Risk factors of real-world immune checkpoint inhibitor-related pneumonitis in patients with lung cancer: a meta-analysis_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

YE Lei ¹ , FANG Shencun ¹ , ZHANG Haitao ¹ , QI Wei ¹ ,  XIA Guanghui ² , XU Xiaoyu ³

1. Department of Respiratory Medicine, Brain Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210024, P. R. China;
2. Nursing Department, Brain Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210024, P. R. China;
3. Department of Intensive Care Medicine, Brain Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210024, P. R. China;

Corresponding?author：

XIA Guanghui, Email: 755411389@qq.com

Keywords：

Lung cancer; immune checkpoint inhibitor-related pneumonitis; immune-related adverse events; real-world study; risk factors; meta-analysis

DOI：

10.7507/1671-6205.202304036

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Objective Risk factors for real-word immune checkpoint inhibitor-related pneumonitis in patients with lung cancer were analyzed by systematic analysis. Methods Computerized retrieval of PubMed, EMbase, Web of Science, the Cochrane Library , WanFang Data, CNKI and VIP databases was carried out. Studies were collected from the database establishment to March 2023. Three researchers independently screened the literature, extracted data, and evaluated the risk of bias in the included studies. Meta-analysis was performed using RevMan5.4.1software. Results A total of 18 studies were included with a total of 4 990 patients. The results of meta-analysis showed that, interstitial pneumonia [odds ratio (OR)=9.32, 95% confidence interval (CI) 4.66 - 18.67, P<0.01], smoking history (OR=2.39, 95%CI 1.29 - 4.45, P<0.01), chronic obstructive pulmonary disease (COPD) (OR=5.54, 95%CI 2.96 - 10.36, P<0.01), chest radiotherapy (OR=2.74, 95%CI 1.80 - 4.19, P<0.01), pulmonary fibrosis (OR=7.46, 95%CI 4.25 - 13.09, P<0.01), high programmed death ligand 1 (PD-L1) expression (OR=2.98, 95%CI 1.71 - 5.22, P<0.01), high absolute eosinophil count (AEC) (OR=3.92, 95%CI 2.17 - 7.08, P<0.01) and pembrolizumab (OR=2.90, 95%CI 1.56 - 5.37, P<0.01) were independent risk factors for immune checkpoint inhibitor-related pneumonitis in lung cancer patients. Conclusions Interstitial pneumonia, smoking history, COPD, Chest radiotherapy, pulmonary fibrosis, high PD-L1expression, high AEC and pembrolizumab are independent risk factors for immune checkpoint inhibitor-related pneumonitis in lung cancer patients. Due to insufficient evidence on the risk factors of low albumin, more studies are needed to further identify it.

Citation： YE Lei, FANG Shencun, ZHANG Haitao, QI Wei, XIA Guanghui, XU Xiaoyu. Risk factors of real-world immune checkpoint inhibitor-related pneumonitis in patients with lung cancer: a meta-analysis. Chinese Journal of Respiratory and Critical Care Medicine, 2023, 22(6): 408-417. doi: 10.7507/1671-6205.202304036 Copy

1.	Cao W, Chen HD, Yu YW, et al. Changing profiles of cancer burden worldwide and in China: a secondary analysis of the global cancer statistics 2020. Chin Med J (Engl), 2021, 134(7): 783-791.
2.	Hanna NH, Schneider BJ, Temin S, et al. Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO and OH (CCO) Joint Guideline Update. J Clin Oncol, 2020, 38(14): 1608-1632.
3.	Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med, 2018, 379(24): 2342-2350.
4.	Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med, 2018, 378(2): 158-168.
5.	Cho JY, Kim J, Lee JS, et al. Characteristics, incidence, and risk factors of immune checkpoint inhibitor-related pneumonitis in patients with non-small cell lung cancer. Lung Cancer, 2018, 125: 150-156.
6.	Nishino M, Giobbie-Hurder A, Hatabu H, et al. Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced cancer: a systematic review and meta-analysis. JAMA Oncol, 2016, 2(12): 1607-1616.
7.	Shi YQ, Fang J, Zhou CZ, et al. Immune checkpoint inhibitor-related adverse events in lung cancer: real-world incidence and management practices of 1905 patients in China. Thorac Cancer, 2022, 13(3): 412-422.
8.	吳建輝, 儲香玲, 王李強, 等. 中國肺癌患者真實世界免疫檢查點抑制劑相關性肺炎的流行病學分析. 中國癌癥雜志, 2022, 32(6): 469-477.
9.	De Velasco G, Je Y, Bossé D, et al. Comprehensive meta-analysis of key immune-related adverse events from CTLA-4 and PD-1/PD-L1 inhibitors in cancer patients. Cancer Immunol Res, 2017, 5(4): 312-318.
10.	中華醫學會呼吸病學會分會肺癌學組. 免疫檢查點抑制劑相關肺炎診治專家共識. 中華結核和呼吸雜志, 2019, 42(11): 820-825.
11.	Ma K, Lu YL, Jiang SS, et al. The relative risk and incidence of immune checkpoint inhibitors related pneumonitis in patients with advanced cancer: a meta-analysis. Front Pharmacol, 2018, 9: 1430.
12.	陳康, 孫步彤. PD-1/PD-L1抑制劑在晚期腫瘤患者中的相關肺炎發生率和發生風險: 一項薈萃分析. 中國肺癌雜志, 2020, 23(11): 927-940.
13.	周巧, 余荷, 梁宗安. 免疫檢查點抑制劑導致免疫相關性肺炎. 中國呼吸與危重監護雜志, 2021, 20(10): 753-756.
14.	Yamaguchi T, Shimizu J, Oya Y, et al. Risk factors for pneumonitis in patients with non-small cell lung cancer treated with immune checkpoint inhibitors plus chemotherapy: a retrospective analysis. Thorac Cancer, 2022, 13(5): 724-731.
15.	Chao YC, Zhou JB, Hsu SJ, et al. Risk factors for immune checkpoint inhibitor-related pneumonitis in non-small cell lung cancer. Transl Lung Cancer Res, 2022, 11(2): 295-306.
16.	Barrón F, Sánchez R, Arroyo-Hernández M, et al. Risk of developing checkpoint immune pneumonitis and its effect on overall survival in non-small cell lung cancer patients previously treated with radiotherapy. Front Oncol, 2020, 10: 570233.
17.	Chu XL, Zhao J, Zhou J, et al. Association of baseline peripheral-blood eosinophil count with immune checkpoint inhibitor-related pneumonitis and clinical outcomes in patients with non-small cell lung cancer receiving immune checkpoint inhibitors. Lung Cancer, 2020, 150: 76-82.
18.	Fukihara J, Sakamoto K, Koyama J, et al. Prognostic impact and risk factors of immune-related pneumonitis in patients with non-small-cell lung cancer who received programmed death 1 inhibitors. Clin Lung Cancer, 2019, 20(6): 442-450.e4.
19.	Osaki M, Arai T, Sumikawa H, et al. Immune checkpoint inhibitor-related pneumonitis in lung cancer patients with interstitial lung disease: significance of radiological pleuroparenchymal fibroelastosis. Oncology, 2023, 101(5): 303-312.
20.	Jia XH, Chu XL, Jiang LL, et al. Predicting checkpoint inhibitors pneumonitis in non-small cell lung cancer using a dynamic online hypertension nomogram. Lung Cancer, 2022, 170: 74-84.
21.	Sawa K, Sato I, Takeuchi M, et al. Risk of pneumonitis in non-small cell lung cancer patients with preexisting interstitial lung diseases treated with immune checkpoint inhibitors: a nationwide retrospective cohort study. Cancer Immunol Immunother, 2023, 72(3): 591-598.
22.	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 Thorac Oncol, 2018, 13(12): 1930-1939.
23.	Atchley WT, Alvarez C, Saxena-Beem S, et al. Immune checkpoint inhibitor-related pneumonitis in lung cancer: real-world incidence, risk factors, and management practices across six health care centers in North Carolina. Chest, 2021, 160(2): 731-742.
24.	Zhang C, Gao FY, Jin SD, et al. Checkpoint inhibitor pneumonitis in Chinese lung cancer patients: clinical characteristics and risk factors. Ann Palliat Med, 2020, 9(6): 3957-3965.
25.	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. Thorac Cancer, 2021, 12(2): 153-164.
26.	Cui PF, Liu ZF, Wang GQ, et al. Risk factors for pneumonitis in patients treated with anti-programmed death-1 therapy: a case-control study. Cancer Med, 2018, 7(8): 4115-4120.
27.	Lin XQ, Deng HY, Yang YL, et al. Peripheral blood biomarkers for early diagnosis, severity, and prognosis of checkpoint inhibitor-related pneumonitis in patients with lung cancer. Front Oncol, 2021, 11: 698832.
28.	郝娜. 晚期非小細胞肺癌免疫檢查點抑制劑相關性肺炎的臨床特征、危險因素及預后分析[D]. 河南: 鄭州大學, 2022.
29.	汪婧媛, 孫虎, 馮慧晶, 等. 免疫檢查點抑制劑治療非小細胞肺癌產生免疫相關不良反應和肺炎的特點及其危險因素分析. 中國腫瘤生物治療雜志, 2022, 29(11): 995-1001.
30.	盧梓榮. 非小細胞肺癌發生免疫相關性肺炎的危險因素研究和列線圖模型構建[D]. 廣州醫科大學, 2022.
31.	Zhou PN, Zhao X, Wang GF. Risk factors for immune checkpoint inhibitor-related pneumonitis in cancer patients: a systemic review and meta-analysis. Respiration, 2022, 101(11): 1035-1050.
32.	Zhai XY, Zhang J, Tian YR, et al. The mechanism and risk factors for immune checkpoint inhibitor pneumonitis in non-small cell lung cancer patients. Cancer Biol Med, 2020, 17(3): 599-611.
33.	Suzuki Y, Karayama M, Uto T, et al. Assessment of immune-related interstitial lung disease in patients with NSCLC treated with immune checkpoint inhibitors: a multicenter prospective study. J Thorac Oncol, 2020, 15(8): 1317-1327.
34.	Mark NM, Kargl J, Busch SE, et al. Chronic obstructive pulmonary disease alters immune cell composition and immune checkpoint inhibitor efficacy in non-small cell lung cancer. Am J Respir Crit Care Med, 2018, 197(3): 325-336.
35.	Sun ZQ, Wang S, Du HD, et al. Immunotherapy-induced pneumonitis in non-small cell lung cancer patients: current concern in treatment with immune-check-point inhibitors. Invest New Drugs, 2021, 39(3): 891-898.
36.	代華平. 纖維化間質性肺疾病正確—早期識別與干預. 國際呼吸雜志, 2021, 41(21): 1601-1604.
37.	成超, 李杰. 放療聯合免疫檢查點抑制劑治療肺癌致放射–免疫相關性肺炎的研究進展. 中國癌癥防治雜志, 2022, 14(6): 687-692.
38.	高鵬云, 武志峰. 免疫檢查點抑制劑相關肺炎的臨床與影像研究. 中華結核與呼吸雜志, 2022, 45(2): 238-242.
39.	Teng FF, Li M, Yu JM. Radiation recall pneumonitis induced by PD-1/PD-L1 blockades: mechanisms and therapeutic implications. BMC Med, 2020, 18(1): 275.
40.	Cousin F, Desir C, Ben Mustapha S, et al. Incidence, risk factors, and CT characteristics of radiation recall pneumonitis induced by immune checkpoint inhibitor in lung cancer. Radiother Oncol, 2021, 157: 47-55.
41.	王慧, 夏茸, 魏清雯, 等. 非小細胞肺癌免疫檢查點抑制劑相關性肺炎的危險因素及預測生物標志物. 國際腫瘤學雜志, 2021, 48(5): 296-301.
42.	謝國鋼. 非小細胞肺癌免疫檢查點抑制劑治療療效預測標志物的研究現狀. 中國醫師進修雜志, 2022, 45(2): 97-100.
43.	Peng TR, Tsai FP, Wu TW. Indirect comparison between pembrolizumab and nivolumab for the treatment of non-small cell lung cancer: a meta-analysis of randomized clinical trials. Int Immunopharmacol, 2017, 49: 85-94.

1. Cao W, Chen HD, Yu YW, et al. Changing profiles of cancer burden worldwide and in China: a secondary analysis of the global cancer statistics 2020. Chin Med J (Engl), 2021, 134(7): 783-791.
2. Hanna NH, Schneider BJ, Temin S, et al. Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO and OH (CCO) Joint Guideline Update. J Clin Oncol, 2020, 38(14): 1608-1632.
3. Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med, 2018, 379(24): 2342-2350.
4. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med, 2018, 378(2): 158-168.
5. Cho JY, Kim J, Lee JS, et al. Characteristics, incidence, and risk factors of immune checkpoint inhibitor-related pneumonitis in patients with non-small cell lung cancer. Lung Cancer, 2018, 125: 150-156.
6. Nishino M, Giobbie-Hurder A, Hatabu H, et al. Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced cancer: a systematic review and meta-analysis. JAMA Oncol, 2016, 2(12): 1607-1616.
7. Shi YQ, Fang J, Zhou CZ, et al. Immune checkpoint inhibitor-related adverse events in lung cancer: real-world incidence and management practices of 1905 patients in China. Thorac Cancer, 2022, 13(3): 412-422.
8. 吳建輝, 儲香玲, 王李強, 等. 中國肺癌患者真實世界免疫檢查點抑制劑相關性肺炎的流行病學分析. 中國癌癥雜志, 2022, 32(6): 469-477.
9. De Velasco G, Je Y, Bossé D, et al. Comprehensive meta-analysis of key immune-related adverse events from CTLA-4 and PD-1/PD-L1 inhibitors in cancer patients. Cancer Immunol Res, 2017, 5(4): 312-318.
10. 中華醫學會呼吸病學會分會肺癌學組. 免疫檢查點抑制劑相關肺炎診治專家共識. 中華結核和呼吸雜志, 2019, 42(11): 820-825.
11. Ma K, Lu YL, Jiang SS, et al. The relative risk and incidence of immune checkpoint inhibitors related pneumonitis in patients with advanced cancer: a meta-analysis. Front Pharmacol, 2018, 9: 1430.
12. 陳康, 孫步彤. PD-1/PD-L1抑制劑在晚期腫瘤患者中的相關肺炎發生率和發生風險: 一項薈萃分析. 中國肺癌雜志, 2020, 23(11): 927-940.
13. 周巧, 余荷, 梁宗安. 免疫檢查點抑制劑導致免疫相關性肺炎. 中國呼吸與危重監護雜志, 2021, 20(10): 753-756.
14. Yamaguchi T, Shimizu J, Oya Y, et al. Risk factors for pneumonitis in patients with non-small cell lung cancer treated with immune checkpoint inhibitors plus chemotherapy: a retrospective analysis. Thorac Cancer, 2022, 13(5): 724-731.
15. Chao YC, Zhou JB, Hsu SJ, et al. Risk factors for immune checkpoint inhibitor-related pneumonitis in non-small cell lung cancer. Transl Lung Cancer Res, 2022, 11(2): 295-306.
16. Barrón F, Sánchez R, Arroyo-Hernández M, et al. Risk of developing checkpoint immune pneumonitis and its effect on overall survival in non-small cell lung cancer patients previously treated with radiotherapy. Front Oncol, 2020, 10: 570233.
17. Chu XL, Zhao J, Zhou J, et al. Association of baseline peripheral-blood eosinophil count with immune checkpoint inhibitor-related pneumonitis and clinical outcomes in patients with non-small cell lung cancer receiving immune checkpoint inhibitors. Lung Cancer, 2020, 150: 76-82.
18. Fukihara J, Sakamoto K, Koyama J, et al. Prognostic impact and risk factors of immune-related pneumonitis in patients with non-small-cell lung cancer who received programmed death 1 inhibitors. Clin Lung Cancer, 2019, 20(6): 442-450.e4.
19. Osaki M, Arai T, Sumikawa H, et al. Immune checkpoint inhibitor-related pneumonitis in lung cancer patients with interstitial lung disease: significance of radiological pleuroparenchymal fibroelastosis. Oncology, 2023, 101(5): 303-312.
20. Jia XH, Chu XL, Jiang LL, et al. Predicting checkpoint inhibitors pneumonitis in non-small cell lung cancer using a dynamic online hypertension nomogram. Lung Cancer, 2022, 170: 74-84.
21. Sawa K, Sato I, Takeuchi M, et al. Risk of pneumonitis in non-small cell lung cancer patients with preexisting interstitial lung diseases treated with immune checkpoint inhibitors: a nationwide retrospective cohort study. Cancer Immunol Immunother, 2023, 72(3): 591-598.
22. 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 Thorac Oncol, 2018, 13(12): 1930-1939.
23. Atchley WT, Alvarez C, Saxena-Beem S, et al. Immune checkpoint inhibitor-related pneumonitis in lung cancer: real-world incidence, risk factors, and management practices across six health care centers in North Carolina. Chest, 2021, 160(2): 731-742.
24. Zhang C, Gao FY, Jin SD, et al. Checkpoint inhibitor pneumonitis in Chinese lung cancer patients: clinical characteristics and risk factors. Ann Palliat Med, 2020, 9(6): 3957-3965.
25. 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. Thorac Cancer, 2021, 12(2): 153-164.
26. Cui PF, Liu ZF, Wang GQ, et al. Risk factors for pneumonitis in patients treated with anti-programmed death-1 therapy: a case-control study. Cancer Med, 2018, 7(8): 4115-4120.
27. Lin XQ, Deng HY, Yang YL, et al. Peripheral blood biomarkers for early diagnosis, severity, and prognosis of checkpoint inhibitor-related pneumonitis in patients with lung cancer. Front Oncol, 2021, 11: 698832.
28. 郝娜. 晚期非小細胞肺癌免疫檢查點抑制劑相關性肺炎的臨床特征、危險因素及預后分析[D]. 河南: 鄭州大學, 2022.
29. 汪婧媛, 孫虎, 馮慧晶, 等. 免疫檢查點抑制劑治療非小細胞肺癌產生免疫相關不良反應和肺炎的特點及其危險因素分析. 中國腫瘤生物治療雜志, 2022, 29(11): 995-1001.
30. 盧梓榮. 非小細胞肺癌發生免疫相關性肺炎的危險因素研究和列線圖模型構建[D]. 廣州醫科大學, 2022.
31. Zhou PN, Zhao X, Wang GF. Risk factors for immune checkpoint inhibitor-related pneumonitis in cancer patients: a systemic review and meta-analysis. Respiration, 2022, 101(11): 1035-1050.
32. Zhai XY, Zhang J, Tian YR, et al. The mechanism and risk factors for immune checkpoint inhibitor pneumonitis in non-small cell lung cancer patients. Cancer Biol Med, 2020, 17(3): 599-611.
33. Suzuki Y, Karayama M, Uto T, et al. Assessment of immune-related interstitial lung disease in patients with NSCLC treated with immune checkpoint inhibitors: a multicenter prospective study. J Thorac Oncol, 2020, 15(8): 1317-1327.
34. Mark NM, Kargl J, Busch SE, et al. Chronic obstructive pulmonary disease alters immune cell composition and immune checkpoint inhibitor efficacy in non-small cell lung cancer. Am J Respir Crit Care Med, 2018, 197(3): 325-336.
35. Sun ZQ, Wang S, Du HD, et al. Immunotherapy-induced pneumonitis in non-small cell lung cancer patients: current concern in treatment with immune-check-point inhibitors. Invest New Drugs, 2021, 39(3): 891-898.
36. 代華平. 纖維化間質性肺疾病正確—早期識別與干預. 國際呼吸雜志, 2021, 41(21): 1601-1604.
37. 成超, 李杰. 放療聯合免疫檢查點抑制劑治療肺癌致放射–免疫相關性肺炎的研究進展. 中國癌癥防治雜志, 2022, 14(6): 687-692.
38. 高鵬云, 武志峰. 免疫檢查點抑制劑相關肺炎的臨床與影像研究. 中華結核與呼吸雜志, 2022, 45(2): 238-242.
39. Teng FF, Li M, Yu JM. Radiation recall pneumonitis induced by PD-1/PD-L1 blockades: mechanisms and therapeutic implications. BMC Med, 2020, 18(1): 275.
40. Cousin F, Desir C, Ben Mustapha S, et al. Incidence, risk factors, and CT characteristics of radiation recall pneumonitis induced by immune checkpoint inhibitor in lung cancer. Radiother Oncol, 2021, 157: 47-55.
41. 王慧, 夏茸, 魏清雯, 等. 非小細胞肺癌免疫檢查點抑制劑相關性肺炎的危險因素及預測生物標志物. 國際腫瘤學雜志, 2021, 48(5): 296-301.
42. 謝國鋼. 非小細胞肺癌免疫檢查點抑制劑治療療效預測標志物的研究現狀. 中國醫師進修雜志, 2022, 45(2): 97-100.
43. Peng TR, Tsai FP, Wu TW. Indirect comparison between pembrolizumab and nivolumab for the treatment of non-small cell lung cancer: a meta-analysis of randomized clinical trials. Int Immunopharmacol, 2017, 49: 85-94.

Chinese Journal of Respiratory and Critical Care Medicine

Risk factors of real-world immune checkpoint inhibitor-related pneumonitis in patients with lung cancer: a meta-analysis

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