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Advances in Clinical Medicine
Vol. 14  No. 01 ( 2024 ), Article ID: 79505 , 5 pages
10.12677/ACM.2024.141131

免疫治疗在非小细胞肺癌中的应用

郭永欣1，姚兵2

1青海大学研究生院，青海 西宁

2青海大学附属医院胸外科，青海 西宁

收稿日期：2023年12月19日；录用日期：2024年1月13日；发布日期：2024年1月19日

摘要

肺癌病死率、发病率在我国多种恶性肿瘤疾病中高居首位。非小细胞肺癌(non-small cell lung cancer, NSCLC)是导致肺癌患者死亡的常见临床类型，约占肺癌整体的80%。免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)形式的免疫治疗在NSCLC的治疗中显示出巨大的益处，现在正被用作不可切除的局部晚期NSCLC放化疗后的巩固治疗，以及可切除NSCLC行手术切除和化疗后的辅助治疗。多项3期研究测试了针对程序性细胞死亡蛋白-1 (programmed death-1, PD-1)抗体，程序性死亡蛋白配体-1 (programmed death ligand-1, PD-L1)和细胞毒性T淋巴细胞抗原-4 (cytotoxic-lymphocyte-associated antigen 4, CTLA-4)抗体的不同药物，联合或不联合化疗。本文通过回顾相关研究对NSCLC的免疫治疗研究进展进行综述。肺癌免疫治疗的前景正在迅速扩大，ICI已成为转移性、局部晚期和可切除NSCLC患者的标准护理治疗，OS有显著改善。

关键词

非小细胞肺癌，免疫治疗，免疫检查点抑制剂

The Application of Immunotherapy in Non-Small Cell Lung Cancer

Yongxin Guo1, Bing Yao2

1Graduate School of Qinghai University, Xining Qinghai

2Department of Thoracic Surgery, Affiliated Hospital of Qinghai University, Xining Qinghai

Received: Dec. 19th, 2023; accepted: Jan. 13th, 2024; published: Jan. 19th, 2024

ABSTRACT

The case fatality rate and incidence rate of lung cancer rank first among many kinds of malignant tumor diseases in China. Non-small cell lung cancer (NSCLC) is a common clinical type of death in lung cancer patients, accounting for about 80% of the overall lung cancer. Immunotherapy in the form of immune checkpoint inhibitors (immune checkpoint inhibitors, ICIs) has shown great benefits in the treatment of NSCLC and is now being used as consolidation therapy after unresectable locally advanced NSCLC, as well as adjuvant therapy after surgical resection and chemotherapy for resectable NSCLC. Several phase 3 studies tested different agents against programmed cell death protein-1 (programmed death-1, PD-1), programmed death protein ligand-1 (programmed death ligand-1, PD-L1) and cytotoxic T lymphocyte antigen-4 (cytotoxic-lymphocyte-associated antigen 4, CTLA-4) antibodies with or in combination with chemotherapy. This review reviews the progress of immunotherapy in NSCLC by reviewing relevant studies. The promise of immunotherapy for lung cancer is rapidly expanding, and ICI has become the standard of care treatment for patients with metastatic, locally advanced and resectable NSCLC, with significant improvement in OS.

Keywords:Non-Small Cell Lung Cancer, Immunotherapy, Immune Checkpoint Inhibitors

Copyright © 2024 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

肺癌病死率、发病率在我国多种恶性肿瘤疾病中高居首位。非小细胞肺癌(non-small cell lung cancer, NSCLC)是导致肺癌患者死亡的常见临床类型，约占肺癌整体的80% [1] 。肺癌的高发病率和高死亡率给社会带来了沉重的疾病负担。相比传统化疗，免疫治疗的逐渐兴起为驱动基因阳性的患者群体带来了新的机遇与挑战。肺癌免疫治疗的前景正在迅速扩大，ICI已成为转移性、局部晚期和可切除NSCLC患者的标准治疗，总生存(overall survival, OS)率有显著改善 [2] 。免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)形式的免疫治疗在NSCLC的治疗中显示出巨大的益处，现在正被用作不可切除的局部晚期NSCLC放化疗后的巩固治疗，以及可切除NSCLC行手术切除和化疗后的辅助治疗。ICIs包括程序性细胞死亡蛋白-1 (programmed death-1, PD-1)抗体，程序性死亡蛋白配体-1 (programmed death ligand-1, PD-L1)和细胞毒性T淋巴细胞抗原-4 (cytotoxic T-lymphocyte-associated antigen 4, CTLA-4)抗体。本文通过回顾相关研究对NSCLC的免疫治疗研究进展进行综述。

2. 纳武利由单抗

纳武利尤单抗是一种靶向PD-4的全人源IgG1抗体。Forica等 [3] 回顾性分析35例IB/IV期NSCLC患者，试验组(n = 15)接受超分割放疗序贯纳武利尤单抗免疫治疗，对照组(n = 20)仅纳武利尤单抗治疗，两组患者1年总生存(overall survival, OS)率分别为57.8%、27.4% (P = 0.043)，1年无进展生存(progression-free survival, PFS)率分别为57.8%、20.6% (P = 0.040)，结果提示试验组在临床疗效方面优于对照组。Bassanelli等 [4] 回顾性分析95例IB/IV期NSCLC患者接受放疗联合纳武利尤单抗治疗，全部患者的中位OS为11.9个月，中位PFS为6.3个月；亚组分析结果显示，纳武利尤单抗免疫治疗60 d内接受放疗的患者放疗结束超过60 d后接受纳武利尤单抗免疫的患者，中位OS分别为22.4个月、8.6个月(P = 0.005)，中位PFS分别为8.7个月6.3个月(P = 0.21)。CheckMate 017 and 057研究中，纳武单抗组的5年OS率为13.4%，与化疗相比，OS率增长了5倍 [5] 。

3. 帕博丽珠单抗

帕博丽珠单抗是一种靶向PD-4的人源化IgG1抗体。Anouti [6] 等的临床研究纳入92例IA/IIB期的NSCLC患者，接受同步放化疗序贯帕博利珠单抗巩固治疗，中位随访时间30.5个月，接受>4周期帕博利珠单抗治疗组77例，接受<4周期帕博利珠单抗治疗组15例，结果提示，4周期免疫治疗比<4周期免疫治疗可明显提高远期疗效，两组PFS与OS差异均有统计学意义(P = 0.04; P = 0.001)。KEYNOTE 189研究 [7] 比较了单独化疗与化疗和帕博利珠单抗联合化疗在非鳞状NSCLC患者中作为一线治疗。使用的化疗是培美曲塞 + 顺铂/卡铂。在任何PD-L1表达水平的非鳞状NSCLC患者中，帕博利珠单抗联合化疗组的OS为22个月，而单独化疗组的OS为10.7个月，HR 0.56。KEYNOTE-024 [8] 研究中比较了帕博利珠单抗与铂类化疗双药治疗PD-L1阳性NSCLC的效果。使用的化疗是研究者选择的铂类化疗双联药。该试验纳入了至少18%的肿瘤细胞上PD-L82表达的鳞状(1%)和非鳞状(50%)组织学患者。大多数患者是现在或既往吸烟者(92%)。帕博利珠单抗组的中位总生存期为30.0个月，化疗组为14.2个月，风险比为0.63，P = 0.002。KEYNOTE042 [9] 纳入了NSCLC的局部晚期或转移性疾病，没有既往治疗，没有EGFR或ALK易位的驱动突变，PD-L1肿瘤比例评分(TPS)为1%或更高。该试验纳入了鳞状和非鳞状组织学患者，其中大多数是现在或既往吸烟者。该实验比较了帕博利珠单抗与研究者选择的铂类化疗双药。帕博利珠单抗组的中位OS为16.7个月，化疗组为12.1个月，风险比为0.81，P = 0.0018。对于PD-L1 TPS为50%或更高的患者，帕博丽珠单抗和化疗组的中位OS分别为20个月和12.2个月。

4. 阿替丽珠单抗

阿替利珠单抗是一种靶向PD-L1的人源化IgG1抗体。IMpower130 [10] 研究比较了阿替利珠单抗联合卡铂加白蛋白–紫杉醇化疗，以及单独化疗作为转移性非鳞状NSCLC的一线治疗。大约一半的患者患有PD-L1阴性肿瘤。阿替利珠单抗加化疗组的中位OS为18.6个月，化疗组为13.9个月；HR 0.79，P = 0.033。亚组分析显示，在所有PD-L1表达水平中，PFS及OS均有获益。IMpower132研究 [11] 对比了阿替利珠单抗联合化疗与化疗在无EGFR突变和无ALK突变的晚期非鳞NSCLC患者中的治疗效果，结果表明，无论PD-L1表达情况，阿替利珠单抗联合组能够改善PFS (7.6个月vs 5.2个月)。基于IMpower132研究，2021年6月中国国家药品监督管理局批准阿替利珠单抗联合培美曲塞和铂类化疗用于无EGFR突变和无ALK突变的转移性非鳞NSCLC一线治疗。

5. 度伐利尤单抗

度伐利尤单抗是一种靶向PD-L1的全人源IgG1 K抗体。Socinski等 [12] 开展的一项多中心、随机、双盲I期临床试验共纳入713例不可切除的III期NSCLC患者接受同步放化疗后序贯度伐利尤单抗或安慰剂，分为≥70岁组(n = 158)和<70岁组(n = 555)。≥70岁组中101例接受度伐利尤单抗、57例接受安慰剂治疗，中位PFS分别为12.3个月、6.1个月，中位OS分别为29个月、26.9个月；<70岁组中375例接受度伐利尤单抗、180例接受安慰剂治疗，中位PFS分别为16.9个月、5.6个月，中位OS分别为未达到、31个月。Inoue等 [13] 回顾性分析30例局部晚期NSCLC患者接受放疗联合度伐利尤单抗治宁的不良反应情况，1，2级肺炎发生率分别为(26.7%，8例)、(46.7%，14例)，未出现3~5级肺炎。

6. 伊匹木单抗

伊匹木单抗是一种靶向CTLA-1的全人源IgG4 K抗体。CHECKMATE-227研究 [14] 包括既往未接受治疗的IV期或复发性NSCLC患者，PD-L1表达水平为1%或以上的患者以1:1:1的比例随机接受纳武利尤单抗加伊匹木单抗、纳武利尤单抗单独使用或化疗。使用的化疗是顺铂或卡铂，联合吉西他滨治疗鳞状细胞NSCLC患者，或培美曲塞治疗非鳞状细胞疾病患者。OS分别为17.1、15.7和14.9个月。PD-L1表达水平低于1%的患者以1:1:1的比例随机分配接受纳武利尤单抗加伊匹木单抗、纳武利尤单抗加化疗或化疗。OS分别为17.2、15.2和12.2个月。CHECKMATE-9LA [15] 将IV期NSCLC患者随机分配到纳武利尤单抗360 mg Q3W + ipilimumab 1 mg/kg Q6W + 两个周期的化疗或单独4个周期的化疗。使用的化疗是顺铂或卡铂联合培美曲塞或紫杉醇。这些数据以摘要格式呈现，并在美国临床肿瘤学会(ASCO) 2020年年会上作为讲座呈现。免疫治疗–化疗组和仅化疗组的中位OS分别为15.6个月和10.9个月。亚组分析显示：无论PD-L1表达如何，免疫治疗–化疗联合治疗的临床获益均优于仅化疗。

7. 小结

免疫治疗是NSCLC的重要治疗方式，为每位患者量身定制治疗方案是实现最佳益处的关键。虽然目标应该是在一线使用“无化疗”或“最小化疗”方案，但重要的是要知道哪些患者不能从这些方案中受益。免疫治疗和化疗相结合的方案在一线治疗中很重要，治疗结果显示出近期疗效和远期疗效均得到提高。但免疫治疗联合放化疗治疗仍有一些的问题，例如联合用药的时序、剂量：药物联合放疗是否同步；方案治疗持续时间；不良反应的处理等。期待更多的高质量、多中心、随机对照临床研究去探索证实。

文章引用

郭永欣,姚 兵. 免疫治疗在非小细胞肺癌中的应用
The Application of Immunotherapy in Non-Small Cell Lung Cancer[J]. 临床医学进展, 2024, 14(01): 921-925. https://doi.org/10.12677/ACM.2024.141131

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