肺癌患者免疫检查点抑制剂相关心肌炎后永久停药与继续免疫治疗的安全性比较

doi:10.3969/j.issn.1674-8115.2026.05.007

摘要/Abstract

摘要：

目的·探讨肺癌患者发生免疫检查点抑制剂相关心肌炎（immune checkpoint inhibitor-associated myocarditis，ICI-M）后，永久停药与继续免疫治疗的安全性差异。方法·采用单中心回顾性队列研究，纳入上海交通大学医学院附属胸科医院2016年6月至2024年8月确诊ICI-M的肺癌患者357例。根据ICI-M后的免疫治疗策略分为永久停药组（n=131）与继续治疗组（n=226）。继续治疗组包括从未停药患者以及暂时停药后重启患者。描述性统计ICI-M复发率及新发其他免疫相关不良事件（immune-related adverse events，irAEs）发生率，比较首次ICI-M与复发ICI-M的严重程度，并探索ICI-M复发或新发其他类型irAEs的危险因素。利用多因素Cox回归分析继续免疫治疗对主要心血管不良事件（major adverse cardiovascular events，MACE）的影响。采用倾向性评分匹配进行敏感性分析，以增强研究结果的稳健性。结果·ICI-M复发率为8.8%（20/226），复发ICI-M时的临床症状严重程度及心肌损伤标志物峰值并未高于首次ICI-M。13.3%（30/226）患者新发其他类型irAEs。ICI-M复发或新发其他类型irAEs的患者首次ICI-M发生时间更早（47.0 d vs 71.0 d，P=0.006），肌酸激酶同工酶MB（creatine kinase-MB，CK-MB）峰值更高（4.8 ng/mL vs 2.8 ng/mL，P=0.019）。多因素Cox回归显示，继续免疫治疗并未显著增加ICI-M患者的远期MACE发生风险（HR=0.75，95%CI 0.28~1.98，P=0.556），且该结果在各亚组中均保持一致（P_相互作用>0.05）。采用倾向性评分匹配进行敏感性分析，结论依然保持稳健（匹配后HR=0.93，95%CI 0.32~2.70，P=0.894）。结论·肺癌患者发生ICI-M后继续免疫治疗总体安全性良好，ICI-M复发率较低，且继续免疫治疗并不显著增加MACE发生风险。研究结果为临床决策提供初步数据支持，未来仍需大规模前瞻性研究对结论加以确认与验证。

关键词: 免疫检查点抑制剂, 心肌炎, 复发, 主要心血管不良事件, 安全性

Abstract:

Objective ·To compare the safety outcomes between immunotherapy continuation and permanent immunotherapy discontinuation in patients with lung cancer who developed immune checkpoint inhibitor-associated myocarditis (ICI-M). Methods ·This single-center retrospective cohort study enrolled 357 lung cancer patients who were diagnosed with ICI-M between June 2016 and August 2024 in Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine. Based on post-ICI-M immunotherapy strategies, patients were categorized into a permanent discontinuation group (n=131) and a continuation group (n=226). The continuation group comprised patients who never interrupted immunotherapy and those who temporarily discontinued but later resumed ICI treatment. The ICI-M recurrence rate and the incidence of other new-onset immune-related adverse events (irAEs) were reported. The severity of initial and recurrent ICI-M was compared, and risk factors for ICI-M recurrence or new-onset irAEs were explored. Multivariable Cox regression analysis was used to evaluate the impact of immunotherapy continuation on major adverse cardiovascular events (MACE). Propensity score matching was performed as a sensitivity analysis to enhance the robustness of the study findings. Results ·The ICI-M recurrence rate was 8.8% (20/226). The clinical severity and peak levels of myocardial injury biomarkers were not higher in recurrent ICI-M than in initial ICI-M. A total of 13.3% (30/226) of patients developed other new-onset irAEs. Patients who experienced ICI-M recurrence or new-onset irAEs had a significantly earlier onset of initial ICI-M (47.0 d vs 71.0 d, P=0.006) and a higher peak creatine kinase-MB (CK-MB) level (4.8 ng/mL vs 2.8 ng/mL, P=0.019). Multivariable Cox regression analysis indicated that immunotherapy continuation did not significantly increase the risk of long-term MACE (HR=0.75, 95%CI 0.28‒1.98, P=0.556), and this result remained consistent across all subgroups (P_interaction>0.05). Sensitivity analysis using propensity score matching confirmed the robustness of this result (after matching: HR=0.93, 95%CI 0.32‒2.70, P=0.894). Conclusion ·Continued immunotherapy after ICI-M in lung cancer patients shows an overall favorable safety profile, with a low ICI-M recurrence rate and no significant increase in MACE incidence. This study provides preliminary evidence to support clinical decision-making; however, large-scale prospective studies are still needed for further confirmation and validation.

Key words: immune checkpoint inhibitor, myocarditis, recurrence, major adverse cardiovascular event, safety

中图分类号:

R542.2

刘智通, 樊子旭, 李想, 张敏. 肺癌患者免疫检查点抑制剂相关心肌炎后永久停药与继续免疫治疗的安全性比较[J]. 上海交通大学学报（医学版）, 2026, 46(5): 612-623.

Liu Zhitong, Fan Zixu, Li Xiang, Zhang Min. Safety outcomes of immunotherapy continuation versus permanent discontinuation after immune checkpoint inhibitor-associated myocarditis in patients with lung cancer[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2026, 46(5): 612-623.

图/表 9

参考文献 30

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Characteristic	CTCAE Grade 1 (n=305)		CTCAE Grade 2 (n=52)		P value
Characteristic	On-treatment or resumed (n=207)	Permanently discontinued (n=98)	On-treatment or resumed (n=19)	Permanently discontinued (n=33)	P value
Clinical characteristic
Age/year	67.0 (61.0, 71.0)	68.0 (61.0, 73.0)	64.0 (61.0, 72.0)	66.0 (62.0, 69.0)	0.593
Male/n(%)	185 (89.4)	74 (75.5)	16 (84.2)	27 (81.8)	0.018
BMI/(kg·m^-2)	22.6 (20.3, 24.7)	22.5 (20.4, 24.9)	23.1 (21.0, 24.5)	22.9 (22.2, 25.6)	0.392
Coronary artery disease/n(%)	33 (15.9)	16 (16.3)	6 (31.6)	10 (30.3)	0.091
Hyperlipidemia/n(%)	13 (6.3)	7 (7.1)	1 (5.3)	3 (9.1)	0.929
Hypertension/n(%)	77 (37.2)	35 (35.7)	4 (21.1)	10 (30.3)	0.497
Diabetes/n(%)	26 (12.6)	13 (13.3)	3 (15.8)	6 (18.2)	0.832
Chronic kidney disease/n(%)	5 (2.4)	4 (4.1)	0 (0)	1 (3.3)	0.739
Histology/n(%)					0.583
Squamous cell carcinoma	74 (35.7)	30 (30.6)	7 (36.8)	10 (30.3)
Adenocarcinoma	84 (40.6)	47 (48.0)	8 (42.1)	14 (42.4)
Other NSCLC	26 (12.6)	7 (7.1)	2 (10.5)	7 (21.2)
SCLC	23 (11.1)	14 (14.3)	2 (10.5)	2 (6.1)
Disease stage/n(%)					0.265
Stage Ⅱ‒Ⅲ	78 (37.7)	28 (28.6)	4 (21.1)	11 (33.3)
Stage Ⅳ	129 (62.3)	70 (71.4)	15 (78.9)	22 (66.7)
ECOG performance status^①/n(%)					0.072
0	24 (14.3)	4 (5.2)	0 (0)	3 (12.5)
1	143 (85.1)	71 (92.2)	9 (90.0)	20 (83.3)
2	1 (0.6)	2 (2.6)	1 (10.0)	1 (4.2)
Baseline laboratory test
Hemoglobin/(g·L^-1)	129.0 (116.0, 141.0)	126.5 (115.0, 139.0)	132.0 (128.0, 144.0)	127.0 (116.0, 139.0)	0.550
Albumin/(g·L^-1)	40.0 (37.0, 42.0)	39.0 (36.0, 41.0)	41.0 (38.0, 42.0)	39.0 (37.0, 42.0)	0.794
HbA1c/%	5.8 (5.6, 6.3)	5.8 (5.3, 6.5)	5.8 (5.3, 6.7)	6.0 (5.7, 6.2)	0.803
eGFR/[mL·(min·1.73 m²)^-1]	94.8 (85.9, 101.1)	94.3 (77.8, 100.9)	99.0 (85.9, 103.4)	91.5 (78.3, 95.9)	0.237
Anti-tumor therapy
Radiotherapy/n(%)	67 (32.4)	33 (33.7)	7 (36.8)	11 (33.3)	0.980
Initial ICI type/n(%)					0.522
PD-1i monotherapy	170 (82.1)	83 (84.7)	18 (94.7)	29 (87.9)
PD-L1i monotherapy	29 (14.0)	14 (14.3)	1 (5.3)	4 (12.1)
Combination therapy	8 (3.9)	1 (1.0)	0 (0)	0 (0)
Number of cycles received prior to ICI-M	2.0 (1.0, 5.0)	3.0 (2.0, 6.0)	3.0 (2.0, 7.5)	2.0 (1.0, 3.0)	0.131
Ongoing treatment/n(%)					0.184
ICIs monotherapy	42 (20.3)	16 (16.3)	7 (36.8)	7 (21.2)
Combination with chemotherapy	138 (66.7)	69 (70.4)	10 (52.6)	20 (60.6)
Combination with targeted therapy	17 (8.2)	8 (8.2)	0 (0)	1 (3.0)
Combination with chemotherapy and targeted therapy	10 (4.8)	5 (5.1)	2 (10.5)	5 (15.2)
Clinical characteristics of initial ICI-M
Time to initial ICI-M/month	2.0 (1.0, 5.0)	3.0 (1.0, 6.0)	3.0 (1.0, 7.5)	2.0 (1.0, 3.0)	0.073
Peak cTnI/(pg·mL^-1)	80.0 (50.0, 140.0)	90.0 (60.0, 190.0)	310.0 (130.0, 550.0)	390.0 (120.0, 610.0)	<0.001
Peak CK-MB/(ng·mL^-1)	3.0 (1.8, 6.3)	3.5 (1.8, 12.1)	4.4 (2.8, 10.1)	11.0 (3.5, 73.7)	<0.001
Management/n(%)
Hospitalization	17 (8.2)	24 (24.5)	11 (57.9)	22 (66.7)	<0.001
Systemic steroids use	13 (6.3)	25 (25.5)	3 (15.8)	21 (63.6)	<0.001

Characteristic	CTCAE Grade 1 (n=305)		CTCAE Grade 2 (n=52)		P value
Characteristic	On-treatment or resumed (n=207)	Permanently discontinued (n=98)	On-treatment or resumed (n=19)	Permanently discontinued (n=33)	P value
Clinical characteristic
Age/year	67.0 (61.0, 71.0)	68.0 (61.0, 73.0)	64.0 (61.0, 72.0)	66.0 (62.0, 69.0)	0.593
Male/n(%)	185 (89.4)	74 (75.5)	16 (84.2)	27 (81.8)	0.018
BMI/(kg·m^-2)	22.6 (20.3, 24.7)	22.5 (20.4, 24.9)	23.1 (21.0, 24.5)	22.9 (22.2, 25.6)	0.392
Coronary artery disease/n(%)	33 (15.9)	16 (16.3)	6 (31.6)	10 (30.3)	0.091
Hyperlipidemia/n(%)	13 (6.3)	7 (7.1)	1 (5.3)	3 (9.1)	0.929
Hypertension/n(%)	77 (37.2)	35 (35.7)	4 (21.1)	10 (30.3)	0.497
Diabetes/n(%)	26 (12.6)	13 (13.3)	3 (15.8)	6 (18.2)	0.832
Chronic kidney disease/n(%)	5 (2.4)	4 (4.1)	0 (0)	1 (3.3)	0.739
Histology/n(%)					0.583
Squamous cell carcinoma	74 (35.7)	30 (30.6)	7 (36.8)	10 (30.3)
Adenocarcinoma	84 (40.6)	47 (48.0)	8 (42.1)	14 (42.4)
Other NSCLC	26 (12.6)	7 (7.1)	2 (10.5)	7 (21.2)
SCLC	23 (11.1)	14 (14.3)	2 (10.5)	2 (6.1)
Disease stage/n(%)					0.265
Stage Ⅱ‒Ⅲ	78 (37.7)	28 (28.6)	4 (21.1)	11 (33.3)
Stage Ⅳ	129 (62.3)	70 (71.4)	15 (78.9)	22 (66.7)
ECOG performance status^①/n(%)					0.072
0	24 (14.3)	4 (5.2)	0 (0)	3 (12.5)
1	143 (85.1)	71 (92.2)	9 (90.0)	20 (83.3)
2	1 (0.6)	2 (2.6)	1 (10.0)	1 (4.2)
Baseline laboratory test
Hemoglobin/(g·L^-1)	129.0 (116.0, 141.0)	126.5 (115.0, 139.0)	132.0 (128.0, 144.0)	127.0 (116.0, 139.0)	0.550
Albumin/(g·L^-1)	40.0 (37.0, 42.0)	39.0 (36.0, 41.0)	41.0 (38.0, 42.0)	39.0 (37.0, 42.0)	0.794
HbA1c/%	5.8 (5.6, 6.3)	5.8 (5.3, 6.5)	5.8 (5.3, 6.7)	6.0 (5.7, 6.2)	0.803
eGFR/[mL·(min·1.73 m²)^-1]	94.8 (85.9, 101.1)	94.3 (77.8, 100.9)	99.0 (85.9, 103.4)	91.5 (78.3, 95.9)	0.237
Anti-tumor therapy
Radiotherapy/n(%)	67 (32.4)	33 (33.7)	7 (36.8)	11 (33.3)	0.980
Initial ICI type/n(%)					0.522
PD-1i monotherapy	170 (82.1)	83 (84.7)	18 (94.7)	29 (87.9)
PD-L1i monotherapy	29 (14.0)	14 (14.3)	1 (5.3)	4 (12.1)
Combination therapy	8 (3.9)	1 (1.0)	0 (0)	0 (0)
Number of cycles received prior to ICI-M	2.0 (1.0, 5.0)	3.0 (2.0, 6.0)	3.0 (2.0, 7.5)	2.0 (1.0, 3.0)	0.131
Ongoing treatment/n(%)					0.184
ICIs monotherapy	42 (20.3)	16 (16.3)	7 (36.8)	7 (21.2)
Combination with chemotherapy	138 (66.7)	69 (70.4)	10 (52.6)	20 (60.6)
Combination with targeted therapy	17 (8.2)	8 (8.2)	0 (0)	1 (3.0)
Combination with chemotherapy and targeted therapy	10 (4.8)	5 (5.1)	2 (10.5)	5 (15.2)
Clinical characteristics of initial ICI-M
Time to initial ICI-M/month	2.0 (1.0, 5.0)	3.0 (1.0, 6.0)	3.0 (1.0, 7.5)	2.0 (1.0, 3.0)	0.073
Peak cTnI/(pg·mL^-1)	80.0 (50.0, 140.0)	90.0 (60.0, 190.0)	310.0 (130.0, 550.0)	390.0 (120.0, 610.0)	<0.001
Peak CK-MB/(ng·mL^-1)	3.0 (1.8, 6.3)	3.5 (1.8, 12.1)	4.4 (2.8, 10.1)	11.0 (3.5, 73.7)	<0.001
Management/n(%)
Hospitalization	17 (8.2)	24 (24.5)	11 (57.9)	22 (66.7)	<0.001
Systemic steroids use	13 (6.3)	25 (25.5)	3 (15.8)	21 (63.6)	<0.001

Variable	No recurrent ICI-M/new irAEs (n=176)	Recurrent ICI-M/new irAEs (n=50)	P value
Age/year	67.0 (61.0, 71.0)	67.0 (62.0, 73.0)	0.535
Male/n(%)	157 (89.2)	44 (88.0)	1.000
BMI/(kg·m^-2)	22.9 ± 3.4	22.5 ± 3.3	0.483
Coronary artery disease/n(%)	28 (15.9)	11 (22.0)	0.427
Hyperlipidemia/n(%)	9 (5.1)	5 (10.0)	0.351
Hypertension/n(%)	63 (35.8)	18 (36.0)	1.000
Diabetes/n(%)	23 (13.1)	6 (12.0)	1.000
Chronic kidney disease/n(%)	2 (1.1)	3 (6.0)	0.129
Histology/n(%)			0.788
Squamous cell carcinoma	64 (36.4)	17 (34.0)
Adenocarcinoma	69 (39.2)	23 (46.0)
Other NSCLC	22 (12.5)	6 (12.0)
SCLC	21 (11.9)	4 (8.0)
Disease stage/n(%)			0.146
Stage Ⅱ‒Ⅲ	59 (33.5)	23 (46.0)
Stage Ⅳ	117 (66.5)	27 (54.0)
ECOG performance status^①/n(%)			0.459
0	20 (14.8)	4 (9.3)
1	113 (83.7)	39 (90.7)
2	2 (1.5)	0 (0)
Hemoglobin/(g·L^-1)	130.0 (116.0, 140.5)	128.5 (118.0, 142.0)	0.951
Albumin/(g·L^-1)	40.0 (37.0, 42.0)	39.0 (36.0, 41.0)	0.366
HbA1c/%	5.8 (5.5, 6.3)	5.8 (5.7, 6.3)	0.384
eGFR/[mL·(min·1.73 m²)^-1]	94.9 (86.3, 101.3)	94.1 (81.6, 101.2)	0.655
Radiotherapy/n(%)	58 (33.0)	16 (32.0)	1.000
ICI type after initial ICI-M/n(%)			1.000
PD-1 monotherapy	150 (85.2)	43 (86.0)
PD-L1 monotherapy	26 (14.8)	7 (14.0)
Anti-tumor treatment after initial ICI-M/n(%)			0.244
ICIs monotherapy	45 (25.6)	15 (30.0)
Combination with chemotherapy	109 (61.9)	27 (54.0)
Combination with targeted therapy	12 (6.8)	7 (14.0)
Combination with chemotherapy and targeted therapy	10 (5.7)	1 (2.0)
Number of cycles received prior to ICI-M	3.0 (2.0, 6.0)	2.0 (1.0, 4.0)	0.029
Time to initial ICI-M/d	71.0 (43.0, 169.0)	47.0 (27.0, 90.0)	0.006
CTCAE grade of initial ICI-M/n(%)			0.864
Grade 1	162 (92.0)	45 (90.0)
Grade 2	14 (8.0)	5 (10.0)
Peak cTnI/(pg·mL^-1)	80.0 (50.0, 160.0)	85.0 (40.0, 260.0)	0.683
Peak CK-MB/(ng·mL^-1)	2.8 (1.8, 5.9)	4.8 (2.4, 9.1)	0.019
Hospitalization/n(%)	21 (11.9)	7 (14.0)	0.882
Systemic steroids use/n(%)	10 (5.7)	6 (12.0)	0.221
Temporary ICI discontinuation/n(%)	41 (23.3)	12 (24.0)	1.000

Variable	No recurrent ICI-M/new irAEs (n=176)	Recurrent ICI-M/new irAEs (n=50)	P value
Age/year	67.0 (61.0, 71.0)	67.0 (62.0, 73.0)	0.535
Male/n(%)	157 (89.2)	44 (88.0)	1.000
BMI/(kg·m^-2)	22.9 ± 3.4	22.5 ± 3.3	0.483
Coronary artery disease/n(%)	28 (15.9)	11 (22.0)	0.427
Hyperlipidemia/n(%)	9 (5.1)	5 (10.0)	0.351
Hypertension/n(%)	63 (35.8)	18 (36.0)	1.000
Diabetes/n(%)	23 (13.1)	6 (12.0)	1.000
Chronic kidney disease/n(%)	2 (1.1)	3 (6.0)	0.129
Histology/n(%)			0.788
Squamous cell carcinoma	64 (36.4)	17 (34.0)
Adenocarcinoma	69 (39.2)	23 (46.0)
Other NSCLC	22 (12.5)	6 (12.0)
SCLC	21 (11.9)	4 (8.0)
Disease stage/n(%)			0.146
Stage Ⅱ‒Ⅲ	59 (33.5)	23 (46.0)
Stage Ⅳ	117 (66.5)	27 (54.0)
ECOG performance status^①/n(%)			0.459
0	20 (14.8)	4 (9.3)
1	113 (83.7)	39 (90.7)
2	2 (1.5)	0 (0)
Hemoglobin/(g·L^-1)	130.0 (116.0, 140.5)	128.5 (118.0, 142.0)	0.951
Albumin/(g·L^-1)	40.0 (37.0, 42.0)	39.0 (36.0, 41.0)	0.366
HbA1c/%	5.8 (5.5, 6.3)	5.8 (5.7, 6.3)	0.384
eGFR/[mL·(min·1.73 m²)^-1]	94.9 (86.3, 101.3)	94.1 (81.6, 101.2)	0.655
Radiotherapy/n(%)	58 (33.0)	16 (32.0)	1.000
ICI type after initial ICI-M/n(%)			1.000
PD-1 monotherapy	150 (85.2)	43 (86.0)
PD-L1 monotherapy	26 (14.8)	7 (14.0)
Anti-tumor treatment after initial ICI-M/n(%)			0.244
ICIs monotherapy	45 (25.6)	15 (30.0)
Combination with chemotherapy	109 (61.9)	27 (54.0)
Combination with targeted therapy	12 (6.8)	7 (14.0)
Combination with chemotherapy and targeted therapy	10 (5.7)	1 (2.0)
Number of cycles received prior to ICI-M	3.0 (2.0, 6.0)	2.0 (1.0, 4.0)	0.029
Time to initial ICI-M/d	71.0 (43.0, 169.0)	47.0 (27.0, 90.0)	0.006
CTCAE grade of initial ICI-M/n(%)			0.864
Grade 1	162 (92.0)	45 (90.0)
Grade 2	14 (8.0)	5 (10.0)
Peak cTnI/(pg·mL^-1)	80.0 (50.0, 160.0)	85.0 (40.0, 260.0)	0.683
Peak CK-MB/(ng·mL^-1)	2.8 (1.8, 5.9)	4.8 (2.4, 9.1)	0.019
Hospitalization/n(%)	21 (11.9)	7 (14.0)	0.882
Systemic steroids use/n(%)	10 (5.7)	6 (12.0)	0.221
Temporary ICI discontinuation/n(%)	41 (23.3)	12 (24.0)	1.000

Factor	Multivariable analysis
Factor	HR (95%CI)	P value
On-treatment or resumed ICIs	0.75 (0.28‒1.98)	0.556
Coronary artery disease	2.53 (1.04‒6.17)	0.041
CTCAE grade of initial ICI-M
Grade 1	Ref
Grade 2	5.26 (1.91‒14.46)	0.001
Systemic steroids use for initial ICI-M	0.63 (0.18‒2.18)	0.469
ECOG performance status
0	Ref
1	1.62 (0.20‒13.20)	0.652
2	1.45 (0.06‒32.45)	0.815
Number of cycles received prior to ICI-M	1.03 (0.97‒1.09)	0.359
Ongoing anti-tumor treatment
ICIs monotherapy	Ref
Combination with chemotherapy	0.70 (0.25‒1.95)	0.500
Combination with targeted therapy	2.38 (0.56‒10.20)	0.243
Combination with chemotherapy and targeted therapy	0.65 (0.07‒5.98)	0.700