非小细胞肺癌围手术期免疫治疗研究进展———新辅助免疫治疗进展

doi:10.3969/j.issn.1006-7795.2024.04.017

摘要/Abstract

摘要： 非小细胞肺癌（non-small cell lung cancer, NSCLC）有较高的发病率和病死率，使其治疗成为全球急需应对的重大健康挑战。随着免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）的引入，治疗NSCLC的新思路不断涌现，并且在晚期NSCLC患者中已显示出显著的生存获益。近年来，研究人员开始探索将ICIs引入新辅助治疗的可行性，并发现其在新辅助治疗中同样可为患者带来治疗获益。本文旨在综述近期关于ICIs在NSCLC新辅助治疗中的研究进展，重点讨论其对患者生存期、病理反应等方面的影响。这些研究成果有望为改善NSCLC患者的新辅助治疗效果提供新的策略和思路。

关键词: 非小细胞肺癌, 围手术期, 免疫治疗, 研究进展

Abstract: The treatment of non-small cell lung cancer (NSCLC) with a considerably high occurrence and lethality represents a significant global health challenge, which urgently needs to be addressed. With the introduction of immune checkpoint inhibitors (ICIs), new treatment avenues for NSCLC have emerged, showing significant survival benefits in patients with advanced NSCLC. In recent years, researchers have begun to explore the feasibility of incorporating ICIs into neoadjuvant therapy, finding that they also offer therapeutic benefits in this context. This article aims to review recent research progress on ICIs in the neoadjuvant treatment of NSCLC, focusing on their impact on patient survival, pathological response, and other aspects. These research findings shed light on new strategies and insights for improving the neoadjuvant treatment outcomes of NSCLC patients.

Key words: non-small cell lung cancer, perioperative, immunotherapy, research progress

中图分类号:

R734.2

郝卓鸿, 云铎, 张颖, 李卉惠, 林海珊, 崔永, 赵磊. 非小细胞肺癌围手术期免疫治疗研究进展———新辅助免疫治疗进展[J]. 首都医科大学学报, 2024, 45(4): 666-677.

Hao Zhuohong, Yun Duo, Zhang Ying, Li Huihui, Lin Haishan, Cui Yong, Zhao Lei. Advances in research of perioperative immunotherapy for non-small cell lung cancer—advances in neoadjuvant immunotherapy[J]. Journal of Capital Medical University, 2024, 45(4): 666-677.

参考文献

［1］ Hyuna S, Jacques F, Rebecca L S, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries［J］. CA Cancer J Clin, 2021, 71(3): 209-249.
［2］ Siegel R L, Miller K D, Fuchs H E, et al. Cancer statistics, 2022［J］. CA Cancer J Clin, 2022, 72(1): 7-33.
［3］ Rosell R, Karachaliou N. Large-scale screening for somatic mutations in lung cancer［J］. Lancet, 2016, 387(10026): 1354-1356.
［4］ Siegel R L, Miller K D, Fuchs H E, et al. Cancer statistics, 2021［J］. CA Cancer J Clin, 2021, 71(1): 7-33.
［5］ Alexopoulos G, Zhang J, Karampelas I, et al. Long-term time series forecasting and updates on survival analysis of glioblastoma multiforme: a 1975-2018 population-based study［J］. Neuroepidemiology, 2022, 56(2): 75-89.
［6］ Le Chevalier T. Adjuvant chemotherapy for resectable non-small-cell lung cancer: where is it going?［J］. Ann Oncol, 2010, 21 (Suppl 7）: vii196-vii198.
［7］ Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small cell lung cancer collaborative group［J］. BMJ, 1995, 311(7010): 899-909.
［8］ Arriagada R, Auperin A, Burdett S, et al. Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data［J］. Lancet, 2010, 375(9722): 1267-1277.
［9］ Goldstraw P, Chansky K, Crowley J, et al. The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer［J］. J Thorac Oncol, 2016, 11(1): 39-51.
［10］ NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data［J］. Lancet, 2014, 383(9928): 1561-1571.
［11］ Lim E, Harris G, Patel A, et al. Preoperative versus postoperative chemotherapy in patients with resectable non-small cell lung cancer: systematic review and indirect comparison meta-analysis of randomized trials［J］. J Thorac Oncol, 2009, 4(11): 1380-1388.
［12］ Kang J, Zhang C, Zhong W Z. Neoadjuvant immunotherapy for non-small cell lung cancer: state of the art［J］. Cancer Commun (Lond), 2021, 41(4): 287-302.
［13］ Berghmans T, Durieux V, Hendriks LEL, et al. Immunotherapy: from advanced NSCLC to early stages, an evolving concept［J］. Front Med (Lausanne), 2020, 7: 90.
［14］ 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.
［15］ Provencio M, Serna-Blasco R, Nadal E, et al. Overall survival and biomarker analysis of neoadjuvant nivolumab plus chemotherapy in operable stage ⅢA non-small-cell lung cancer (NADIM phase II trial)［J］. J Clin Oncol, 2022, 40(25): 2924-2933.
［16］ Liu S Y, Dong S, Yang X N, et al. Neoadjuvant nivolumab with or without platinum-doublet chemotherapy based on PD-L1 expression in resectable NSCLC (CTONG1804): a multicenter open-label phase II study［J］. Signal Transduct Target Ther, 2023, 8(1): 442.
［17］ Cascone T, Leung C H, Weissferdt A, et al. Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non-small cell lung cancer: the phase 2 platform NEOSTAR trial［J］. Nat Med, 2023, 29(3): 593-604.
［18］ Cascone T, William W N J, Weissferdt A, et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial［J］. Nat Med, 2021, 27(3): 504-514.
［19］ Anon. Discussion to: surgical outcomes after chemotherapy plus nivolumab and chemotherapy plus nivolumab and ipilimumab in patients with non-small cell lung cancer［J］. J Thorac Cardiovasc Surg, 2024, 167(4): 1454-1455.
［20］ Zhao Z R, Yang C P, Chen S, et al. Phase 2 trial of neoadjuvant toripalimab with chemotherapy for resectable stage Ⅲ non-small-cell lung cancer［J］. Oncoimmunology, 2021, 10(1): 1996000.
［21］ 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.
［22］ Rusch V W, Nicholas A, Patterson G A, et al. Surgical results of the Lung Cancer Mutation Consortium 3 trial: A phase II multicenter single-arm study to investigate the efficacy and safety of atezolizumab as neoadjuvant therapy in patients with stages ⅠB-select ⅢB resectable non-small cell lung cancer［J］. J Thorac Cardiovasc Surg, 2023, 165(3): 828-839.e5.
［23］ Sun C, Wang X, Xu Y, et al. Efficiency and safety of neoadjuvant PD-1 inhibitor (sintilimab) combined with chemotherapy in potentially resectable stage ⅢA/ⅢB non-small cell lung cancer: Neo-Pre-IC, a single-arm phase 2 trial［J］. EClinicalMedicine, 2024, 68: 102422.
［24］ Sun C, Liu Y, Zhang P, et al. Interim analysis of the efficiency and safety of neoadjuvant PD-1 inhibitor (sintilimab) combined with chemotherapy (nab-paclitaxel and carboplatin) in potentially resectable stage ⅢA/ⅢB non-small cell lung cancer: a single-arm, phase 2 trial［J］. J Cancer Res Clin Oncol, 2023, 149(2): 819-831.
［25］ Eichhorn F, Klotz LV, Kriegsmann M, et al. Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience［J］. Lung Cancer, 2021, 153: 150-157.
［26］ Eichhorn F, Klotz L V, Bischoff H, et al. Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable nodal positive stage Ⅱ/Ⅲa non-small-cell lung cancer (NSCLC): the NEOMUN trial［J］. BMC Cancer, 2019, 19(1): 413.
［27］ Altorki N K, McGraw T E, Borczuk A C, et al. Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial［J］. Lancet Oncol, 2021, 22(6): 824-835.
［28］ Gao S G, Li N, Gao S Y, et al. Neoadjuvant PD-1 inhibitor (Sintilimab) in NSCLC［J］. J Thorac Oncol, 2020, 15(5): 816-826.
［29］ Zhang F, Guo W, Zhou B, et al. Three-year follow-up of neoadjuvant programmed cell death protein-1 inhibitor (sintilimab) in NSCLC［J］. J Thorac Oncol, 2022, 17(7): 909-920.
［30］ Zhang P, Dai J, Sun F H, et al. Neoadjuvant sintilimab and chemotherapy for resectable stage ⅢA non-small cell lung cancer［J］. Ann Thorac Surg, 2022, 114(3): 949-958.
［31］ Chaft J E, Rusch V, Ginsberg M S, et al. Phase II trial of neoadjuvant bevacizumab plus chemotherapy and adjuvant bevacizumab in patients with resectable nonsquamous non-small-cell lung cancers［J］. J Thorac Oncol, 2013, 8(8): 1084-1090.
［32］ Curioni-Fontecedro A, Perentes J Y, Gelpke H, et al. Preoperative chemotherapy and radiotherapy concomitant to cetuximab in resectable stage ⅢB NSCLC: a multicentre phase 2 trial (SAKK 16/08)［J］. Br J Cancer, 2019, 120(10): 968-974.
［33］ Zhu X, Sun L, Song N, et al. Safety and effectiveness of neoadjuvant PD-1 inhibitor (toripalimab) plus chemotherapy in stage Ⅱ-Ⅲ NSCLC (LungMate 002): an open-label, single-arm, phase 2 trial［J］. BMC Med, 2022, 20(1): 493.
［34］ 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.
［35］ Yang C J, McSherry F, Mayne N R, et al. Surgical outcomes after neoadjuvant chemotherapy and ipilimumab for non-small cell lung cancer［J］. Ann Thorac Surg, 2018, 105(3): 924-929.
［36］ 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.
［37］ Heymach J V, Harpole D, Mitsudomi T, et al. Perioperative durvalumab for resectable non-small-cell lung cancer［J］. N Engl J Med, 2023, 389(18): 1672-1684.
［38］ Heymach J V, Harpole D, Reck M. Perioperative durvalumab for resectable non-small-cell lung cancer. Reply［J］. N Engl J Med, 2024, 390(3): 287-288.
［39］ Heymach J V, Mitsudomi T, Harpole D, et al. Design and rationale for a phase Ⅲ, double-blind, placebo-controlled study of neoadjuvant durvalumab +cchemotherapy followed by adjuvant durvalumab for the treatment of patients with resectable stages Ⅱ and Ⅲ non-small-cell lung cancer: the AEGEAN trial［J］. Clin Lung Cancer, 2022, 23(3): e247-e251.
［40］ 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.
［41］ 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.
［42］ Horita N, Fujiwara Y. Perioperative durvalumab for resectable non-small-cell lung cancer［J］. N Engl J Med, 2024, 390(3): 287.
［43］ Yue D, Wang W, Liu H, et al. VP1-2024: RATIONALE-315: event-free survival (EFS) and overall survival (OS) of neoadjuvant tislelizumab (TIS) plus chemotherapy (CT) with adjuvant TIS in resectable non-small cell lung cancer (NSCLC)［J］. Esmo Virtual Plenary Abstracts, 2024, 35(3): 332-333.
［44］ 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.
［45］ Felip E, Altorki N, Zhou C, et al. Overall survival with adjuvant atezolizumab after chemotherapy in resected stage Ⅱ-ⅢA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase Ⅲ trial［J］. Ann Oncol, 2023, 34(10): 907-919.
［46］ O'Brien M, Paz-Ares L, Marreaud S, et al. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage ⅠB-ⅢA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial［J］. Lancet Oncol, 2022, 23(10): 1274-1286.
［47］ Lv C, Fang W, 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.
［48］ Zhong W Z, Chen KN, Chen C, et al. Erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of stage ⅢA-N2 EGFR-mutant non-small-cell lung cancer (EMERGING-CTONG 1103): a randomized phase II study［J］. J Clin Oncol, 2019, 37(25): 2235-2245.

[1]	蒋欢, 李姣清, 徐浩森, 兰金意, 杨单植, 张婷, 刘沛敏, 吴丹凤, 白晓燕. 神经轴突导向分子Slit3的相关研究进展[J]. 首都医科大学学报, 2024, 45(5): 917-922.
[2]	李铁铮, 胥凯凯, 邓钰卿, 王沛豪, 秦齐, 郭康顺, 王炳仁, 常栋, 崔永. PD-1单抗联合化学药物治疗在局部晚期非小细胞肺癌新辅助治疗中的疗效和安全性分析[J]. 首都医科大学学报, 2024, 45(4): 636-641.
[3]	吴朝真, 郑华, 盛舒言, 张权, 张卉, 李杰, 吕嘉林, 钱哲, 王守正, 李曦, 胡瑛. 新辅助免疫联合化疗在非小细胞肺癌中的初步疗效观察[J]. 首都医科大学学报, 2024, 45(4): 642-648.
[4]	徐源, 梁乃新, 刘洪生. 非小细胞肺癌新辅助免疫治疗的预后影响因素:病理淋巴结转移程度与原发灶缓解程度[J]. 首都医科大学学报, 2024, 45(4): 649-653.
[5]	王居巳, 宋伟安, 狄守印, 刘军强, 范博士, 周少华, 岳彩迎, 赵嘉华, 陈思禹, 龚太乾. 新辅助化疗联合免疫抑制剂对Ⅲ期非小细胞肺癌治疗有效性分析[J]. 首都医科大学学报, 2024, 45(4): 660-665.
[6]	朱琳, 许永崧, 冯晓彤, 赵冬, 柯静. 糖尿病视网膜病变的药物治疗进展[J]. 首都医科大学学报, 2024, 45(3): 438-445.
[7]	李明嘉, 赵苗妙, 杨金奎. 组织蛋白酶在糖尿病及糖尿病肾病作用机制中的研究进展[J]. 首都医科大学学报, 2023, 44(3): 413-419.