手术期免疫治疗热点问题中国专家共识》(下称《共识》)。随后召开共识研讨会,与会专家对初稿进行深度讨论及正式投票;执笔专家依据专家意见和投票结果对共识内容进行修订完善,最终完成定稿。本共识的推荐级别见表1。

表1 共识陈述推荐级别

|推荐分级|定义| |---|---| |强|专家共识度≥80%| |中|专家共识度60%~80%| |弱|专家共识度<60%|

问题1: 更优的可切除 NSCLC 围手术期免疫治疗策略是什么?

新辅助治疗、辅助治疗以及围手术期治疗(新辅助治疗+辅助治疗)是目前临床针对可切除NSCLC的最主要的三种治疗模式。

CheckMate 159研究率先探索了纳武利尤单抗(2个周期)单药用于可切除NSCLC新辅助治疗安全性和可行性,研究数据显示,患者病理完全缓解(pathologic complete response, pCR)率与主要病理缓解(major pathologic response, MPR)率分别为15%与45%,开启了NSCLC新辅助免疫治疗先河[5]。其长期随访数据显示,接受纳武利尤单抗单药治疗的患者5年无复发生存(recurrence free survival,RFS)率与OS率分别为60%与80%,进一步展现了新辅助免疫治疗的临床应用潜力[6]。样本量更大的LCMC3研究亦提示,新辅助免疫治疗可提升患者临床获益,为围手术期免疫治疗临床应用

提供了证据支撑[7, 8]。

随着化疗与免疫治疗的协同作用机制逐步明确,免疫联合化疗在可切除NSCLC围手术期治疗中的临床应用得到了进一步探索[9-13]。III期CheckMate 816研究证实,新辅助免疫联合化疗用于IB(≥4 cm)~III A期[美国癌症联合委员会(American Joint Committee on Cancer, AJCC)/国际抗癌联盟(Union for International Cancer Control, UICC)第7版]患者较单纯化疗显著提升pCR率,延长中位无事件生存期(event free survival, EFS),并呈现OS获益趋势[14, 15]。此后,CheckMate 77T、KEYNOTE-671等多项III期研究相继验证,在新辅助免疫联合化疗基础上术后延续辅助免疫治疗的围手术期免疫治疗模式,可进一步改善可切除II~III期患者生存获益,尤其在驱动基因阴性人群中效果更为显著[16-21]。围手术期免疫治疗数据汇总见表2。

术后辅助治疗为患者带来的生存获益提升目前尚存争议。术前未接受新辅助治疗的可切除NSCLC患者在术后接受辅助化疗序贯免疫治疗时,不同PDL表示水平人群的无病生存期(disease free survival, DFS)与OS获益存在异质性[26, 28, 29]。而术前已接受新辅助免疫治疗联合化疗的患者,虽然对CheckMate 816研究与CheckMate 77T研究的对比分析显示,相较于单纯新辅助免疫治疗联合化疗,围手术期免疫治疗或可进一步提升患者EFS获益[16, 23, 30]。然而多项荟萃分析表明,新辅助免疫治疗联合化疗与围手术期免疫治疗之间的EFS/PFS获益与OS获益未见显著差异[31-33]。因此,围手术期免疫治疗虽能提升患者疾病缓解与生存获益,但其适用人群尚需精确筛选。有研究指出,接受新辅助免疫治疗联合化疗后未达到pCR以及术后分子残留病灶(molecular residual disease, MRD)阳性患者肿瘤复发风险更高,接受辅助免疫治疗获益更为显著,可能更适用于围手术期免疫治疗[34-37]。

陈述1:新辅助和围手术期免疫治疗是驱动基因阴性切除II~III期NSCLC患者的标准治疗方案,对于新辅助治疗后未达到pCR的驱动基因阴性可切除II~III期NSCLC患者更推荐围手术期免疫治疗(一致率:100%)。

问题2: II期 NSCLC 患者是否需要开展新辅助免疫治疗?

可切除Ⅱ期NSCLC患者术后仍面临较高复发

围手术期免疫治疗热点问题共识专家组.可切除非小细胞肺癌围手术期免疫治疗热点问题中国专家共识3

|研究名称|pCR率|MPR率|中位EFS/中位DFS|2年OS率|3年OS率|4年或5年OS率| |---|---|---|---|---|---|---| |CheckMate 816 研究$^{[14, 15]}$|24.0% vs. 2.2%|36.9% vs. 8.9%|43.8个月 vs. 18.4个月|82.7% vs. 70.6%|77% vs. 64%|65% vs. 55% (5年OS率)| |CheckMate 77T 研究$^{[22]}$|25.3% vs. 4.7%|35.4% vs. 12.1%|40.1个月 vs. 17.0个月|NA|NA|NA| |AEGEAN 研究$^{[23]}$|17.2% vs. 4.3%|33.3% vs. 12.3%|NR vs. 30.0个月|65.0% vs. 54.4%|67.1% vs. 63.9%|NA| |KEYNOTE-671 研究$^{[17]}$|18.1% vs. 4.0%|30.2% vs. 11.0%|57.1个月 vs. 18.4个月|78.7% vs. 74.8%|72.1% vs. 65.5%|68.0% vs. 56.7% (4年OS率)| |NEOTORCH 研究$^{[24]}$|24.8% vs. 1.0%|48.5% vs. 8.4%|NR vs. 15.5个月|81.2% vs. 74.3%|NA|NA| |RATIONALE-315 研究$^{[20]}$|40.7% vs. 5.7%|56.2% vs. 15.0%|NR vs. NR|88.6% vs. 79.4%|NA|NA| |IMpower 010 研究$^{[25]}$|||65.6个月 vs. 47.8个月 (PD-L1≥1%, I B~ III A期人群)|NA|79.3% vs. 81.1%|70.9% vs. 69.8% (5年OS率)| |KEYNOTE-091 研究$^{[26, 27]}$|||53.8个月 vs. 43.0个月 (所有PD-L1表达水平, I B~III A期人群)|89% vs. 88%|82% vs. 80%|NA| |BR.31研究$^{[28]}$|||59.9个月 vs. 60.3个月 (PD-L1≥1%, 驱动 基因阴性, I B~III A 期人群)|NA|NA|NA|

注: DFS, disease-free survival, 无病生存期; NA, not available, 无数据; NR, not reached, 未达到。

转移风险,约20%的I~II期患者术后中位35个月内发生肿瘤复发、转移,且以远处复发、转移为主[38-40]。多项大型III期临床研究证实,新辅助或围手术期免疫治疗可改善可切除II期NSCLC患者的EFS[16-20]。两项荟萃分析进一步验证该结论:一项针对 KEYNOTE-671、NADIM II以及AEGEAN研究数据进行的汇总分析显示,围手术期免疫治疗组较安慰剂Ⅱ期患者疾病进展与死亡风险降低31%[41]。另一项纳入6项临床研究2941例患者的荟萃分析显示,围手术期PD-1/PD-L1抑制剂组II期患者EFS获益得到显著提升[风险比(hazard ratio, HR)=0.66, 95%可信区间 confidence interval, CI) 0.51~0.86][42]。值得关注的是,II期患者接受新辅助或围手术期免疫治疗的EFS获益幅度虽低于III期患者,但2年EFS率更高[14, 16, 18, 20, 43]。新型双抗药物依沃西单抗[PD-1/血管内皮生长因子(vascular endothelial growth factor, VEGF)双特异性抗体]联合化疗更可实现57.1%的PCR率和85.7%的MRP率[44]。综合以上生存和病理缓解获益,围手术期免疫治疗为可切除II期NSCLC提供了具有临床意义的治疗选择。

淋巴结受累程度、PD-L1 表达水平以及病理类

型均可能成为患者预后的重要影响因素。多项研究表明,新辅助免疫治疗联合化疗可降低患者淋巴结分期[45],CheckMate 77T研究与KEYNOTE-671研究中分别有46%以及38.9%的患者实现淋巴结降期ypN0比例达41%和34.3%),基线cN1患者半数以上降为ypN0;且基线淋巴结分期越高的可切除NSCLC患者在接受纳武利尤单抗联合化疗治疗后,EFS获益越明显[16]。多项大型Ⅲ期研究亚组分析显示,患者PD-L1表达水平与其pCR、MPR率、EFS呈正相关[14, 16, 18, 43],这一结果在多项荟萃分析中得到了验证[14, 16-20, 32, 46, 47]。在病理类型方面,尽管Ⅲ期临床研究中新辅助或围手术期免疫治疗均可使鳞癌或非鳞癌患者获得生存改善[47],但回顾性分析提示,肺腺癌患者的5年OS率优于鳞癌患者(88.9%~90% vs.68.4%~77%)[48, 49]。这表明所有病理类型均可从围手术期免疫治疗获益,但肺鳞癌因基础预后较差更需强化治疗。

陈述2: 新辅助免疫治疗联合化疗在驱动基因阴性可切除Ⅱ~Ⅲ期 NSCLC 患者中已显示出 EFS的获益, 但亚组分析提示Ⅱ期患者获益不如Ⅲ期, 仅呈现获益趋势。对存在淋巴结转移、PD-L1 高表达等因素的驱动基因阴性可切除Ⅱ期 NSCLC 患

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者更推荐采用免疫治疗联合化疗方案开展新辅助治疗(一致率:100%)。

问题3:可切除 NSCLC术前/术后免疫治疗最佳周期分别是多久?

问题3.1:可切除 NSCLC术前新辅助免疫治疗最佳周期是多久?

术前新辅助免疫治疗联合化疗通过降低患者肿瘤分期及消除微转移病灶,可显著降低患者术后肿瘤复发转移风险,延长患者的生存时长[50]。目前大型Ⅲ期临床研究中普遍采用3~4个周期免疫治疗联合化疗的新辅助治疗方案,多数设计为术前4个周期新辅助免疫治疗联合化疗;而NEOTORCH研究以及 ORIENT-99 研究则采用术前3个周期免疫治疗联合化疗新辅助治疗+术后1个周期免疫治疗联合化疗序贯免疫治疗单药维持治疗;SHR-1316-III-303 研究则采用了术前3个周期免疫治疗联合化疗新辅助治疗+术后16个周期单纯免疫治疗辅助治疗。以上临床研究均显示,术前3~4个周期新辅助免疫治疗联合化疗可显著提高患者pCR与MPR率,延长中位EFS,且这一周期设定与既往晚期NSCLC研究中免疫联合化疗的中位至缓解时间(约2个月,3~4个周期)高度吻合[11, 12, 14, 16-20, 51-58]。

基于以上研究结果,新辅助免疫治疗周期数的优化已成为临床关注重点。2024年欧洲肺癌大会(European Lung Cancer Congress, ELCC)公布的CheckMate 77T 研究亚组分析显示,未完成4个周期新辅助治疗(4%患者为3个周期,13%≤2个周期)的患者仍获得与完成4个周期新辅助治疗相近的疾病缓解以及生存获益[59]。另有多项研究显示出2个周期免疫治疗药物新辅助治疗的明显临床获益[7, 60-62]。这一结果提示新辅助治疗期间应积极进行影像学评估以确定其新辅助治疗的周期数,如在患者完成新辅助治疗后,于术前及完成第2个周期新辅助治疗后进行影像学评估,以判断其接受新辅助免疫治疗联合化疗的疗效以及接受手术治疗的可能性[14, 16-19, 21]。但需要注意的是,II期 neoSCORE研究中2个周期信迪利单抗联合化疗的pCR与MPR均低于3个周期方案,因此对条件允许的患者可考虑为其进行3个周期或以上新辅助治疗[63, 64]。此外,目前正在进行的III期 neoSCORE II研究将头对头比较3个周期与4个周期信迪利单抗联合化疗用于可切除鳞状NSCLC新辅助治疗的疗效和安全性,有望明确最佳用药周期[65]。

陈述3:对于驱动基因阴性可切除Ⅱ~Ⅲ期NSCLC,建议根据新辅助免疫治疗联合化疗阶段的影像学评估和耐受性,确定新辅助治疗的周期数,推荐尽可能完成3~4个周期(一致率:88%)。

问题3.2:可切除 NSCLC术后辅助免疫治疗最佳周期是多久?

术后辅助免疫治疗可通过逆转术后免疫抑制状态、增强抗肿瘤免疫反应及清除残留微转移病灶,降低术后肿瘤复发转移风险并延长生存[50]。对于术前未接受新辅助免疫治疗联合化疗的可切除NSCLC患者,多项研究采用化疗序贯持续1年免疫治疗的辅助治疗方案,但不同PD-L1表达水平、疾病分期患者间疗效存在差异[26, 28, 29, 66]:PD-L1表达≥1%的患者DFS可得到进一步延长(尤其≥50%亚组获益更显著)[25, 26, 29];II期和IIA期(AJCC/UICC第7版)DFS获益更为显著[25, 26]。而对于术前已接受了新辅助免疫治疗联合化疗的可切除NSCLC患者,多项III期临床研究均采用了最长持续1年免疫单药治疗的辅助治疗方案,生存获益明显;NEOTORCH研究的“3+1”模式(术后1年特瑞普利单抗维持)亦验证该策略的临床价值,提示术后1年免疫维持治疗是保障患者生存获益的关键[16-18, 20]。

对于术前接受了新辅助免疫治疗联合化疗的可切除 NSCLC患者,辅助免疫治疗的给药方案呈现多样性但疗效一致:RATIONALE-315研究采用替雷利珠单抗400mgQ6W共8个周期的辅助治疗方案,II期NADIMII研究使用纳武利尤单抗480mgQ4W为期6个月的辅助治疗,两种差异化用药方案均显示出显著的生存获益提升[13,20]。对于术前未接受新辅助治疗的可切除 NSCLC患者,NADIM-ADJUVANT研究目前正在探索纳武利尤单抗(360mg)联合化疗Q3W×4个周期序贯纳武利尤单抗(480mg)单药Q4W×6个周期辅助治疗方案的疗效与安全性[67]。由此可见,对于可切除NSCLC术后辅助免疫治疗,未来在筛选优势人群、优化给药方案方面仍需进行进一步探索。

陈述4:对于术前未接受新辅助免疫治疗联合化疗的患者,术后辅助免疫的参考:PD-L1 表达水平、分期状态等,但不同临床研究尚无统一结论。对于术前接受过新辅助免疫治疗联合化疗的患者,经多学科团队(multidisciplinary team, MDT)讨论决定术后是否采用辅助免疫治疗,目前建议根据现有高级别循证证据术后免疫治疗时间为1年(一致

围手术期免疫治疗热点问题共识专家组.可切除非小细胞肺癌围手术期免疫治疗热点问题中国专家共识

5

率: 100%)。

问题4: 新辅助治疗是否可能重新定义“术式/必要性/适用手术患者”？

问题4.1: 新辅助免疫治疗联合化疗是否会影响患者手术式选择？

多项Ⅲ期研究显示,新辅助免疫联合化疗可能有助于优化手术实施条件:试验组手术率与对照组相当或略高,且因疾病进展或不良反应(adverse event, AE)导致手术取消的比例普遍更低;且肺叶切除术实施率较于对照组提高约3.7%~16.5%,仅NEOTORCH研究中占比略低[14, 16-20, 68-70]。同时,Check-Mate 816研究、AEGEAN研究以及RATIONALE-315研究均提示,试验组相较于对照组而言微创手术比例增加、中转开胸率更低、R0切除率更高[14, 16-20, 68-70]。围手术期免疫治疗外科结局汇总见表3。由此可见,新辅助免疫治疗联合化疗可在保证患者手术可行性以及切除完整性的前提下促进微创技术应用,实现手术精准化与肿瘤控制的协同优势。

陈述5: 新辅助免疫治疗联合化疗后, 手术前要进行更严格的再评估再分期, 对确有病理分期降期的患者, 经 MDT 讨论后缩小手术切除范围, 尽量避免全肺切除(一致率: 88%)。

问题4.2: 新辅助免疫治疗联合化疗能否帮助不可切除的局部晚期 NSCLC 患者实现转化,从

而接受根治性手术治疗？

免疫治疗显著改变了局部晚期 NSCLC 的治疗策略。对于不可切除Ⅲ期患者,PACIFIC 研究已证实同步放化疗序贯免疫巩固治疗可显著改善患者PFS(16.9个月 vs. 5.6个月, HR=0.55, 95%CI 0.45~0.68)与OS(47.5个月 vs. 29.1个月, HR=0.72, 95%CI 0.59~0.89)[71,72]。GEMSTONE-301 研究进一步显示,无论患者采用同步或序贯放化疗后续进一步接受免疫巩固治疗,其PFS均可得到显著延长[73]。这一研究结果已在多项真实世界回顾性研究中得到验证[74,75]。基于此,同步或序贯放化疗后进行免疫巩固治疗成为了目前临床针对不可切除Ⅲ期 NSCLC的标准治疗方案。

相较于新辅助化疗,新辅助免疫治疗联合化疗为可切除NSCLC患者带来了显著的生存与疾病缓解获益。多项Ⅲ期临床研究显示,新辅助或围手术期免疫治疗可显著改善可切除Ⅲ期患者的生存结局,疾病进展或死亡风险降低40%~60%,Ⅲ-N2期患者生存获益得到显著提升[14, 16-19, 76, 77]。这一进展不仅证实了围手术期免疫联合化疗在改善可切除患者生存结局上的优势,更引发了关于其在初始不可切除局部晚期NSCLC转化治疗中的关键科学问题:是否可通过诱导治疗实现肿瘤降期,使部分患者获得根治性手术机会,进而改善生存预后。既往研究显示,免疫治疗联合化疗具有使不可切除局部晚期

|研究名称|手术率|R0切除率|因疾病进展或AE取消手术比例|微创手术比例|开胸手术比例|微创转开胸比例|肺叶切除比例|全肺切除比例|手术时间|手术相关AE| |---|---|---|---|---|---|---|---|---|---|---| |CheckMate 816研究|83.2% vs. 75.4%|83.2% vs. 77.8%|7.8% vs. 10.1%|29.5% vs. 21.5%|59.1% vs. 63.0%|11.4% vs. 15.6%|77.2% vs. 60.7%|16.8% vs. 25.2%|185.0 min vs. 213.5 min|41.6% vs. 46.7%| |CheckMate 77T研究|77.7% vs. 76.7%|89.3% vs. 90.4%|8.7% vs. 11.2%|NA|NA|NA|79.8% vs. 71.9%|9.0% vs. 13.5%|NA|41.0% vs. 38.9%| |AEGEAN研究|80.6% vs. 80.7%|94.7% vs. 91.3%|8.2% vs. 8.9%|49.2% vs. 47.0%|49.2% vs. 50.7%|NA|65.0% vs. 59.1%|7.4% vs. 7.8%|210.0 min vs. 198.0 min|40.2% vs. 39.2%| |KEYNOTE-671研究|82.1% vs. 79.5%|92.0% vs. 84.2%|10.3% vs. 12.5%|NA|NA|NA|78.8% vs. 75.1%|11.4% vs. 12.3%|NA|NA| |NEOTORCH研究|82.2% vs. 73.3%|95.8% vs. 92.6%|5.5% vs. 15.3%|NA|NA|NA|80.7% vs. 83.1%|9.0% vs. 9.5%|NA|74.4% vs. 70.3%| |RATIONALE-315研究|84.1% vs. 76.2%|95.3% vs. 93.1%|5.4% vs. 8.4%|60.0% vs. 50.3%|34.2% vs. 40.5%|5.8% vs. 9.2%|71.6% vs. 61%|8.4% vs. 12.1%|162.0 min vs. 168.0 min|63.7% vs. 61.3%|

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NSCLC 患者实现转化获得手术治疗机会的可能性[78-81], 一项前瞻性、概念验证性Ⅱ期 TRAILBL-AZER 研究发现, 免疫治疗联合化疗后进行手术(术后双抗维持治疗)或根治性放疗后ⅢA期、ⅢB期以及ⅢC期患者转化率分别为37%、26%以及16%, 手术组12个月与18个月EFS率均高于放疗组, 分别为81.5%(放疗组为61.3%)与74.1%(放疗组为57.3%)[82]。这些证据提示免疫联合化疗可能为部分局部晚期患者创造根治手术机会, 提高生存获益, 但仍需前瞻性研究确认。

陈述6:对于传统认为不可切除的局部晚期NSCLC,同步或序贯放化疗后进行免疫巩固治疗仍是目前标准治疗模式。经MDT讨论后,可基于患者治疗情况为部分不可切除ⅢA期、ⅢB期NSCLC患者尝试“新辅助”免疫治疗联合化疗,争取手术机会(一致率:100%)。

问题4.3:新辅助治疗后达到影像学完全缓解(complete response, CR)的患者是否有必要进行手术?

多项研究数据证实,新辅助免疫治疗联合化疗具有很好的肿瘤缓解能力,约0.4%~3.1%的患者可于术前达到影像学CR并接受手术探查[14, 16, 18, 68]。然而与术后病理分期相比,正电子发射断层显像(positron emission tomography, PET)-CT评估的临床分期准确性仍存在不足[83-86]。基于循环肿瘤DNA(circulating tumor DNA, ctDNA)的MRD监测虽可预测预后(ctDNA-MRD阴性患者疾病复发风险相对较低),但仍存在异质性,如IMpower 010研究中显示,无论 ctDNA状态如何,患者均可从辅助免疫治疗中获益[87-94]。因此,通过影像学以及相关肿瘤生物标志物监测能否代替病理评估,使患者免于手术治疗,仍有待进一步验证。

陈述7:对于接受新辅助免疫治疗联合化疗后达到影像学CR的患者,建议进行手术探查。能否通过ctDNA-MRD等标志物或采用PET-CT对患者进行监测使其免于手术治疗,目前尚有争议,鼓励未来开展更多研究进行探索(一致率:100%)。

问题5:新辅助治疗后肿瘤未得到明显缓解或出现疾病进展的患者后续如何进行治疗?

现有Ⅲ期临床数据显示,接受新辅助免疫治疗联合化疗的患者因疾病进展取消手术比例<7%,这部分患者的后续治疗尚缺乏大型研究数据支持。CheckMate 816研究中,新辅助治疗阶段肿瘤出现

进展的患者,根据其疾病不同进展情况分别接受单纯放疗、单纯化疗、单纯免疫治疗以及放疗或放化疗联合免疫治疗,其中多数患者为Ⅲ期患者[14]。KEYNOTE-671研究中17例取消手术的患者则接受预设放疗方案[17]。国际肺癌研究协会(International Association for the Study of Lung Cancer, IASLC)明确指出,对于有证据表明肿瘤出现进展或手术可行性存疑的患者,需召开MDT讨论为患者制定个体化治疗方案[95]。

陈述8:对于接受新辅助治疗后,肿瘤未得到明显缓解或出现疾病进展的患者,建议召开MDT讨论为患者制定治疗方案。根据实体肿瘤疗效评价标准1.1版(Response Evaluation Criteria in Solid Tumors version 1.1, RECIST v1.1),疗效评估为疾病稳定(stable disease, SD)或疾病进展(progressive disease, PD)的患者,若能够达到R0切除,应为患者进行根治性手术治疗;疗效评估为SD或PD,不能够达到R0切除,但对于局部晚期的患者,可按不可切除局部晚期NSCLC进行治疗;疗效评估为PD且出现广泛进展的患者,可按晚期NSCLC进行治疗(一致率:94%)。

问题6: 新辅助治疗后达到pCR的患者的后续治疗策略如何?

多项研究显示,接受新辅助治疗后达到pCR的患者,其EFS获益较于未达到pCR的患者更优[17, 19, 22, 23, 34, 96]。一项纳入7项临床研究2940例患者的荟萃分析显示,达到pCR与2年EFS率存在强相关性(R$^{2}$=0.82, β=0.64),且pCR的比值比(odds ratio, OR)值与EFS的HR值之间同样存在一定相关性(R$^{2}$=0.58, β=0.19)[35]。然而2024年公布的CheckMate 816研究与CheckMate 77T研究对比分析亦显示,无论新辅助免疫治疗联合化疗后是否达到pCR,围手术期免疫治疗组患者EFS均展现出了优于新辅助治疗组患者的趋势,pCR患者EFS的HR值为0.58(95%CI 0.14~2.40),这提示即便患者达到pCR,仍可从术后辅助免疫治疗中获益[30]。由此可见,即便患者接受新辅助治疗后达到pCR仍具有一定肿瘤复发、转移风险,且临床实践过程中存在误到pCR的可能,患者术后或仍可能需要接受辅助治疗。

此外,MRD 监测对接受根治性治疗的 NSCLC 患者具有显著预后价值,MRD 阳性与患者更高的 肿瘤复发、转移风险以及更短的OS有强相关

围手术期免疫治疗热点问题共识专家组,可切除非小细胞肺癌围手术期免疫治疗热点问题中国专家共识

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性[87, 97, 98],术后MRD阳性患者接受辅助治疗潜在获益更大,提示该部分患者可能从强化治疗中获益更显著[36]。因此,MRD状态的持续监测可能有助于评估患者术后肿瘤复发风险,为辅助治疗决策提供指导,但这仍需更多大型临床研究加以探索、验证。

陈述9:对于新辅助免疫治疗联合化疗的病理学疗效评价,建议加强肺癌病理科医生同质化认定,避免pCR的误判。若确实为pCR的患者则预后较好,长期存率高且稳定,但因仍有一定的复发风险,是否免除免疫辅助治疗存在争议,建议开展以MRD为基础的适应性治疗的前瞻性临床试验(一致率:94%)。

问题7: MRD在可切除NSCLC 围手术期免疫治疗中的临床实践办法为何?

问题7.1:如何看待MRD 监测对可切除NSCLC 围手术期免疫治疗疗效的预测价值?

MRD 也称微小残留病灶(minimal residual disease)或可测量残留病灶(masurable residual disease),即通过 ctDNA 等技术检测出的影像学隐匿性微转移灶。多项研究亦显示,接受新辅助或围手术期免疫治疗后实现 ctDNA 清除的患者,其生存获益较未实现 ctDNA 清除的患者更优[15, 22, 92, 99]。然而也有研究显示,不论患者是否实现 ctDNA 清除,试验组相较于对照组均具有总体生存优势。CheckMate 816 研究显示,ctDNA 清除状态与病理缓解和生存获益显著相关,ctDNA 清除者中免疫联合化疗组 pCR 率达46%而化疗组仅13%,ctDNA未清除组 pCR 率分别为0%与4%;生存分析显示,试验组患者中 ctDNA 清除患者 OS 获益显著优于ctDNA 未清除患者(HR=0.31, 95%CI 0.10~0.90),且对照组中 ctDNA 清除患者亦显示出了OS 获益趋势(HR=0.58, 95%CI 0.20~1.64),表明 ctDNA 清除不仅是免疫治疗敏感性的预测指标,更是生存预后的独立影响因素[15],多项研究亦可观察到类似结果[22, 92-94]。这提示临床,ctDNA-MRD 可能是用于评估可切除 NSCLC 患者接受围手术期免疫治疗疗效可靠的预后标志物,但其作为指导医生临床决策的预测标志物可能尚存一定争议——即无法通过 ctDNA 状态预判患者是否从免疫治疗中获益,治疗组优势独立于MRD 状态存在。未来需前瞻性研究验证 MRD 监测对治疗调整的预测效能。

陈述 10: MRD 是可用于可切除 NSCLC 患者术后疗效监测、判断肿瘤复发、转移风险较好的预测法。

后标志物,但其作为临床预测标志物的价值仍有待验证(一致率:100%)。

问题7.2:如何为接受围术期药物治疗的可切除NSCLC患者选择MRD检测方法?

MRD 检测在实体瘤尤其是可切除 NSCLC 围手术期免疫治疗中的价值虽日益明确,但临床转化仍缺乏统一的检测策略与判读规范,且不同MRD检测方法在患者预后评估价值上亦所有差异,在肿瘤复发的阳性预测值(70%~100%)和阴性预测值(80%~97%)波动较大[100, 101]。为确保MRD检测结果的准确性及其对临床医生诊疗决策的指导价值,临床应选择阳性预测值、阴性预测值均达到90%及以上的MRD检测方法为患者进行检测。《实体瘤分子残留病灶检测共识》同样指出,MRD检测在进入临床应用之前需要经过充分的性能验证,性能指标包括但不限于:分析灵敏度、分析特异度、精密度以及准确度等关键指标[102]。

陈述11:用于指导适应性治疗的MRD检测技术必须经过临床的充分验证,其阴性预测值和阳性预测值均需要达到90%及以上(一致率:94%)。

问题7.3;术后MRD阴性患者是否需要接受辅助治疗?

基于现有研究证据,MRD状态对可切除NSCLC术后复发风险分层及辅助治疗决策具有重要指导意义,术后MRD阳性患者的肿瘤复发、转移风险是MRD阴性患者的10~20倍,而术后持续MRD阴性者5年复发率<5%,提示术后MRD持续阴性患者或可免于接受术后辅助治疗[87, 97, 103, 104]。LUNGCA-1/2研究进一步发现,围手术期(术前、术后3天及术后1个月)ctDNA阳性是复发独立危险因素[88],辅助治疗前ctDNA阳性者接受化疗可改善RFS(HR=0.55),但MRD阴性患者辅助化疗未显示生存获益(HR=1.08)[37]。2024美国临床肿瘤学会(American Society of Clinical Oncology, ASCO)年会公布的TRACERx研究探索分析同样显示出了相似结果[36]。由此可见,对于术后MRD阴性患者或可考虑暂不进行辅助治疗,而是通过持续MRD监测进行管理。然而,现有研究多为小样本研究,临床目前高缺乏相关高级别循证证据。因此MRD在可切除NSCLC围手术期免疫治疗中的应用的可行性尚需进一步探索。

陈述12: 相比于MRD阳性患者,MRD阴性患者预后相对更好,是否能够免除辅助免疫治疗尚

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无高级别证据,未来鼓励开展MRD指导下的适应性治疗的前瞻性临床试验(一致率:94%)。

问题8: 驱动基因(EGFR/ALK)阳性的患者, 是否应进行免疫新辅助治疗?

对于驱动基因表皮生长因子受体(epidermal growth factor receptor, EGFR)或间变性淋巴瘤激酶(anaplastic lymphoma kinase, ALK)阳性可切除II~III A期 NSCLC,手术+术后辅助靶向治疗已成为标准治疗方案[105-108]。但针对驱动基因(EGFR/ALK)阳性可切除NSCLC术前新辅助治疗,目前临床仍存在诸多争议。

对于EGFR阳性可切除NSCLC,术前新辅助靶向治疗给患者带来的临床获益较为有限[109],Ⅱ期研究中奥希替尼用于EGFR阳性Ⅱ~ⅢB期(T3~4, N2)NSCLC 围手术期治疗[110]或Ⅰ~ⅢA期(AJCC/UICC 第7版)NSCLC新辅助治疗或围手术期治疗时pCR与MPR率均较低[111]。相比之下,ALK阳性可切除NSCLC患者接受新辅助治疗展现出了一定临床应用潜力[112],2024世界肺癌大会(Would Conference on Lung Cancer, WCLC)公布的单臂、Ⅱ期临床研究ALNEO研究显示,阿来替尼用于ALK阳性潜在可切除Ⅲ期NSCLC患者围手术期治疗时pCR与MPR率分别为17%与39%[113]。另一项单臂、多中心、Ⅱ期临床研究显示,ALK阳性可切除局部晚期NSCLC患者接受塞瑞替尼围手术期治疗,客观缓解率为100%,MPR率为57%,pCR率为29%[114]。可见,当前证据支持ALK阳性患者可能从新辅助靶向治疗获益,但受限于Ⅱ期单臂研究样本量较小,仍需Ⅲ期研究验证。

近年针对驱动基因(EGFR/ALK)阳性患者能否采用新辅助免疫治疗联合化疗为患者带来显著的生存获益提升,已成为临床所关注的热点问题之一[11, 17, 18, 115, 116]。一项多中心汇总分析显示,在驱动基因阳性患者中,新辅助免疫治疗联合化疗组pCR率(10.5% vs. 0%, P=0.489)与MPR率(42.1% vs. 12.5%, P=0.071)均高于新辅助靶向治疗或新辅助化疗组[117]。前瞻性Ⅱ期CTONG 2104研究显示免疫治疗联合化疗用于EGFR阳性患者新辅助治疗时,患者pCR率与MPR率分别为34.3%与11.4%,中位EFS为21.1个月[118, 119]。对于ALK阳性患者,由于ALK融合肿瘤免疫原性较低,患者肿瘤微环境缺乏肿瘤浸润淋巴细胞以及免疫激活性生物标志物表达低等特征,ALK阳性患者从免疫治疗中获益

的可能性相对较低[120-121]。真实世界回顾性分析显示,ALK阳性晚期NSCLC患者接受免疫治疗中位PFS为2.34个月(95%CI 1.55~3.09),中位至停止免疫治疗时间为2.17个月(95%CI 1.41~3.32)[122]。IMpower 010研究亚组分析也发现,ALK阳性患者DFS与OS获益较ALK阴性或ALK突变情况未知患者更低,且试验组患者DFS与OS获益低于对照组[25,29,123]。

综上,驱动基因(EGFR/ALK)阳性可切除NSCLC患者应根据驱动类型选择合适的术前新辅助治疗方案:针对EGFR阳性可切除NSCLC患者,免疫治疗联合化疗可能是其更好的新辅助治疗选择,但目前现有临床数据多为小样本研究数据,临床对其需谨慎解读。针对ALK阳性可切除NSCLC患者,现有研究数据显示靶向治疗是其更有潜力的围手术期治疗选择。

陈述13:对于驱动基因阳性(EGFR/ALK)可切除NSCLC,手术+辅助靶向治疗是患者首选标准治疗方案。其中对于肿瘤学不可切除的患者,鼓励开展诱导靶向或免疫治疗的前瞻性临床研究,使部分患者达到降期效果,提高手术切除率(一致率:47%)。

固手术期免疫治疗热点问题共识专家组

专家组组长:吴一龙(广东省人民医院)

专家组副组长:王长利(天津医科大学肿瘤医院),王洁(中国医学科学院附属肿瘤医院)

专家组:(按姓名首字母顺序)

陈克能(北京大学肿瘤医院),褚倩(华中科技大学同济医学院附属同济医院),储天晴(上海市胸科医院),范云(浙江省肿瘤医院),胡坚(浙江大学医学院附属第一医院),胡洁(上海市老年医学中心(复旦大学附属中山医院闵行院区)),刘安文(南昌大学第二附属医院),潘琰(广东省人民医院),邬麟(湖南省肿瘤医院),闫小龙(空军军医大学唐都医院),杨帆(北京大学人民医院),杨懿(成都市第三人民医院),赵军(北京大学肿瘤医院),钟文昭(广东省人民医院),周清(广东省人民医院)

[参考文献]

[1] 郑荣寿,陈茹,韩冰峰,等.2022年中国恶性肿瘤流行情况分析[J].中华肿瘤杂志,2024,46(3):221-231. doi: 10.3760/

围手术期免疫治疗热点问题共识专家组.可切除非小细胞肺癌围手术期免疫治疗热点问题中国专家共识

9

cm.a.j.cn 112152-20240119-00035.

[2] 中国抗癌协会肺癌专业委员会,中华医学会肿瘤学分会肺癌学组.Ⅲ期非小细胞肺癌多学科诊疗专家共识(2019版)[J]. 中华肿瘤杂志,2019,41(12): 881-890. doi: 10.3760/cma.j.issn.0253-3766.2019.12.001.

[3] 王家乐,崔亚男,邱天羽,等.非小细胞肺癌围手术期免疫治疗进展[J].中华转移性肿瘤杂志,2024,7(3):76-278. doi: 10.3760/cma.j.cn101548-20240129-00020.

[4] VANSTEENKISTE J, WAUTERS E, REYMEN B, et al. Current status of immune checkpoint inhibition in early-stage NSCLC[J]. Ann Oncol, 2019, 30(8): 1244-1253. doi: 10.1093/annonc/mdz175.

[5] FORDE P M, CHAFT J E, SMITH K N, et al. Neoadjuvant PD-1 blockade in resectable lung cancer[J]. N Engl J Med, 2018, 378(21): 1976-1986. doi: 10.1056/NEJMoa1716078.

[6] ROSNER S, REUSS J E, ZAHURAK M, et al. Five-year clinical outcomes after neoadjuvant nivolumab in resectable non-small cell lung cancer [J]. Clin Cancer Res, 2023, 29(4): 705-710. doi: 10.1158/1078-0432.CCR-22-2994.

[7] CHAFT J E, OEZKAN F, KRIS M G, et al. Neoadjuvant atezolizumab for resectable non-small cell lung cancer: an open-label, single-arm phase II trial[J]. Nat Med, 2022, 28(10): 2155-2161. doi: 10.1038/s41591-022-01962-5.

[8] CARBONE D P, WAQAR S N, CHAFT J, et al. 1450 MP- dated survival, efficacy and safety of adjuvant (adj) atezolizumab (atezo) after neoadjuvant (neoadj) atezo in the phase II LCMC3 study[J]. J Thor Oncol, 2023, 18(4): S90-S91. doi: 10.1016/S1556-0864(23)00339-8.

[9] SALAS-BENITO D, PÉREZ-GRACIA J L, PONZ-SAR-VISÉ M, et al. Paradigms on immunotherapy combinations with chemotherapy[J]. Cancer Discov, 2021, 11(6): 1353-1367. doi: 10.1158/2159-8290.CD-20-1312.

[10] LEIGHL N. ES01.02 Chemotherapy enhances the efficacy of immunotherapy[J]. J Thor Oncol, 2019, 14(10): S13-S14. doi: 10.1016/j.jtho.2019.08.070.

[11] PROVENCIO M, NADAL E, INSA A, et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial[J]. Lancet Oncol, 2020, 21(11): 1413-1422. doi: 10.1016/S1470-2045(20)30453-8.

[12] PROVENCIO M, NADAL E, INSA A, et al. Perioperative chemotherapy and nivolumab in non-small-cell lung cancer (NADIM): 5-year clinical outcomes from a multicentre, single-arm, phase 2 trial[J]. Lancet Oncol., 2024, 25(11): 1453-1464. doi: 10.1016/S1470-2045(24)00498-4.

[13] PROVENCIO M, NADAL E, GONZÁLEZ-LARRIBA J L, et al. Perioperative nivolumab and chemotherapy in stage III non-small-cell lung cancer [J N Engl J Med, 2023, 389(6): 504-513. doi: 10.1056/NEJMoa2215530.

[14] FORDE P M, SPICER J, LU S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer[J]. N Engl J

Med, 2022, 386(21): 1973-1985. doi: 10.1056/NEJMoa2202170.

[15] SPICER J, GIRARD N, PROVENCIO M, et al. Neoadjuvant nivolumab (NIVO) + chemotherapy (chemo) vs chemo in patients (pts) with resectable NSCLC: 4-year update from CheckMate 816[J]. J Clin Oncol, 2024, 42(17S): AbstrLB-A8010. doi: 10.1200/JCO.2024.42.17_suppl.LBA8010.

[16] CASCONE T, AWAD M M, SPICER J D, et al. Perioperative nivolumab in resectable lung cancer[J]. N Engl J Med, 2024, 390(19): 1756-1769. doi: 10.1056/NEJMoa2311926.

[17] WAKELEE H, LIBERMAN M, KATO T, et al. Perioperative pembrolizumab for early-stage non-small-cell lung cancer[J]. N Engl J Med, 2023, 389(6): 491-503. doi: 10.1056/NEJMoa2302983.

[18] HEYMACH J V, HARPOLE D, MITSUDOMI T, et al. Peri-operative durvalumab for resectable non-small-cell lung cancer [J]. N Engl J Med, 2023, 389(18): 1672-1684. doi: 10.1056/NEJMoa2304875.

[19] LU S, ZHANG W, WU L, et al. Perioperative toripalimab plus chemotherapy for patients with resectable non-small cell lung cancer: the neotorch randomized clinical trial[J]. JAMA, 2024, 331(3): 201–211. doi: 10.1001/jama.2023.24735.

[20] YUE D, WANG W, LIU H, et al. VP1-2024: RATIONALE-315: event-free survival (EFS) and overall survival (OS) of neoadjuvant tisleizumab (TIS) plus chemotherapy (CT) with adjuvant TIS in resectable non-small cell lung cancer (NSCLC)[J]. Ann Oncol, 2024, 35(3): 332-333. doi: 10.1016/j.annonc.2024.01.005.

[21] YUE D S, WANG W X, LIU H X, et al. Perioperative tisleizumab plus neoadjuvant chemotherapy for patients with resectable non-small-cell lung cancer (RATIONALE-315): an interim analysis of a randomised clinical trial[J]. Lancet Respir Med, 2025, 13(2): 119-129. doi: 10.1016/S2213-2600(24)00269-8.

[22] PROVENCIO PULLA M, AWAD M, CASCONE T, et al. LBA50 Perioperative nivolumab (NIVO) v placebo (PBO) in patients (pts) with resectable NSCLC: clinical update from the phase III CheckMate 77T study[J]. Ann Oncol, 2024, 35(2S): S1239-S1240. doi: 10.1016/j.annonc.2024.08.2291.

[23] HEYMACH J V, HARPOLE D, MITSUDOMI T, et al. OA13.03 Perioperative durvalumab for resectable NSCLC (R-NSCLC): updated outcomes from the phase 3 AEGEAN trial[J]. J Thor Oncol, 2024, 19(10): S38-S39. doi: 10.1016/j.jtho.2024.09.069.

[24] LU S, WU L, ZHANG W, et al. Perioperative toripalimab + platinum-doublet chemotherapy vs chemotherapy in resectable stage II/III non-small cell lung cancer (NSCLC): interim event-free survival (EFS) analysis of the phase III NEOTORCH study[J]. J Clin Oncol, 2023, 41(16S): Abstr8501. doi: 10.1200/JCO.2023.41.16_suppl.8501.

[25] WAKELEE H A, ALTORKI N K, ZHOU C C, et al. IM-

10

循证医学

2025年第25卷第X期

power010: final disease-free survival (DFS) and second over-all survival (OS) interim results after ≥5 years of follow up of a phase III study of adjuvant atezolizumab vs best support-ive care in resected stage IB-IIIA non-small cell lung cancer (NSCLC)[J]. J Clin Oncol, 2024, 42(175): AbstrLBA8035. doi: 10.1200/JCO.2024.42.17_suppl.LBA8035. [26] O'BRIEN M, PAZ-ARES L, MARREAUD S, et al. Pembrolizumab versus placebo as adjuvant therapy for completely re-sected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a random-ised, triple-blind, phase 3 trial[J]. Lancet Oncol, 2022, 23(10): 1274-1286. doi: 10.1016/S1470-2045(22)00518-6. [27] BESSE B, HAVEL L, PETERS S, et al. 120MO Adjuvant pembrolizumab versus placebo for early-stage NSCLC after resection and optional chemotherapy: updated results from PEARLS/KEYNOTE-091[J]. Immuno-Oncol Technol, 2023, 20(S): 100592. doi: 10.1016/J.IOTECH.2023.100592. [28] GOSS G, DARLING G E, WESTEEL V, et al. LBA48 CCTG BR. 31: a global, double-blind placebo-controlled, randomized phase III study of adjuvant durvalumab in completely resected non-small cell lung cancer (NSCLC)[J]. Ann Oncol, 2024, 35: S1238. doi: 10.1016/j.anncon.2024.08.2289. [29] FELIP E, ALTORKI N, ZHOU C C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial[J]. Lancet, 2021, 398(10308): 1344-1357. doi: 10.1016/S0140-6736(21)02098-5. [30] FORDE P M, PETERS S, DONINGTON J, et al. PL02.08 Perioperative vs neoadjuvant nivolumab for resectable NSCLC: patient-level data analysis of CheckMate 77T vs CheckMate 816[J]. J Thorac Oncol, 2024, 19(10S): S2. doi: 10.1016/j.jtho.2024.09.014. [31] NUCCIO A, VISCARDI G, SALOMONE F, et al. Systematic review and meta-analysis of immune checkpoint inhibitors as single agent or in combination with chemotherapy in early-stage non-small cell lung cancer: impact of clinicopathological factors and indirect comparison between treatment strategies[J]. Eur J Cancer, 2023, 195: 113404. doi: 10.1016/j.jeca.2023.113404. [32] ZHOU Y X, LI A L, YU H, et al. Neoadjuvant-adjuvant vs neoadjuvant-only PD-1 and PD-L1 inhibitors for patients with resectable NSCLC: an indirect meta-analysis[J]. JAMA Netw Open, 2024, 7(3): e241285. doi: 10.1001/jamanet-workopen.2024.1285. [33] MARINELLI D, NUCCIO A, DI FEDERICO A, et al. MA01.12 Survival outcomes and pathologic response after chemo-immunotherapy in resectable NSCLC: an individual patient data meta-analysis[J]. J Thorac Oncol, 2024, 19(10S): 55. doi: 10.1016/j.jtho.2024.09.098. [34] WASER N A, ADAM A, SCHWEIKERT B, et al. 1243P

Pathologic response as early endpoint for survival following neoadjuvant therapy (NEO-AT) in resectable non-small cell lung cancer (rNSCLC): systematic literature review and meta-analysis[J]. Ann Oncol, 2020, 31(4S): S806. doi: 10.1016/j.annonc.2020.08.116. [35] HINES J B, CAMERON R B, ESPOSITO A, et al. Evaluation of major pathologic response and pathologic complete response as surrogate end points for survival in randomized controlled trials of neoadjuvant immune checkpoint blockade in resectable in NSCLC[J]. J Thorac Oncol, 2024, 19(7): 1108-1116. doi: 10.1016/j.jtho.2024.03.010. [36] ISBELL J M, GOLDSTEIN J S, HAMILTON E G, et al. Ultrasensitive circulating tumor DNA (ctDNA) minimal residual disease (MRD) detection in early stage non-small cell lung cancer (NSCLC)[J]. J Clin Oncol, 2024, 42(16S): Abstr8078. doi: 10.1200/JCO.2024.42.16_suppl.8078. [37] XI A, PU Q, KANG R, et al. Dynamic ctDNA to inform the precise management of resected NSCLC: LUNGCA-2 study[J]. J Clin Oncol, 2023, 41(16S): Abstr8528. doi: 10.1200/JCO.2023.41.16_suppl.8528. [38] XU Y W, WAN B, ZHU S H, et al. Effect of adjuvant chemotherapy on survival of patients with 8th edition stage IB non-small cell lung cancer[J]. Front Oncol, 2022, 11: 784289. doi: 10.3389/fonc.2021.784289. [39] LOU F R, SIMA C S, RUSCH V W, et al. Differences in patterns of recurrence in early-stage versus locally advanced non-small cell lung cancer [J]. Ann Thorac Surg, 2014, 98(5): 1755-1761. doi: 10.1016/j.athoracsur.2014.05.070. [40] CHANSKY K, DETTERBECK F C, NICHOLSON A G, et al. The IASLC lung cancer staging project: external validation of the revision of the TNM stage groupings in the eighth edition of the TNM classification of lung cancer[J]. J Thorac Oncol, 2017, 12(7): 109-1121. doi: 10.1016/j.jtho.2017.04.011. [41] YU A P, FU F, LI X Y, et al. Perioperative immunotherapy for stage II-III non-small cell lung cancer: meta-analysis base on randomized controlled trials[J]. Front Oncol, 2024, 14: 1351359. doi: 10.3389/fonc.2024.1351359. [42] HUANG H, LI L Y, TONG L, et al. Perioperative PD-1/PD-L1 inhibitors for resectable non-small cell lung cancer: meta-analysis based on randomized controlled trials[J]. PLoS One, 2024, 19(9): e0310808. doi: 10.1371/journal.pone.0310808. [43] YUE D, WANG W, LIU H, et al. LBA58 Pathological response to neoadjuvant tisleizumab (TIS) plus platinum-doublet (PtDb) chemotherapy (CT) in resectable stage II-IIIAS NSCLC patients (pts) in the phase III (Ph3) RATIONALE-315 trial[J]. Ann Oncol, 2023, 34: S1299. doi: 10.1016/j.annonc.2023.10.054. [44] WANG C, ZHAO X, ZHANG L, et al. OA01.06 A phase II study of perioperative ivonescimab alone or combined with chemotherapy in resectable non-small cell lung cancer[J]. J

围手术期免疫治疗热点问题共识专家组.可切除非小细胞肺癌围手术期免疫治疗热点问题中国专家共识

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Thorac Oncol, 2024, 19(10S): S10. doi: 10.1016/j.jtho.2024.09.025. [45] HUANG S J, WU J H, LI S P, et al. Evaluation of combined pathological responses in primary tumor and lymph nodes following neoadjuvant chemoimmunotherapy in non-small cell lung cancer[J]. Lung Cancer, 2023, 186: 107401. doi: 10.1016/j.lungcan.2023.107401. [46] BANNA G L, HASSAN M A, SIGNORI A, et al. Neoadjuvant chemo-immunotherapy for early-stage non-small cell lung cancer: a systematic review and meta-analysis[J]. JAMA Netw Open, 2024, 7(4): 4e24637. doi: 10.1001/jamanet-workopen.2024.6837. [47] SORIN M, PROSTY C, GHALEB L, et al. Neoadjuvant chemoimmunotherapy for NSCLC: a systematic review and meta-analysis[J]. JAMA Oncol, 2024, 10(5): 621-633. doi: 10.1001/jamaoncol.2024.0057. [48] IZAKI Y, MIMAE T, KAGIMOTO A, et al. Differences in postoperative prognosis between early-stage lung adenocarcinoma and squamous cell carcinoma[J]. Jpn J Clin Oncol, 2024, 54(7): 813-821. doi: 10.1093/jico/hyae049. [49] NAKAMURA H, SAKAI H, KIMURA H, et al. Difference in postsurgical prognostic factors between lung adenocarcinoma and squamous cell carcinoma[J]. Ann Thorac Cardiovasc Surg, 2017, 23(6): 291-297. doi: 10.5761/atcs.oa.17-00020. [50] MOUNTZIOS G, REMON J, HENDRIKS L E L, et al. Immune-checkpoint inhibition for resectable non-small-cell lung cancer-opportunities and challenges[J]. Nat Rev Clin Oncol, 2023, 20(10): 664-677. doi: 10.1038/s41571-023-00794-7. [51] YAN W P, ZHONG W Z, LIU Y H, et al. Adebrelimab (SHR-1316) in combination with chemotherapy as perioperative treatment in patients with resectable stage II to III NSCLCs: an open-label, multicenter, phase 1b trial[J]. J Thorac Oncol, 2023, 18(2): 194-203. doi: 10.1016/j.jtho.2022.09.222. [52] GANDHI L, RODRÍGUEZ-ABREU D, GADGEEL S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer[J]. N Engl J Med, 2018, 378(22): 2078-2092. doi: 10.1056/NEJMoa1801005. [53] PAZ-ARES L, LUFT A, VICENTE D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer[J]. N Engl J Med, 2018, 379(21): 2040-2051. doi: 10.1056/NEJMoa1810865. [54] ZHOU C C, CHEN G Y, HUANG Y C, et al. Camrelizumab plus carboplatin and pemetrezed versus chemotherapy alone in chemotherapy-naive patients with advanced non-squam-ous non-small-cell lung cancer(CameL): a randomised, open-label, multicentre, phase 3 trial[J]. Lancet Respir Med, 2021, 9(3): 305-314. doi: 10.1016/S2213-2600(20)30365-9. [55] YANG Y P, WANG Z H, FANG J, et al. Efficacy and safety of sintilimab plus pemetrezed and platinum as first-line treatment for locally advanced or metastatic nonsquamous

NSCLC: a randomized, double-blind, phase 3 study (oncology pRogram by InnovENT anti-PD-1-11)[J]. J Thorac Oncol, 2020, 15(10): 1636-1646. doi: 10.1016/j.jtho.2020.07.014. [56] ZHOU C C, WU L, FAN Y, et al. Sintilimab plus platinum and gemcitabine as first-line treatment for advanced or meta-static squamous NSCLC: results from a randomized, double-blind, phase 3 trial (ORIENT-12)[J]. J Thorac Oncol, 2021, 16(9): 1501-1511. doi: 10.1016/j.jtho.2021.04.011. [57] LU S, WANG J, YU Y, et al. Tislelizumab plus chemotherapy as first-line treatment for locally advanced or metastatic nonsquamous NSCLC (RATIONALE 304): a randomized phase 3 trial[J]. J Thorac Oncol, 2021, 16(9): 1512-1522. doi: 10.1016/j.jtho.2021.05.005. [58] ZHONG H, SUN S J, CHEN J H, et al. First-line penpulimab combined with paclitaxel and carboplatin for metastatic squamous non-small-cell lung cancer in China (AK105-302): a multicentre, randomised, double-blind, placebo-controlled phase 3 clinical trial[J]. Lancet Respir Med, 2024, 12(5): 355-365. doi: 10.1016/S2213-2600(23)00431-9. [59] AWAD M, CASCONE T, SPICER J, et al. LBA2 Clinical outcomes with perioperative nivolumab (NIVO) in patients (PTS) with resectable NSCLC from the phase III CheckMate 77T study[J]. ESMO Open, 2024, 9(3S): 102985. doi: 10.1016/j.esmoop.2024.102985. [60] ROTHSCHILD S I, ZIPPELIUS A, EBOULET E I, et al. SAKK 16/14: durvalumab in addition to neoadjuvant chemotherapy in patients with stage IIIA(N2) non-small-cell lung cancer-a multicenter single-arm phase II trial[J]. J Clin Oncol, 2021, 39(26): 2872-2880. doi: 10.1200/JCO.21.00276. [61] TONG B C, GU L, WANG X F, et al. Perioperative outcomes of pulmonary resection after neoadjuvant pembrolizumab in patients with non-small cell lung cancer[J]. J Thorac Cardiovasc Surg, 2022, 163(2): 427-436. doi: 10.1016/j.jtcvs.2021.02.099. [62] GAO S G, LI N, GAO S Y, et al. Neoadjuvant PD-1 inhibitor or (Sintilimab) in NSCLC[J]. J Thorac Oncol, 2020, 15(5): 816-826. doi: 10.1016/j.jtho.2020.01.017. [63] SHAO M E, YAO J, WANG Y K, et al. Two vs three cycles of neoadjuvant sintilumab plus chemotherapy for resectable non-small-cell lung cancer: neoSCORE trial[J]. Signal Transport Target Ther, 2023, 8(1): 146. doi: 10.1038/s41392-023-01355-1. [64] QIU F M, FAN J Q, SHAO M E, et al. Final survival outcomes and exploratory biomarker analysis from the randomized, phase 2 neoSCORE trial: two versus three cycles of neoadjuvant sintilumab plus chemotherapy for resectable non-small cell lung cancer[J]. J Clin Oncol, 2024, 42(16S): Abstr8048. doi: 10.1200/JCO.2024.42.16_suppl.8048. [65] ZHANG X Y, SHAO M E, YAO J, et al. NeoSCORE II:

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three vs four cycles of neoadjuvant sintimilab + chemotherapy for squamous non-small-cell lung cancer[J]. Future Oncol, 2024, 20(3): 121-129. doi: 10.2217/fon-2024-0026. [66] CHAFT J E, DAHLBERG S E, KHULLAR O V, et al. EA5142 Adjuvant nivolumab in resected lung cancers (AN-VIL)[J]. J Clin Oncol, 2018, 36(1S): AbstrTPS8581. doi: 10.1200/JCO.2018.36.15_suppl.TPS8581. [67] CALVO V, DOMINE M, SULLIVAN I, et al. A phase III clinical trial of adjuvant chemotherapy versus chemoimmunotherapy for stage IB-IIIA completely resected non-small cell lung cancer (NSCLC) patients nadim-adjuvant: new adjuvant trial of chemotherapy versus chemoimmunotherapy[J]. J Clin Oncol, 2021, 39(1S): AbstrTPS8581. doi: 10.1200/JCO.2021.39.15_suppl.TPS8581. [68] YUE D, TAN L, XU S, et al. 1080 Surgical outcomes from RATIONALE-315: randomized, double-blind, phase III study of perioperative tisleizumab with neoadjuvant chemotherapy in resectable NSCLC[J]. ESMO Open, 2024, 9(3S): 102687. doi: 10.1016/j.esmoop.2024.102687. [69] SPICER J, WANG C L, TANAKA F, et al. Surgical outcomes from the phase 3 CheckMate 816 trial: nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC)[J]. J Clin Oncol, 2021, 39(1S): Abstr8503. doi: 10.1200/JCO.2021.39.15_suppl.8503. [70] MITSUDOMI T, HEYMACH J V, RECK M, et al. OA12.05 Surgical outcomes with neoadjuvant durvalumab + chemotherapy followed by adjuvant durvalumab in resectable NSCLC (AEGEAN)[J]. J Thorac Oncol, 2023, 18(11S): S71-S72. doi: 10.1016/j.jtho.2023.09.070. [71] ANTONIA S J, VILLEGAS A, DANIEL D, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer[J]. N Engl J Med, 2017, 377(20): 1919-1929. doi: 10.1056/NEJMoa1709937. [72] SPIGEL D R, FAIVRE-FINN C, GRAY J E, et al. Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoroadiotherapy in stage III non-small-cell lung cancer[J]. J Clin Oncol, 2022, 40(12): 1301-1311. doi: 10.1200/JCO.21.01308. [73] ZHOU Q, CHEN M, JIANG O, et al. Sugemalimab versus placebo after concurrent or sequential chemoradiotherapy in patients with locally advanced, unresectable, stage III non-small-cell lung cancer in China (GEMSTONE-301): interim results of a randomised, double-blind, multicentre, phase 3 trial[J]. Lancet Oncol, 2022, 23(2): 209-219. doi: 10.1016/S1470-2045(21)00630-6. [74] GIRARD N, BAR J, GARRIDO P, et al. Treatment characteristics and real-world progression-free survival in patients with unresectable stage III NSCLC who received durvalumab after chemoradiotherapy: findings from the PACIFIC-R

[75] study[J]. J Thorac Oncol, 2023, 18(2): 181-193. doi: 10.1016/j.jtho.2022.10.003. [76] PARK C K, OH H J, KIM Y C, et al. Korean real-world data on patients with unresectable stage III NSCLC treated with durvalumab after chemoradiotherapy: PACIFIC-KR[J]. J Thorac Oncol, 2023, 18(8): 1042-1054. doi: 10.1016/j.jtho.2023.04.008. [76] PROVENCIO M, AWAD M M, SPICER J, et al. Clinical outcomes with perioperative nivolumab (NIVO) by nodal status among patients (pts) with stage III resectable NSCLC: results from the phase 3 CheckMate 77T study[J]. J Clin Oncol, 2024, 42(17S): AbstrLBA8007. doi: 10.1200/JCO.2024.12.19suppl.LBA8007. [77] HEYMACH J, RECK M, MITSUDOMI T, et al. Outcomes with perioperative durvalumab (D) in pts with resectable NSCLC and baseline N2 lymph node involvement (N2 R-NSCLC): an exploratory subgroup analysis of AEGEAN[J]. J Clin Oncol, 2024, 42(16S): Abstr8011. doi: 10.1200/JCO.2024.12.19suppl.8011. [78] HU H L, ZOU S, XU R F, et al. Conversion therapy from N3 unresectable lung adenocarcinoma to radical surgery: a case report[J]. Ann Transl Med, 2019, 7(20): 590. doi: 10.21037/atm.2019.09.113. [79] JIA G H, ZHOU S M, XU T P, et al. Conversion therapy from unresectable stage IIIC non-small-cell lung cancer to radical surgery via anti-PD-1 immunotherapy combined with chemotherapy and anti-angiogenesis: a case report and literature review[J]. Front Oncol, 2022, 12: 954685. doi: 10.3389/foc.2022.954685. [80] FU Y, DUAN W C, XU R, et al. Conversion therapy with immunotherapy plus chemotherapy achieves a pathological complete response in stage IIIC NSCLC[J]. Front Immunol, 2023, 14: 1268153. doi: 10.3389/fimmu.2023.1268153. [81] DENG H S, LIU J, CAI X Y, et al. Radical minimally invasive surgery after immuno-chemotherapy in initially-unresectable stage IIIB non-small cell lung cancer[J]. Ann Surg, 2022, 275(3): e600-e602. doi: 10.1097/SLA.0000000000005233. [82] ZHOU Q, PAN Y, YANG X N, et al. Neoadjuvant SHR-1701 with or without chemotherapy in unresectable stage III non-small-cell lung cancer: a proof-of-concept, phase 2 trial[J]. Cancer Cell, 2024, 42(7): 1258-1267. e2, doi: 10.1016/j.ccc.2024.05.024. [83] ZHANG L, E H R, HUANG J, et al. Clinical utility of [18]FFDG PET/CT in the assessment of mediastinal lymph node disease after neoadjuvant chemoimmunotherapy for non-small cell lung cancer[J]. Eur Radiol, 2023, 33(12): 8564-8572. doi: 10.1007/s00330-023-09910-8. [84] CHEN Z Y, FU R, TAN X Y, et al. Dynamic $^{18}$F-FDG PET/CT can predict the major pathological response to neoadjuvant immunotherapy in non-small cell lung cancer[J].

围手术期免疫治疗热点问题共识专家组.可切除非小细胞肺癌围手术期免疫治疗热点问题中国专家共识

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Thorac Cancer, 2022, 13(17): 2524-2531. doi: 10.1111/1759-7714.14562. [85] CHENG Y, CHEN Z Y, HUANG J J, et al. Efficacy evaluation of neoadjuvant immunotherapy plus chemotherapy for non-small-cell lung cancer: comparison of PET/CT with post-operative pathology[J]. Eur Radiol, 2023, 33(10): 6625-6635. doi: 10.1007/s00330-023-09922-4. [86] KIM S H, LEE J H, LEE G J, et al. Interpretation and prognostic value of positron emission tomography-computed tomography after induction chemotherapy with or without radiation in IIIA-N2 non-small cell lung cancer patients who receive curative surgery[J]. Medicine (Baltimore), 2015, 94(24): e955. doi: 10.1097/MD.0000000000000955. [87] ZHANG J T, LIU S Y, GAO W, et al. Longitudinal undetectable molecular residual disease defines potentially cured population in localized non-small cell lung cancer[J]. Cancer Discov, 2022, 12(7): 1690-1701. doi: 10.1158/2159-8290.CD-21-1486. [88] XIA L, MEI J D, KANG R, et al. Perioperative etDNA-based molecular residual disease detection for non-small cell lung cancer: a prospective multicenter cohort study (LUNGCA-1)[J]. Clin Cancer Res, 2022, 28(15): 3308-3317. doi: 10.1158/1078-0432.CCR-21-3044. [89] FORDE P M, SPICER J, LU S, et al. Abstract CT003: Ni-volumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment (tx) for resectable (IB-IIIA) non-small cell lung cancer (NSCLC) in the phase 3 CheckMate 816 trial[J]. Cancer Res, 2021, 81(13S): CT003. doi: 10.1158/1538-7445.AM2021-CT003. [90] RECK M, GALE D, HARPOLE D, et al. LBA59 Associations of ctDNA clearance and pathological response with neoadjuvant treatment in patients with resectable NSCLC from the phase III AEGEAN trial[J]. Ann Oncol, 2023, 34: S1300. doi: 10.1016/j.annonc.2023.10.055. [91] GALE D, ZHU Z, LAI Z W, et al. Abstract CT238: Associations of ctDNA levels during neoadjuvant treatment with pathological response in patients with resectable NSCLC from the phase 3 AEGEAN trial[J]. Cancer Res, 2024, 84(7S): CT238. doi: 10.1158/1538-7445.AM2024-CT238. [92] RECK M, GALE D, ZHU Z, et al. LBA49 Associations of ctDNA clearance (CL) during neoadjuvant Tx with pathological response and event-free survival (EFS) in pts with resectable NSCLC (R-NSCLC): expanded analyses from AE-GEAN[J]. Ann Oncol, 2024, 35(2S): S1239. doi: 10.1016/j.annonc.2024.08.2290. [93] FELIP E, SRIVASTAVA M, RECK M, et al. 10 IMpower010: ctDNA status in patients (pts) with resected NSCLC who received adjuvant chemotherapy (chemo) followed by atezolizumab (atezo) or best supportive care (BSC)[J]. Immuno-Oncol Technol, 2022, 16(1S): 100106. doi: 10.1016/j.iotech.2022.100106.

[94] ZHOU C, DAS THAKUR M, SRIVASTAVA M K, et al. 20 IMpower010: biomarkers of disease-free survival (DFS) in a phase III study of atezolizumab (atezo) vs best supportive care (BSC) after adjuvant chemotherapy in stage IB-IIIA NSCLC[J]. Ann Oncol, 2021, 32: S1374. doi: 10.1016/j.annonc.2021.10.018. [95] SPICER J D, CASCONE T, WYNES M W, et al. Neoadjuvant and adjuvant treatments for early stage resectable NSCLC: consensus recommendations from the international association for the study of lung cancer[J]. J Thorac Oncol, 2024, 19(10): 1373-1414. doi: 10.1016/j.jtho.2024.06.010. [96] SPICER J, FORDE P M, PROVENCIO M, et al. Clinical outcomes with neoadjuvant nivolumab (N) + chemotherapy (C) vs C by definitive surgery in patients (pts) with resectable NSCLC: 3-y results from the phase 3 CheckMate 816 trial[J]. J Clin Oncol, 2023, 41(16S): Abstr8521. doi: 10.1200/JCO.2023.41.16_suppl.8521. [97] CHEN K Z, YANG F, SHEN H F, et al. Individualized tumor-informed circulating tumor DNA analysis for postoperative monitoring of non-small cell lung cancer[J]. Cancer Cell, 2023, 41(10): 1749-1762. e6. doi: 10.1016/j.ccell.2023.08.010. [98] PAN Y, ZHANG J T, GAO X, et al. Dynamic circulating tumor DNA during chemoradiotherapy predicts clinical outcomes for locally advanced non-small cell lung cancer patients[J]. Cancer Cell, 2023, 41(10): 1763-1773. e4, doi: 10.1016/j.ccell.2023.09.007. [99] PROVENCIO M, NADAL E, INSA A, et al. MA01.08 Five-year clinical outcomes of perioperative nivolumab and chemotherapy in stage III non-small-cell lung cancer (NADIM Trial)[J]. J Thorac Oncol, 2024, 19(10S): S54-S55. doi: 10.1016/j.jtho.2024.09.095. [100] PELLINI B, CHAUDHURI A A. Circulating tumor DNA minimal residual disease detection of non-small-cell lung cancer treated with curative intent[J]. J Clin Oncol, 2022, 40(6): 567-575. doi: 10.1200/JCO.21.01929. [101] MALLA M, LOREE J M, KASI P M, et al. Using circulating tumor DNA in colorectal cancer: current and evolving practices[J]. J Clin Oncol, 2022, 40(24): 2846-2857. doi: 10.1200/JCO.21.02615. [102] 中华医学会病理学分会,国家病理质控中心.实体瘤分子残留病灶检测共识[J].中华病理学杂志,2024,53(11):1088-1096. doi: 10.3760/cma.j.cn112151-20240627-00420. [103] CHAUDHURI A A, CHABON J J, LOVEJOY A F, et al. Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling[J]. Cancer Discov, 2017, 7(12): 1394-1403. doi: 10.1158/2159-8290. CD-17-0716. [104] GALE D, HEIDER K, RUIZ-VALDEPENAS A, et al. Residual ct DNA after treatment predicts early relapse in patients with early-stage non-small cell lung cancer[J]. Ann Oncol,

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2025年第25卷第X期

[105] HERBST R S, WU Y L, JOHN T, et al. Adjuvant osimertin- ib for resected EGFR-mutated stage IB-IIIA non-small-cell lung cancer: updated results from the phase III randomized ADAURA trial[J]. J Clin Oncol, 2023, 41(10): 1830-1840. doi: 10.1200/JCO.22.02186. [106] TSUBOI M, HERBST R S, JOHN T, et al. Overall survival with osimertinib in resected EGFR-mutated NSCLC[J]. N Engl J Med, 2023, 389(2): 137-147. doi: 10.1056/NEJMoa23 04594. [107] HE J X, SU C X, LIANG W H, et al. Icotinib versus chemo- therapy as adjuvant treatment for stage II-IIIA EGFR-mutant non-small-cell lung cancer (EVIDENCE): a randomised, open-label, phase 3 trial[J]. Lancet Respir Med, 2021, 9(9): 1021-1029. doi: 10.1016/S2213-2600(21)00134-X. [108] WU Y L, DZIADZIUSZKO R, AHN J S, et al. Alectinib in resected ALK-positive non-small-cell lung cancer[J]. N Engl J Med, 2024, 390(14): 1265-1276. doi: 10.1056/NEJMoa23 10532. [109] ZHONG W Z, CHEN K N, CHEN C, et al. Erlotinib versus gemacitabine plus cisplatin as neoadjuvant treatment of stage IIIA-N2 EGFR-mutant non-small-cell lung cancer (EMER- GING-CTONG 1103): a randomized phase II study[J]. J Clin Oncol, 2019, 37(25): 2235-2245. doi: 10.1200/JCO.19. 00075. [110] LV C, FANG W T, WU N, et al. Osimertinib as neoadjuvant therapy in patients with EGFR-mutant resectable stage II-IIIB lung adenocarcinoma (NEOS): a multicenter, single-arm, open-label phase 2b trial[J]. Lung Cancer, 2023, 178: 151-156. doi: 10.1016/j.lungcan.2023.02.011. [111] BLAKELY C M, URISMAN A, GUBENS M A, et al. Neo- adjuvant osimertinib for the treatment of stage I-IIIA epi- dermal growth factor receptor-mutated non-small cell lung cancer: a phase II multicenter study[J]. J Clin Oncol, 2024, 42(26): 3105-3114. doi: 10.1200/JCO.24.00071. [112] LEE J M, TOLOZA E M, PASS H I, et al. P2.01-06 NAUT- IKA1 study: preliminary efficacy and safety data with neoad- juvant alectinib in patients with stage IB-III ALK+ NSCLC[J]. J Thorac Oncol, 2023, 18(11S): S297-S298. doi: 10.1016/j.jtho.2023.09.511. [113] LEONETTI A, MINARI R, BONI L, et al. EP02.04-001 Alectinib as neoadjuvant treatment in surgically resectable stage III ALK-positive NSCLC: ALNEO phase II trial (GOIRC-01-2020)[J]. J Thorac Oncol, 2022, 17(9): S231. doi: 10.1016/j.jtho.2022.07.386. [114] ZENKE Y, YOH K, SAKAKIBARA-KONISHI J, et al.

P1.18-04 Neoadjuvant ceritinib for locally advanced non-small cell lung cancer with ALK rearrangement: SAKULA trial[J]. J Thorac Oncol, 2019, 14(10): S626-S627. doi: 10.1016/j.jtho.2019.08.1320. [115] SHU C A, GAINOR J F, AWAD M M, et al. Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial[J]. Lancet Oncol, 2020, 21(6): 786-795. doi: 10.1016/S1470-2045(20)30140-6. [116] ZHAO Z R, LIN Z C, SHEN J F, et al. Neoadjuvant immuno-therapy in oncogene-positive non-small cell lung cancer: a multicenter study[J]. Ann Thorac Surg, 2023, 116(4): 703-710 doi: 10.1016/j.athoracsur.2022.11.035. [117] ZHANG C, CHEN H F, YAN S, et al. Induction immun�-checkpoint habitors for resectable oncogene-mutant NSCLC: a multicenter pooled analysis[J]. npj Precis Oncol, 2022, 6(1): 66. doi: 10.1038/s41698-022-00301-8. [118] ZHANG C, SUN Y X, YI D C, et al. Neoadjuvant sintilimab plus chemotherapy in EGFR-mutant NSCLC: phase 2 trial in-terim results (NEOTIDE/CTONG2104)[J]. Cell Rep Med, 2024, 5(7): 101615. doi: 10.1016/j.xcrm.2024.101615. [119] ZHANG C, JIANG B Y, YAN L X, et al. MA15.11 Neoad-juvant sintilimab plus chemotherapy in EGFR-mutant NSCLC followed by adjuvant osimertinib or observation: a phase II CTONG2104 trial[J]. J Thorac Oncol, 2024, 19(10S): S119-S120. doi: 10.1016/j.jtho.2024.09.214. [120] NEGRAO M V, SKOULIDIS F, MONTESION M, et al. On-cogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer[J]. J Immunother Cancer, 2021, 9(8): e002891. doi: 10.1136/jitc-2021-002891. [121] OTA K, AZUMA K, KAWAHARA A, et al. Induction of PD-L1 expression by the EML4-ALK oncoprotein and down-stream signaling pathways in non-small cell lung cancer[J]. Clin Cancer Res, 2015, 21(17): 4014-4021. doi: 10.1158/1078-0432.CCR-15-0016. [122] JAHANZEB M, LIN H M, PAN X Y, et al. Immunotherapy treatment patterns and outcomes among ALK-positive pa-tients with non-small-cell lung cancer[J]. Clin Lung Cancer, 2021, 22(1): 49-57. doi: 10.1016/j.cllc.2020.08.003. [123] FELIP E, ALTORKI N, ZHOU C, et al. Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIA non-small-cell lung cancer (Impower010): a randomised, multicentre, open-label, phase III trial[J]. Ann Oncol, 2023, 34(10): 907-919. doi: 10.1016/j.annonc.2023.07.001.

[收稿日期] 2025-07-22

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