Clinical characteristics and prognostic impact of immune checkpoint inhibitor-associated myocarditis in advanced non-small cell lung cancer

doi:10.21203/rs.3.rs-3115558/v1

Download PDF

Research Article

Clinical characteristics and prognostic impact of immune checkpoint inhibitor-associated myocarditis in advanced non-small cell lung cancer

https://doi.org/10.21203/rs.3.rs-3115558/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 30 Oct, 2023

Read the published version in Investigational New Drugs →

You are reading this latest preprint version

Background: Myocarditis is a rare immune-related adverse events (irAEs) with high mortality rates, with few reports on its clinical characteristics and prognostic impact. This study designed to explore the associations between cardiac parameters and outcomes of myocarditis in advanced non-small cell lung cancer (NSCLC) who treated with immune checkpoint inhibitor (ICI).

Methods: Fourteen patients diagnosed with ICI-associated myocarditis by clinicians were admitted to the study analysis. By Cox univariate and multivariate survival analyses, potential risk factors for the development of severe myocarditis were identified. Survival analysis was also performed to explore the prognosis of patients with myocarditis.

Results: Among patients with myocarditis, higher B-type natriuretic peptide (BNP) levels (P=0.04) and conduction block (P=0.03) were associated with progression to severe myocarditis.In addition, high lactate dehydrogenase (LHD)levels (P=0.04) and myocarditis onset within 2 months (P=0.02) were prognostic factors of severe myocarditis. The median progression-free survival (PFS) time and median overall survival (OS) time for all patients were 5.9 months and 18.5 months, respectively. However, there were no statistical differences between mild and severe cohorts in terms of PFS and OS (PFS: 4.5 vs. 8.5 months, P=0.17; OS: 21.3 vs. 18.5months, P=0.36). And we found that the earlier occurrence of myocarditis, worse PFS prognosis (4.5 months vs. 10.5 months, P=0.008), while no difference in OS (18.5 months vs. 21.3 months, P=0.35).

Conclusion: Compared to mild myocarditis, severe myocarditis presented with higher BNP levels and cardiac conduction abnormalities. In addition, patients with mild and early myocarditis tended to have better survival rates.

Immune checkpoint inhibitors (ICIs)

ICI-associated myocarditis

non-small cell lung cancer (NSCLC)

cardiac biomarkers

With the help of in-depth studies on tumor immune response mechanisms and tumor microenvironment, a variety of immune checkpoint inhibitors (ICIs) have been utilized in the clinic over the course of the last decade. ICIs approved by the Food and Drug Administration for non-small cell lung cancer (NSCLC) treatment include anti-programmed death 1 (anti-PD-1) antibodies, anti-programmed death ligand-1 (anti-PD-L1) antibodies, and cytotoxic T lymphocyte antigen (CTLA-4) agents.

Although using ICIs results in significantly improved survival in advanced NSCLC patients, adverse effects related to immunotherapy cannot be ignored. It has been reported that the incidence of cardiovascular toxicity in patients who received ICIs was 11 times higher than in those who did not [1]. Among these adverse events, it was reported that myocarditis has low incidence(0.06–1%) [2] and high mortality (46%) rates [3]. Furthermore, compared to monotherapy, combined use of ICIs has been strongly related to increased morbidity, severity, and mortality of myocarditis [4, 5]. The concomitant non-cardiovascular immune-related adverse events (irAEs), including myositis, encephalitis, and hepatitis, may also be risk factors for myocarditis [6].

Clinical characteristics of myocarditis include the median time to onset of 1–2 months after immunotherapy [1, 7]. Myocarditis symptoms vary. Mild cases may present with nonspecific symptoms, such as nausea [8], cough, and fever. Severe cases manifest via chest pain, dyspnea, palpitation, arrhythmias, and even cardiogenic shock [4, 9]. A retrospective study has suggested that higher troponin I and Creatine kinase-MB (CK-MB) levels indicated progression to severe myocarditis [10].

However, few studies have reported on the clinical characteristics and prognostic impact of ICI-associated myocarditis in advanced NSCLC. The aim of this study was to explore whether the levels of cardiac biomarkers increased in ICI-associated myocarditis, and whether these parameters were related to subsequent clinical outcomes.

2.1Patients

Patients suffering from myocarditis (n = 14) and diagnosed with ICI-related myocarditis at the Zhejiang Cancer Hospital between November 2019 and December 2022 were included in the study. All patients were diagnosed with advanced NSCLC. The present retrospective study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Zhejiang Cancer Hospital (IRB-2022-297).

Inclusion criteria for the study were as follows: 1) NSCLC diagnosis via pathology analysis; 2) at least one cycle of ICI treatment; 3) cardiac biomarker abnormalities, myocarditis-related symptoms, or cardiac conduction abnormalities that were responsive to corticosteroids after ICI treatment; and 4) retained baseline data. Exclusion criteria included the following: 1) previous history of myocarditis, autoimmune diseases, chronic hepatitis, and chronic renal insufficiency; 2) small cell lung cancer diagnosis by pathology; and 3) myocarditis due to infection or autoimmune disease.

2.2Treatments and response assessments

Disease was evaluated by computed tomography (CT) scan after two cycles of therapy. Myocardial enzyme, electrocardiogram, and echocardiography measurements were carried out before each treatment cycle. These tests were performed weekly for patients with a previously diagnosed cardiovascular disease. Criteria for myocarditis severity were adapted from the Common Terminology Criteria for Adverse Events V.5.0 [11] (Supplementary Table). Grade 1–2 myocarditis presented only with elevated cardiac biomarker, without or with mild clinical symptoms, which considered as mild or subclinical myocarditis. Grade 3 or higher myocarditis that required hospitalization was considered to be severe myocarditis, which considered as severe myocarditis. Using the Response Evaluation Criteria in Solid Tumors Version 1.1, progression-free survival (PFS) was assessed from the commencement of ICI treatment until the earliest symptom of progressive disease (PD) from any cause or the last follow-up. Overall survival (OS) means the date of ICI treatment initiation until death or the last follow-up evaluation.

Statistical analysis

The date of last follow-up was March 2, 2023. Follow-up data were obtained for all patients. Summary statistical parameters were computed, including medians and interquartile range (IQR) for continuous variables and percentages for categorical variables. Statistical analysis was performed using the t-test and Fisher’s exact test. Kaplan–Meier estimates and log-rank test were used to compare PFS and OS. By Cox regression model, we performed the univariate and multivariate analyses. All analyses were performed using SPSS version 25.0(Chicago, IL, USA) and GraphPad Prism version 9(San Diego, California, USA). Two-sided P values of < 0.05 were considered statistically significant.

3.1Patient characteristics

A total of 14 patients eligible for inclusion were enrolled in this study. Patients were divided into two groups according to the severity of ICI-associated myocarditis. The baseline characteristics for all patients are summarized in Table 1 and the time to initiation of ICI treatment to discontinuation is represented in Fig. 1. All treatments involved the administration of PD-1 inhibitors. The Eastern Cooperative Oncology Group physical status scores were 0–1.

The mean age of patients with myocarditis was 66.9 ± 9.7 years, and most of the patients were male (13/14, 92.9%). In terms of histological types, squamous cell carcinoma (8/14, 57.1%) and adenocarcinoma (6/14, 42.9%) accounted for similar proportions of all of the cases. Eight (8/14, 57.1%) patients were smokers, and six (6/14, 42.9%) patients had previous cardiovascular history (hypertension, coronary heart disease, and atrial fibrillation). No statistically difference was observed incidence of cardiovascular diseases and risk factors between the mild and severe cohorts. There were two cases with negative (PD-L1 expression < 1%) and two cases with PD-L1 high expression (PD-L1 expression ≥ 50%). One of the patients expressed PD-L1 as 1–49%, while nine patients were undetectable. Most of the patients were assessed as advanced NSCLC (11/14, 78.6%), and only three patients suffered from locally advanced NSCLC. There was no significant difference between the mild and severs cohorts. In terms of treatment regimens, the patients underwent immunotherapy, including monotherapy (4/14, 28.6%) and combination therapy. Combination therapy regimens included immunotherapy combined with chemotherapy (7/14, 50%) and anti-vascular targeted therapy (3/14, 21.4%).

Table 1

Characteristics of patients with severe and mild ICI-associated myocarditis
Characteristic	Total(n = 14)	Mild(n = 9)	Severe (n = 5)	P value
Age	66.86 ± 9.694	63.78 ± 10.686	72.40 ± 4.159	0.05
Male	13(92.9%)	9(100%)	4(80%)	0.36
Smoking	8(57.1%)	6(66.7%)	2(40%)	0.58
cardiovascular disease	6(42.9%)	3(33.3%)	3(60%)	0.58
Histological				0.09
Adenocarcinoma	6(42.9%)	2(22.2%)	4(80%)
Squamous	8(57.1%)	7(77.8%)	1(20%)
PD-L1 expression				0.13
≥ 50%	2(14.3%)	1(11.1%)	1(20%)
1%-49%	1(7.1%)	1(11.1%)	0
༜1%	2(14.3%)	0	2(40%)
not detected	9(64.3%)	7(77.8%)	2(40%)
TNM Stage^*				1
IV	11(78.6%)	7(77.8%)	4(80%)
III	3(21.4%)	2(22.2%)	1(20%)
Metastases	10(71.4%)	6(66.7%)	4(80%)	1
Therapy line				1
First line	6(42.9%)	4(44.4%)	2(40%)
≥Second line	8(57.1%)	5(55.6%)	3(60%)
Therapy mode				0.37
Monotherapy	4(28.6%)	3(33.3%)	1(20%)
Combination chemotherapy	7(50%)	3(33.3%)	4(80%)
Combination targeted-therapy	3(21.4%)	3(33.3%)	0
*Abbreviations: TNM stage, Tumor Node Metastasis stage

3.2Parametric characteristics of myocarditis

Cardiac enzyme parameters (troponin T; B-type natriuretic peptide, BNP; creatine kinase, CK; CK-MB and lactate dehydrogenase, LDH), electrocardiograms (ECG), and echocardiograms (ejection fraction, EF%) were analyzed in mild and severe cohorts (Table 2). The results showed that there was a statistically significant difference in BNP level and ECG conduction block (BNP: 236.8 ± 83.4 vs. 1072.2 ± 265.7, P = 0.04; conduction block: 0 vs. 3 (30%), P = 0.03). Due to the small sample size, troponin T (P = 0.11), LDH (P = 0.08), and ST/T wave changes (P = 0.09) were not statistically significantly different, although the above indicators still need to be monitored.

Table 2

Cardiac parameters among mild and severe ICI-associated myocarditis
	Mild(n = 9)	Severe (n = 5)	P value
Laboratory tests
Troponin T (ug/L)	0.034 ± 0.013	0.614 ± 0.759	0.11
BNP (ng/L) ^*	236.8 ± 83.4	1072.2 ± 265.7	0.04
CK (U/L) ^*	70.67 ± 16	1618 ± 2216	0.61
CK-MB (U/L) ^*	2.69 ± 0.5	105.9 ± 125.6	0.37
LDH (U/L) ^*	260 ± 45	547.5 ± 381	0.08
ECG ^*
PR (ms)	172.7 ± 24.1	175 ± 1.4	0.70
QRS (ms)	89.3 ± 8.1	98 ± 2.8	0.92
QT (ms)	376 ± 34.7	365 ± 15.6	0.07
Abnormal	7(77.8%)	5(100%)	0.51
Conduction block	0	3(60%)	0.03
Premature beats	0	1(20%)	0.36
	4(44.4%)	5(100%)	0.09
Echocardiography
EF (%) ^*	61(61, -)	65(64, -)	0.46
*Abbreviations: BNP, B-type natriuretic peptide; CK, creatine kinase; CK-MB, creatine kinase-MB; LDH, lactate dehydrogenase; ECG, electrocardiograph; EF, ejection fraction

Furthermore, the association among cardiac parameters, ICI-associated myocarditis onset timing, and clinical survival outcomes was explored. A two-month cutoff was chosen by observation as an important time node to assess tumor progression in patients with ICI-myocarditis. Univariate analysis demonstrated that LDH (P = 0.04) and onset of myocarditis within 2 months (P = 0.02) were independent prognostic factors of progression, and multivariate analyses showed that myocarditis within 2 months (P = 0.05) may be the only significant prognostic factor of tumor progression (Table 3).

Table 3

Association with tumor progression by univariate and multivariable analyses
	Univariate			Multivariable
	HR	95%CI	P value	HR	95%CI	P value
Conduction block	3.976	0.878-18	0.07
LDH (U/L)	1.004	1-1.008	0.04	1.002	0.998–1.006	0.23
Bone metastases	0.027	0-9.857	0.23
myocarditis within two months	0.145	0.028–0.740	0.02	0.181	0.032–1.007	0.05

3.3Association between myocardial and treatment outcomes

In the present study cohort, partial remission (PR) was the best response to immunotherapy as a treatment for NSCLC, with 11 patients who progressed and seven who died. Six of these patients died due to disease progression and one due to massive pericardial effusion. The survival analyses of the two cohorts are presented in Fig. 2. The median PFS (mPFS) and median OS (mOS) were 5.9 months and 18.5 months, respectively. No significant difference was observed in PFS and OS (PFS: 8.5 vs. 4.5 months, P = 0.17; OS: 21.3 vs. 18.5 months, P = 0.36). However, patients with mild myocarditis tended to have better survival rates than those with severe myocarditis.

In addition, the association between time of ICI treatment commencement to the onset of myocarditis and treatment outcomes was analyzed (Fig. 3). The median time of myocarditis onset was 51 days (IQR 31.5–189 days) in the severe group and 107 days (IQR 43–177 days) in the mild group, although this difference was not statistically significant (P = 0.46). However, the association between disease progression was statistically significant (PFS: 4.5 months [within 2 months] vs. 10.5 months [after 2 months], P = 0.008) in patients who developed myocarditis within or after 2 months. This relationship was not reflected in survival time (OS:18.5 months [within 2 months] vs. 21.3 months [after 2 months], P = 0.35).

The difference in outcomes between groups with or without non-cardiotoxic irAEs is compared in Fig. 4. Some of the 14 participants developed non-cardiotoxic irAEs, including pneumonia (one patients), hypothyroidism (two patients), arthritis (one patient), and myositis (one patient). These results were not statistically significant (PFS: 4.9 vs. 8.5 months, P = 0.12; OS: 18.5 vs. 16.3months, P = 0.73).

The present study investigated myocarditis in patients with advanced NSCLC who treated with immunotherapy. This was the first study to comprehensively describe the association among myocarditis severity, clinical features, and prognostic factors in NCSLC patients. High BNP levels and appearance of conduction block were associated with progression to severe myocarditis. In addition, earlier myocarditis incidence was correlated with faster tumor progression.

Immunotherapy regimens have brought new hope to patients with advanced NSCLC. However, irAEs that can target any organ or gland still require attention. In particular, ICI-associated myocarditis with a potentially high risk of death deserves particular vigilance. A previous study has demonstrated that immunotherapy for lung cancer and malignant melanoma increased the rates of cardiac event occurrence compared to other solid tumors. The absolute risk of cardiac events in lung cancer patients within 1 year was 9.7% [12].

The symptoms of myocarditis vary. Mild cases may present with non-specific symptoms, while severe myocarditis can even lead to explosive death. Besides, the median time to myocarditis onset after immunotherapy varies, with 30 days [4]and 65 days [7] reported in the literature.

The mathematical mechanism of myocarditis was not completely understood. Pre-clinical genetic mouse models have shown that mice with PD-1-deficient develop dilated cardiomyopathy and die prematurely due to overexpression of antibodies for cardiac troponin I. CTLA-4-deficient mice develop lymphoproliferative myocarditis caused by systemic inflammation and fatal multi-organ failure [5].

During heart injury, cardiac autoantigens are exposed to T lymphocytes, and immune checkpoints are upregulated in cardiomyocytes to inhibit T cell invasion. ICI treatment dysregulates the protective mechanisms of the heart [13]. This explains the large number of CD4 and CD8 T cells and CD68 macrophages infiltrating the myocardium and cardiac conduction system by biopsy in fulminant myocarditis [4]. Spurr have found that local ablative radiotherapy stimulated the immune response [14]. Receiving radiotherapy may result in potential exposure to cardiac autoantigens in patients with NSCLC. ICI treatment eliminates this cardioprotective mechanism, activating T cell immunity and resulting in a higher incidence of cardiotoxicity [15].

The awareness about prevention and treatment of ICI-associated myocarditis has gradually increased since fatality rates of 46% have been reported [16]. For severe myocarditis (grade 3 or higher), initiation of high dose corticosteroids should be deemed to advantageous [17]. In addition, temporary or permanent discontinuation of ICI is also necessarily. A high index of suspicion for myocarditis usually results in prompt and accurate identification of ICI-associated myocarditis. In the present study, symptomatic treatment was carried out and none of the cases died due to ICI-associated myocarditis.

History of smoking and heart disease was not significantly associated with the severity of myocarditis in this study. Ganatra and Neilan have stated that underlying heart disease, diabetes, autoimmune diseases, and combination immunotherapy were additional risk factors of ICI-related myocarditis [18].

Furthermore, there was no difference in OS and PFS between mild and severe myocarditis cases in this study. However, the prognosis of mild myocarditis cases was significantly better than that of severe cases. Coincidentally, a retrospective study has also pointed out that severe cardiotoxicity was significantly associated with poor OS compared to mild cases [7, 15].

In the present study, a two-month cutoff was chosen to assess tumor progression in patients with ICI-associated myocarditis. The results showed that the earlier the occurrence of myocarditis, the worse the PFS prognosis, without any apparent differences in OS. Few studies have discussed the association between the time of myocarditis onset and tumor prognosis.

Furthermore, the available data on cardiac biomarkers in patients presenting with myocarditis were collected. None of the noninvasive diagnostic tests had a high sensitivity and specificity. It was determined that higher BNP levels may be related to progression to severe myocarditis. In addition, LDH was an independent prognostic factor for tumor progression determined using univariate Cox survival analysis. Generally, troponin and CK-MB are considered to be early and reliable predictors of progression to severe myocarditis and mortality [7, 8, 19]. Mahmood have shown a four-fold increase in the risk of major adverse cardiac events (MACEs) with troponin T level of ≥ 1.5 ng/mL [20]. Because the present investigation was a single center study with a small sample size, high troponin T and CK levels were the only subtle connections to severe myocarditis, which was not a statistically significant result. Therefore, large and multicenter studies are needed to identify more sensitive and specific biomarkers of myocarditis. Besides, risk prediction for ICI-associated myocarditis needed to be addressed in the future.

In addition, the role of ECG in evaluation of myocarditis severity was also explored. Most patients with severe myocarditis presented with a conduction block on an ECG. Prolonged QRS duration has been demonstrated to point to an increased risk of subsequent MACE [21]. Therefore, regular monitoring of myocardial biomarkers and ECG in immunotherapy patients can benefit to the diagnosis and risk-stratification of ICI-associated myocarditis.

Cardiac magnetic resonance (CMR) is the preferred choice for the diagnosis of myocarditis among all of the imaging tests. Myocardial inflammation and edema can be discovered via late gadolinium enhancement and T2-weighted imaging. However, this method is not readily available. A previous study has found that most patients (61%) with myocarditis had a normal LVEF (≥ 50%) [22], which showed that CMR was not sensitive enough to diagnose myocarditis. In addition, myocardial biopsy is the gold standard for diagnosing myocarditis, but is not commonly used clinically due to its invasive nature.

Another key point to remember is that a subset of patients with myocarditis also present with irAEs in other organs or glands. A retrospective study has found that 40% of immune-associated myositis patients present with myocarditis. Having ptosis was significantly associated with concurrent myocarditis [23]. In the present study, concomitant non-cardiovascular irAEs were also observed in some patients with myocarditis, including pneumonia, hypothyroidism, and myositis. However, non-cardiovascular irAEs were not associated with clinical outcomes. Nonetheless, presentation with non-cardiovascular irAEs, especially myositis, should alert medical professionals to be vigilant to the development of myocarditis.

The present study had some limitations. First, because ICI-associated myocarditis is rare, the study’s small sample size limited the interpretation of statistical analysis results. Second, the nature of this single center retrospective study resulted in inevitable biases, such as investigator bias. Third, only ICI-associated myocarditis cases diagnosed by clinicians were included in the study after reviewing electronic records. Some asymptomatic patients with elevated myocardial biomarkers may have been missed. Therefore, large prospective studies are needed to explore biomarkers and prognostic indicators associated with myocarditis in the future.

The present study retrospectively explored the clinical features and prognostic impact of ICI-associated myocarditis in advanced NSCLC patients treated with ICI. High BNP levels and appearance of conduction block were associated with progression to severe myocarditis. In addition, high LDH level and onset of myocarditis within 2 months were prognostic factors of progression. Finally, earlier incidence of myocarditis was correlated with faster tumor progression.

Acknowledgements

This study was funded by the Medical Scientific Research Foundation of Zhejiang Province (No. 2022KY653). Zhengbo Song was sponsored by Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents. Besides, we would like to appreciate all patients and all research staff for their cooperation and participation.

We also thank International Science Editing (http://www.internationalscienceediting.com) for editing this manuscript.

Funding

This work was supported by Medical Scientific Research Foundation of Zhejiang Province (No. 2022KY653). Zhengbo Song has received research supported from Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Author Contributions

Zhengbo Song and Weiping Zhang contributed to the study conception and design. Material preparation, data collection and analysis were performed by Lan Xu, Manyi Xu and Wei Sun. The first draft of the manuscript was written by Lan Xu. Manyi Xu and Wei Sun commented on previous versions of the manuscript. Zhengbo Song provided research funding. All authors read and approved the final manuscript.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of University of Zhejiang Cancer Hospital (Date: May 10,2022/No: IRB-2022-297).

Salem JE, Manouchehri A, Moey M, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol 2018;19(12):1579-89. doi:10.1016/S1470-2045(18)30608-9
Ganatra S, Neilan TG. Immune checkpoint inhibitor-associated myocarditis. Oncologist 2018;23(8):879-86. doi:10.1634/theoncologist.2018-0130
Moslehi JJ, Salem JE, Sosman JA, et al. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet 2018;391(10124):933. doi:10.1016/S0140-6736(18)30533-6
Johnson DB, Balko JM, Compton ML, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 2016;375(18):1749-55. doi:10.1056/NEJMoa1609214
Wei SC, Meijers WC, Axelrod ML, et al. A Genetic Mouse Model Recapitulates Immune Checkpoint Inhibitor-Associated Myocarditis and Supports a Mechanism-Based Therapeutic Intervention. Cancer Discov. 2021 Mar;11(3):614-625. doi: 10.1158/2159-8290.CD-20-0856.
Guha A, Al-Kindi S, Jain P, et al. Association between myocarditis and other immune-related adverse events secondary to immune checkpoint inhibitor use. Int J Cancer. 2020 Sep 15;147(6):1753-1754. doi: 10.1002/ijc.32960.
Escudier M, Cautela J, Malissen N, et al. Clinical features, management, and outcomes of immune checkpoint inhibitor-related cardiotoxicity. Circulation 2017;136(21):2085-7. doi:10.1161/CIRCULATIONAHA.117.030571
Norwood TG, Westbrook BC, Johnson DB, et al. Smoldering myocarditis following immune checkpoint blockade. J Immunother Cancer 2017;5(1):91. doi:10.1186/s40425-017-0296-4
Puzanov I, Subramanian P, Yatsynovich YV, et al. Clinical characteristics, time course, treatment and outcomes of patients with immune checkpoint inhibitor-associated myocarditis. J Immunother Cancer 2021;9(6):e002553. doi:10.1136/jitc-2021-002553
Puzanov I, Subramanian P, Yatsynovich YV, et al. Clinical characteristics, time course, treatment and outcomes of patients with immune checkpoint inhibitor-associated myocarditis. J Immunother Cancer. 2021 Jun;9(6):e002553. doi: 10.1136/jitc-2021-002553.
Haratani K, Hayashi H, Chiba Y, et al. Association of immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer. JAMA Oncol 2018;4(3):374-8. doi:10.1001/jamaoncol.2017.2925
D’Souza M, Nielsen D, Svane IM, et al. The risk of cardiac events in patients receiving immune checkpoint inhibitors: a nationwide Danish study. Eur Heart J 2021;42(16):1621-31. doi:10.1093/eurheartj/ehaa884
Hu JR, Florido R, Lipson EJ, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors. Cardiovasc Res. 2019 Apr 15;115(5):854-868. doi: 10.1093/cvr/cvz026.
Spurr LF, Martinez CA, Kang W, et al. Highly aneuploid non-small cell lung cancer shows enhanced responsiveness to concurrent radiation and immune checkpoint blockade. Nat Cancer 2022;3(12):1498-512. doi:10.1038/s43018-022-00467-x
Chen X, Jiang A, Zhang R, et al. Immune checkpoint inhibitor-associated cardiotoxicity in solid tumors: real-world incidence, risk factors, and prognostic analysis. Front Cardiovasc Med 2022;9:882167. doi:10.3389/fcvm.2022.882167
Moslehi JJ, Salem JE, Sosman JA, et al. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet 2018;391(10124):933. doi:10.1016/S0140-6736(18)30533-6
Schneider BJ, Naidoo J, Santomasso BD, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO Guideline Update. J Clin Oncol 2021;39(36):4073-126. doi:10.1200/JCO.21.01440
Ganatra S, Neilan TG. Immune checkpoint inhibitor-associated myocarditis. Oncologist 2018;23(8):879-86. doi:10.1634/theoncologist.2018-0130
Sarocchi M, Grossi F, Arboscello E, et al. Serial troponin for early detection of nivolumab cardiotoxicity in advanced non-small cell lung cancer patients. Oncologist 2018;23(8):936-42. doi:10.1634/theoncologist.2017-0452
Mahmood SS, Fradley MG, Cohen JV, et al. Myocarditis in Patients Treated With Immune Checkpoint Inhibitors. J Am Coll Cardiol. 2018 Apr 24;71(16):1755-1764. doi: 10.1016/j.jacc.2018.02.037.
Zlotoff DA, Hassan MZO, Zafar A, et al. Electrocardiographic features of immune checkpoint inhibitor associated myocarditis. J Immunother Cancer 2021;9(3):e002007. doi:10.1136/jitc-2020-002007
Zhang L, Awadalla M, Mahmood SS, et al. Cardiovascular magnetic resonance in immune checkpoint inhibitor-associated myocarditis. Eur Heart J 2020;41(18):1733-43. doi:10.1093/eurheartj/ehaa051
Hamada N, Maeda A, Takase-Minegishi K, et al. Incidence and distinct features of immune checkpoint inhibitor-related myositis from idiopathic inflammatory myositis: a single-center experience with systematic literature review and meta-analysis. Front Immunol 2021;12:803410. doi:10.3389/fimmu.2021.803410

No competing interests reported.

Supplementarytable.docx

Download PDF

Journal Publication

published 30 Oct, 2023

Read the published version in Investigational New Drugs →

Editorial decision: Major revision
17 Sep, 2023
Reviews received at journal
17 Sep, 2023
Reviewers agreed at journal
13 Sep, 2023
Reviewers invited by journal
30 Jun, 2023
Submission checks completed at journal
29 Jun, 2023
Editor assigned by journal
29 Jun, 2023
First submitted to journal
27 Jun, 2023

You are reading this latest preprint version

Clinical characteristics and prognostic impact of immune checkpoint inhibitor-associated myocarditis in advanced non-small cell lung cancer

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Material and methods

2.1Patients

2.2Treatments and response assessments

Statistical analysis

Results

3.1Patient characteristics

3.2Parametric characteristics of myocarditis

3.3Association between myocardial and treatment outcomes

Discussion

Conclusions

Declarations

References

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1