免疫检查点抑制剂在非小细胞肺癌治疗中的不良反应及危险因素

摘要/Abstract

摘要：

免疫检查点抑制剂（ICI）已广泛应用于非小细胞肺癌（NSCLC）的治疗，然而其在使用过程中，可产生ICI相关肺炎、心肌炎、皮疹、结肠炎、神经系统免疫相关不良反应（irAE）、甲状腺功能减退、眼部irAE、肝脏irAE等，有些irAE甚至是致命性的。全身性炎症生物标志物以及化疗、较高的体质量指数、表皮生长因子受体突变是其发生的危险因素。分析常见irAE及危险因素，以期提高临床医生对ICI的认识。

关键词:癌，非小细胞肺,免疫检查点抑制剂,治疗,药物相关性副作用和不良反应,危险因素

Abstract:

Immune checkpoint inhibitors （ICIs） have been widely used in the treatment of non-small cell lung cancer （NSCLC）. However， ICIs related pneumonia， myocarditis， rash， colitis， nervous system immune-related adverse events （irAEs）， as well as hypothyroidism， ocular irAEs， liver irAEs，etc.， can be generated in the process of use， and some irAEs are even fatal. Systemic inflammatory biomarkers as well as chemotherapy， higher body mass index， epidermal growth factor receptor mutation are risk factors for its occurrence. The common irAEs and risk factors are analyzed in order to improve the clinician's understanding of ICIs.

Key words:Carcinoma， non-small-cell lung,Immune checkpoint inhibitors,Therapy,Drug-related side effects and adverse reactions,Risk factors

邓隽军, 赵大勇, 李淼. 免疫检查点抑制剂在非小细胞肺癌治疗中的不良反应及危险因素[J]. 国际肿瘤学杂志, 2023, 50(9): 564-568.

Deng Juanjun, Zhao Dayong, Li Miao. Adverse reactions and risk factors of immune checkpoint inhibitors in the treatment of non-small cell lung cancer[J]. Journal of International Oncology, 2023, 50(9): 564-568.

参考文献42

[1]	Sung H, Ferlay J, Siegel RL, 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. DOI:10.3322/caac.21660.
[2]	董熠, 魏月华, 胡伟国, 等. 非小细胞肺癌孤立性骨转移的治疗[J].国际肿瘤学杂志,2017,44(1): 60-62. DOI:10.3760/cma.j.issn.1673-422X.2017.01.016.
[3]	Hsu ML, Naidoo J. Principles of immunotherapy in non-small cell lung cancer[J].Thorac Surg Clin,2020,30(2): 187-198. DOI:10.1016/j.thorsurg.2020.01.009. pmid:32327177
[4]	Robert C. A decade of immune-checkpoint inhibitors in cancer therapy[J].Nat Commun,2020,11(1): 3801. DOI:10.1038/s41467-020-17670-y. pmid:32732879
[5]	Rahma OE, Reuss JE, Giobbie-Hurder A, et al. Early 3+3 trial dose-escalation phase Ⅰ clinical trial design and suitability for immune checkpoint inhibitors[J].Clin Cancer Res,2021,27(2): 485-491. DOI:10.1158/1078-0432.CCR-20-2669.
[6]	Breimer LH, Nousios P, Olsson L, et al. Immune checkpoint inhibitors of the PD-1/PD-L1-axis in non-small cell lung cancer: promise, controversies and ambiguities in the novel treatment paradigm[J].Scand J Clin Lab Invest,2020,80(5): 360-369. DOI:10.1080/00365513.2020.1742369. pmid:32238062
[7]	Cathcart-Rake EJ, Sangaralingham LR, Henk HJ, et al. A population-based study of immunotherapy-related toxicities in lung cancer[J].Clin Lung Cancer,2020,21(5): 421-427.e2. DOI:10.1016/j.cllc.2020.04.003. pmid:32446852
[8]	Wang DY, Salem JE, Cohen JV, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis[J].JAMA Oncol,2018,4(12): 1721-1728. DOI:10.1001/jamaoncol.2018.3923. pmid:30242316
[9]	Pozzessere C, Bouchaab H, Jumeau R, et al. Relationship between pneumonitis induced by immune checkpoint inhibitors and the underlying parenchymal status: a retrospective study[J].ERJ Open Res,2020,6(1): 00165-2019. DOI:10.1183/23120541.00165-2019.
[10]	Cadranel J, Canellas A, Matton L, et al. Pulmonary complications of immune checkpoint inhibitors in patients with nonsmall cell lung cancer[J].Eur Respir Rev,2019,28(153): 190058. DOI:10.1183/16000617.0058-2019.
[11]	Nishino M, Sholl LM, Awad MM, et al. Sarcoid-like granulomatosis of the lung related to immune-checkpoint inhibitors: distinct clinical and imaging features of a unique immune-related adverse event[J].Cancer Immunol Res,2018,6(6): 630-635. DOI:10.1158/2326-6066.CIR-17-0715. pmid:29622582
[12]	Isono T, Kagiyama N, Takano K, et al. Outcome and risk factor of immune-related adverse events and pneumonitis in patients with advanced or postoperative recurrent non-small cell lung cancer treated with immune checkpoint inhibitors[J].Thorac Cancer,2021,12(2): 153-164. DOI:10.1111/1759-7714.13736. pmid:33201587
[13]	Huang A, Xu Y, Zang X, et al. Radiographic features and prognosis of early- and late-onset non-small cell lung cancer immune checkpoint inhibitor-related pneumonitis[J].BMC Cancer,2021,21(1): 634. DOI:10.1186/s12885-021-08353-y. pmid:34051746
[14]	Tonk EHJ, Verhoeff JJC, et al. Acute-onset pneumonitis while administering the first dose of durvalumab[J].Case Rep Oncol,2019,12(2): 621-624. DOI:10.1159/00050 2202. pmid:31543778
[15]	Costa RB, Benson A, Yaghmai V, et al. An extremely rapid case of pneumonitis with the use of nivolumab for pancreatic adenocarcinoma[J].Case Rep Oncol Med,2018,2018: 6314392. DOI:10.1155/2018/6314392.
[16]	Suresh K, Voong KR, Shankar B, et al. Pneumonitis in non-small cell lung cancer patients receiving immune checkpoint immunotherapy: incidence and risk factors[J].J Thorac Oncol,2018,13(12): 1930-1939. DOI:10.1016/j.jtho.2018.08.2035. pmid:30267842
[17]	Kennedy LB, Salama AKS. A review of immune-mediated adverse events in melanoma[J].Oncol Ther,2019,7(2): 101-120. DOI:10.1007/s40487-019-0096-8.
[18]	Chen DY, Huang WK, Chien-Chia Wu V, et al. Cardiovascular toxicity of immune checkpoint inhibitors in cancer patients: a review when cardiology meets immuno-oncology[J].J Formos Med Assoc,2020,119(10): 1461-1475. DOI:10.1016/j.jfma.2019.07.025.
[19]	Varricchi G, Marone G, Mercurio V, et al. Immune checkpoint inhibitors and cardiac toxicity: an emerging issue[J].Curr Med Chem,2018,25(11): 1327-1339. DOI:10.2174/0929867324666170407125017. pmid:28403786
[20]	Canale ML, Camerini A, Casolo G, et al. Incidence of pericardial effusion in patients with advanced non-small cell lung cancer receiving immunotherapy[J].Adv Ther,2020,37(7): 3178-3184. DOI:10.1007/s12325-020-01386-y. pmid:32436027
[21]	Isawa T, Toi Y, Sugawara S, et al. Incidence, clinical characteristics, and predictors of cardiovascular immune-related adverse events associated with immune checkpoint inhibitors[J].Oncologist,2022,27(5): e410-e419. DOI:10.1093/oncolo/oyac056.
[22]	Li H, Han D, Zhang L, et al. PD-1/L1 inhibitors may increase the risk of pericardial disease in non-small-cell lung cancer patients: a meta-analysis and systematic review[J].Immunotherapy,2022,14(7): 577-592. DOI:10.2217/imt-2021-0223. pmid:35373580
[23]	Zhang Q, Wang W, Yuan Q, et al. Correlation between immune-related adverse events and the efficacy of PD-1/PD-L1 inhibitors in the treatment of non-small cell lung cancer: systematic review and meta-analysis[J].Cancer Chemother Pharmacol,2022,89(1): 1-9. DOI:10.1007/s00280-021-04375-2.
[24]	Hosoya K, Fujimoto D, Morimoto T, et al. Association between early immune-related adverse events and clinical outcomes in patients with non-small cell lung cancer treated with immune checkpoint inhibitors[J].Clin Lung Cancer,2020,21(4): e315-e328. DOI:10.1016/j.cllc.2020.01.003. pmid:32113737
[25]	Kichenadasse G, Miners JO, Mangoni AA, et al. Multiorgan immune-related adverse events during treatment with atezolizumab[J].J Natl Compr Canc Netw,2020,18(9): 1191-1199. DOI:10.6004/jnccn.2020.7567.
[26]	Wang ZH, Shen L. Management of gastrointestinal adverse events induced by immune-checkpoint inhibitors[J].Chronic Dis Transl Med,2018,4(1): 1-7. DOI:10.1016/j.cdtm.2017.12.001.
[27]	Tong ZQ, Wu DY, Liu D, et al. Incidence risk of PD-1/PD-L1-related pneumonia and diarrhea in non-small cell lung cancer (NSCLC) patients: a systematic review and meta-analysis of randomized controlled trials[J].Eur J Clin Pharmacol,2021,77(8): 1079-1088. DOI:10.1007/s00228-020-03083-9.
[28]	Mirabile A, Brioschi E, Ducceschi M, et al. PD-1 inhibitors-related neurological toxicities in patients with non-small-cell lung cancer: a literature review[J].Cancers (Basel),2019,11(3): 296. DOI:10.3390/cancers11030296.
[29]	Robert L, Langner-Lemercier S, Angibaud A, et al. Immune-related encephalitis in two patients treated with immune checkpoint inhibitor[J].Clin Lung Cancer,2020,21(5): e474-e477. DOI:10.1016/j.cllc.2020.03.006. pmid:32299770
[30]	Ferrari SM, Fallahi P, Elia G, et al. Autoimmune endocrine dysfunctions associated with cancer immunotherapies[J].Int J Mol Sci,2019,20(10): 2560. DOI:10.3390/ijms20102560.
[31]	Shao J, Wang C, Ren P, et al. Treatment- and immune-related adverse events of immune checkpoint inhibitors in advanced lung cancer[J].Biosci Rep,2020,40(5): BSR20192347. DOI:10.1042/BSR20192347.
[32]	Li M, Hou X, Chen J, et al. Comparing organ-specific immune-related adverse events for immune checkpoint inhibitors: a Bayesian network meta-analysis[J].Clin Transl Med,2021,11(2): e291. DOI:10.1002/ctm2.291. pmid:33634972
[33]	Reddy M, Chen JJ, Kalevar A, et al. Immune retinopathy associated with nivolumab administration for metastatic non-small cell lung cancer[J].Retin Cases Brief Rep,2020,14(2): 120-126. DOI:10.1097/ICB.0000000000000675. pmid:29176534
[34]	Makri OE, Dimitrakopoulos FI, Tsapardoni F, et al. Isolated optic neuritis after pembrolizumab administration for non-small-cell lung carcinoma[J].Int J Neurosci,2022,132(7): 643-648. DOI:10.1080/00207454.2020.1831489.
[35]	Nakako S, Nakashima Y, Okamura H, et al. Delayed immune-related neutropenia with hepatitis by pembrolizumab[J].Immunotherapy,2022,14(2): 101-105. DOI:10.2217/imt-2021-0131.
[36]	Yamamoto T, Ito T, Hase T, et al. Immune-related liver injury is a poor prognostic factor in patients with nonsmall cell lung cancer treated with immune checkpoint inhibitors[J].Cancer Invest,2022,40(2): 189-198. DOI:10.1080/07357907.2021.1994586.
[37]	Fujimoto A, Toyokawa G, Koutake Y, et al. Association between pretreatment neutrophil-to-lymphocyte ratio and immune-related adverse events due to immune checkpoint inhibitors in patients with non-small cell lung cancer[J].Thorac Cancer,2021,12(15): 2198-2204. DOI:10.1111/1759-7714.14063.
[38]	Huang Y, Soon YY, Aminkeng F, et al. Risk factors for immune-related adverse events from anti-PD-1 or anti-PD-L1 treatment in an Asian cohort of nonsmall cell lung cancer patients[J].Int J Cancer,2022,150(4): 636-644. DOI:10.1002/ijc.33822.
[39]	Xu H, Feng H, Zhang W, et al. Prediction of immune-related adverse events in non-small cell lung cancer patients treated with immune checkpoint inhibitors based on clinical and hematological markers: real-world evidence[J].Exp Cell Res,2022,416(1): 113157. DOI:10.1016/j.yexcr.2022.113157.
[40]	Melson J, Reed D, Horton BJ, et al. Immune-related adverse events in advanced NSCLC treated with immunotherapy alone or concurrent chemotherapy and immunotherapy[J].J Clin Oncol,2019,37(8_suppl): 83. DOI:10.1200/JCO.2019.37.8_suppl.83.
[41]	Murphy WJ, Longo DL. The surprisingly positive association between obesity and cancer immunotherapy efficacy[J].JAMA,2019,321(13): 1247-1248. DOI:10.1001/jama.2019.0463. pmid:30882850
[42]	Cortellini A, Bersanelli M, Santini D, et al. Another side of the association between body mass index (BMI) and clinical outcomes of cancer patients receiving programmed cell death protein-1 (PD-1)/ programmed cell death-ligand 1 (PD-L1) checkpoint inhibitors: a multicentre analysis of immune-related adverse events[J].Eur J Cancer,2020,128: 17-26. DOI:10.1016/j.ejca.2019.12.031. pmid:32109847