Disease progression in non-small cell lung cancer on immune-checkpoint inhibition, what are the options?
Review Article

非小细胞肺癌免疫检查点抑制剂耐药后的治疗选择

Rudolf M. Huber1,2

1Division of Respiratory Medicine and Thoracic Oncology, Department of Medicine, University of Munich – Campus Innenstadt, Munich, Germany; 2Thoracic Oncology Centre Munich, Member of the German Centre for Lung Research (DZL, CPC-M), Munich, Germany

Correspondence to: Rudolf M. Huber. Division of Respiratory Medicine and Thoracic Oncology, Department of Medicine, University of Munich – Campus Innenstadt, Ziemssenstraße 1, D-80336 Munich, Germany. Email: huber@med.uni-muenchen.de.

摘要：多数晚期驱动基因阴性的非小细胞肺癌患者会接受或即将接受帕博利珠单抗治疗(PD-L1高表达)或PD-1-/PD-L1联合化疗，或PD-1联合CTLA4抑制剂治疗。Ⅲ期肺癌进行同步放化疗后予以度伐利尤单抗强化治疗已在临床中应用。即使一线治疗有效，大部分患者仍然会出现复发和疾病进展。问题在于我们如何为患者选择治疗方案。随着PD-1以及PD-L1抑制剂在复发肿瘤中的应用，我们充分依据随机临床研究寻求理想的治疗选择。随着免疫检查点抑制剂逐渐推向一线治疗，我们应寻找复发性和难治型肿瘤的其他选择。迄今未有相关数据指出最佳方案。根据早期的经验推断，我们建议如下方案，但仍需前瞻性临床研究证实。(I)如果一线治疗仅为帕博利珠单抗，二线治疗应选择经典的双药化疗。若出现孤立/寡病灶进展，可增加局部治疗。此外免疫调节药物的增加可在临床试验中得以验证；(Ⅱ)如果一线治疗为免疫检查点抑制剂联合化疗，经典二线化疗是合理的。培美曲塞二钠若在一线治疗中未使用，则可用于二线治疗非鳞非小细胞肺癌，否则通常选用多西他赛。出于快速复发/进展的考虑，在早期进展/复发期间可选用抗血管生成药物。免疫调节药物可在前瞻性临床试验中得以验证，在孤立/寡病灶进展中局部治疗得以讨论。(Ⅲ)如果一线治疗选择PD-1抑制剂联合CTLA4抑制剂，经典的双药化疗方案可能为更合适的选择。此外，前瞻性临床试验可进一步验证免疫调节药物。在孤立/寡转移病灶进展的情况下，可用局部治疗评估疗效。对于二次复发的患者，可提供个体化的治疗。总之，对于免疫检查点抑制剂治疗后出现疾病进展后如何选择，目前仍无良好的循证医学证据。目前亟需通过前瞻性的临床研究为驱动基因突变阴性的晚期NSCLC的治疗排兵布阵，提供理想的选择。

关键词：非小细胞肺癌；肿瘤免疫；免疫检查点抑制剂；复发

Received: 11 March 2019; Accepted: 18 March 2019; Published: 12 April 2019.

doi: 10.21037/pcm.2019.03.01

简介

对于驱动基因阴性的非小细胞肺癌(NSCLC)，免疫检查点抑制剂已逐渐走向一线治疗。对于PD-L1者，例如肿瘤比例评分(TPS)大于或等于50%者，帕博利珠单抗单药治疗在毒性反应、无进展生存期和总生存期上均优于双药化疗[1,2]。有关PD-L1表达的所有宣传中，非鳞NSCLC的帕博利珠单抗联合培美曲塞和顺铂/卡铂均优于单纯化疗[3]。阿特珠单抗联合多西紫杉醇，卡铂和贝伐珠单抗也优于三药方案[4]。在鳞癌中，阿特珠单抗联合卡铂和白蛋白紫杉醇提高了PFS和OS[5]。帕博利珠单抗联合紫杉醇或白蛋白紫杉醇和卡铂也获得了同样的疗效[6]。在高突变负荷的NSCLC中，无论PD-L1的表达情况如何，PD-1抑制剂和CTL4抑制剂的联合治疗获益均优于化疗[7]。此外，在同步放化疗后序贯度伐利尤单抗的强化治疗显示相应的生存优势[8,9]。充分的证据证明在一线化疗后PD-1和PD-L1抑制剂有效[10-13]，然而几乎没有前瞻性数据为一线使用免疫检查点抑制剂后肿瘤复发和进展后续治疗提供依据。因此根据不同的一线治疗情况，以下我们将阐述一线免疫检查点抑制剂治疗后如何治疗的策略。当然，上述方案有待在未来通过注册的临床试验数据进行证实。

因毒性反应停止免疫检查点治疗后或者经长程治疗后出现疾病进展

若因毒性反应停止免疫检查点抑制剂治疗，其后出现进展，重新启用免疫检查点抑制剂不失为选择[14]。长期使用免疫检查点抑制剂治疗并获得持久的疗效，进展时再次引入免疫检查点抑制剂具备合理性[15]。该议题将在本期PCM的另一篇文章中阐述。

PD-1抑制剂单药治疗期间出现疾病进展

在PD-1抑制剂单药治疗过程中若出现疾病进展，可予以经典的双药化疗方案[3]，且治疗强度合适。如果是单一/寡病灶进展，可添加局部治疗，特别是放射治疗[16,17]。放射治疗会产生免疫效应，可能导致照射区域外远处的肿瘤消退(远隔效应)[18]。一篇系统综述包含了从1969年到2014年共46个病例，在不同病种的各种不同临床情况下均可观察到远隔效应，最晚可在放疗后12个月出现[19]。远隔效应也可出现于放疗联合伊匹单抗治疗后[20]。在一项Ⅱ期临床试验中，寡转移局部消融治疗后予以帕博利珠单抗获得了良好的PFS和OS[21]。放疗和其他免疫治疗的联合也可作为临床试验中的选择[22,23]。获得性耐药的原因包括T细胞耗竭，可以通过增加旁路刺激克服上述问题。例如在CTLA-4抗体，伊匹单抗基础上增加纳武单抗[24]。PD-1联合靶向TGF-β也可作为选择方案[25]。

免疫检查点抑制剂联合化疗(加贝伐珠单抗)治疗中或治疗后疾病进展

在免疫检查点抑制剂联合双药化疗(加贝伐珠单抗)治疗后，采用标准的二线单药化疗方案：多西他赛或者培美曲塞(非鳞NSCLC，且一线治疗中没有使用过)也许是合理的选择。化疗也具备免疫原性并有利于后续的免疫检查点抑制剂治疗[26]。在双药化疗后的二线治疗中，雷莫芦单抗或者尼达尼布(非鳞NSCLC)的加入可获益，尤其适用于早期复发和进展的肿瘤[27-29]。这也可能适用于免疫检查点抑制剂治疗后，甚至在化疗和纳武利尤单抗后的三线治疗[30,31]。如上所述，在免疫检查点抑制剂联合化疗(加贝伐珠单抗)后孤立或寡转移进展，局部消融治疗有用。后续的免疫治疗策略如有机会，可在临床试验中验证[32]。例如pegilodecakin(IL-10)[33]，恩替诺特（HDAC抑制剂)[34]，Toll样受体9激动剂，例如lefitolimod[35]、腺苷抑制剂[36,37]以及经肿瘤浸润淋巴细胞的过继细胞疗法[38]。

PD-1抑制剂联合CTLA4抑制剂治疗中或后进展

如果一线治疗联合使用PD-1抑制剂和CTLA4抑制剂，经典的双药化疗会是更优选择。其他的免疫调节剂可以进一步在前瞻性临床试验中验证。在孤立或者寡病灶进展中，上述的局部治疗可以用于评估。

必要的研究

如果一线使用双药化疗，那么在驱动基因阴性NSCLC中，二线治疗的选择上证据充足。随着免疫治疗逐渐推至一线，我们却无足够的证据来支持初次进展或复发后的处理。在一线治疗的临床试验中，必须监测二线和三线治疗，包含治疗方案、疗效、二线和三线的无进展生存期，这样此时上述问题才能得以解决。对一线接受免疫治疗的患者进行前瞻性登记随访也有帮助。尽管如此，通过设计临床试验来验证多线治疗后的最佳策略仍是必要的。

结论

随着免疫治疗在驱动基因阴性NSCLC中逐渐推入一线，亟需复发进展后的治疗方案。而目前只有专家的共识推荐可供参考。我们的推荐见图1。根据一线治疗方案，二线治疗多数为化疗：双药化疗，如果一线方案仅为免疫治疗，一线方案为免疫治疗联合双药化疗(加贝伐珠单抗)或免疫治疗联合放化疗，二线u西安则静丹单药化疗。如果早期出现进展/复发发生较早，加抗血管生成药物(尼达尼布，雷莫芦单抗)可能提高疗效。若为孤立病灶或寡病灶进展，局部消融治疗已足够，且增强了免疫检查点抑制剂疗效。免疫治疗进一步的组合通常可在临床试验中应用。总之，我们亟需前瞻性的数据解答以上问题。

图1
图1 NSCLC一线应用免疫检查点抑制剂后复发和进展的治疗流程。NSCLC，非小细胞肺癌。

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor Nir Peled for the series dedicated to the Congress on Clinical Controversies in Lung Cancer (CCLC 2018) published in Precision Cancer Medicine. The article has undergone external peer review.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/pcm.2019.03.01). The series dedicated to the Congress on Clinical Controversies in Lung Cancer (CCLC 2018) was commissioned by the editorial office without any funding or sponsorship. RMH reports grants and personal fees from Astra Zeneca, and personal fees from Takeda, Merrimak, Chugai, Abbvie, Novartis, Bayer, BMS, Boehringer Ingelheim, Celgene, Pfizer, Roche, Lilly, Guardant Health, Mologen, MSD, outside the submitted work . The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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译者介绍
赵欣宇
2015年毕业于中国医科大学七年制，获得临床医学学士，肿瘤学硕士（放射治疗）学位。2015年7月起于中国医科大学附属第一医院放疗科工作，现职称为讲师/主治医师，主要工作方向为胸部肿瘤放射治疗和立体定向放射治疗。同时于2018年考取于金明院士全日制定向博士，目前肿瘤学博士在读。从上学起我校采取专业课全英文教学，英语学习也是我的个人爱好，学生时期有过字幕组、环球科学科技新闻翻译等工作经验，工作后参加卫生部考试入选全球卫生后备人才库。从硕士阶段起了解到AME出版集团，陆续翻译多篇AME杂志、书籍等文献。（更新时间：2021/9/4）
审校介绍
戴映
安徽医科大学第一附属医院肿瘤内科
主治医师，肿瘤学博士
主攻胸部肿瘤内科治疗
2014年毕业于海德堡大学医学院
2017年德国汉堡大学UKE医院肿瘤中心访问学者
2017年入选全球卫生后备人才库
主持课题3项，参与省级课题多项，德国科学研究基金及德国癌症援助基金各1项
2013年度美国波士顿ASTRO会议及德国DEGRO会议壁报汇报
2020年新加坡世界肺癌大会壁报汇报
以第一作者发表SCI论文2篇，通讯作者发表SCI论文1篇
「学术任职」
安徽省全科医学会肿瘤内科分会青年委员
中国抗癌协会肿瘤营养专业委员会老年肿瘤营养学组委员
（更新时间：2021/9/4）

（本译文仅供学术交流，实际内容请以英文原文为准。）

doi: 10.21037/pcm.2019.03.01
Cite this article as: Huber RM. Disease progression in non-small cell lung cancer on immune-checkpoint inhibition, what are the options? Precis Cancer Med 2019;2:13.

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