Safety outcomes of immunotherapy continuation versus permanent discontinuation after immune checkpoint inhibitor-associated myocarditis in patients with lung cancer

doi:10.3969/j.issn.1674-8115.2026.05.007

Abstract

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

CLC Number:

R542.2

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.

Figures/Tables 9

TrendMD

References 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