ICIs-Related Cardiotoxicity in Different Types of Cancer: Comparison
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Immune checkpoint inhibitors (ICIs), antibodies that target the checkpoints in immune cells, work to activate inhibited T-cells and other cells of the innate and adaptive arms, resulting in the robust activation of the immune system and productive antitumor immune responses. However, ICIs-related cardiotoxicity has been recognized as a rare but fatal consequence. Although there has been extensive research based on different types of ICIs, these studies have not indicated whether cardiotoxicity is specific to a type of cancer.

  • immune checkpoint inhibitors
  • cardiotoxicity
  • cardio-oncology
  • cancer-type-specific

1. Introduction

Cardiovascular disease (CVD) and cancer are global health issues with high morbidity and mortality [1], and numerous studies suggest that there is an overlap in epidemiology, risk factors, and pathophysiologic processes (Figure 1) .
Jcdd 09 00203 g001 550
Figure 1. (a) Risk factors for CVD and cancer; (b) Common pathophysiologic processes of CVD and cancer.
With the widespread application of anticancer drugs, the survival of patients has significantly improved, but the related cardiotoxicity affects long-term therapeutic outcomes, and this has attracted considerable attention. Immune checkpoint inhibitors (ICIs), antibodies that target the checkpoints in immune cells, work to activate inhibited T-cells and other cells of the innate and adaptive arms, resulting in the robust activation of the immune system and productive antitumor immune responses. This new type of immunotherapy drug has significantly improved the survival of cancer patients [2][3][4]. However, their use is associated with adverse side effects involving different organs [5][6]. ICIs-related cardiotoxicity, which may develop even without a history of significant cardiac risk factors, includes myocarditis, pericarditis, heart failure, arrhythmias, and vasculitis [7]. In reported cases of adverse ICIs-related events, 6.2% were cardiac adverse events (CAEs), which can be the main determinants of quality of life and increased mortality [8][9][10]. 

2. Cardiotoxicity in Melanoma

In 16 studies, 24 of 6710 patients on ICIs [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] developed CAEs. This corresponded with an incidence of 0.20–4.93% in which grade 3–5 CAEs accounted for 41.7%. Commonly encountered cardiotoxicities included hypertension (50%), hypotension (16.7%), and myocarditis (8.3%). Treatment-related hypertension was linked to the application of lambrolizumab (58.3%) (PD-1). Nivolumab may have had a correlation with ICIs-related hypotension. Patients treated with a higher dose of ipilimumab, particularly 10 mg/kg × 4 doses/3 weeks, were more prone to fatal adverse events such as cardiac arrest (Table 1).
Table 1.
 Cardiotoxicity in melanoma.
Author, Year Study Type Phase Sample Size Drug Dose and Frequency Non-CAE CAE Manifestation 3–5 Grade CAE
Author, Year Study Type Phase Sample Size Drug Dose and Frequency Non-CAE CAE Manifestation 3–5 Grade CAE
Omid Hamid et al., 2017 [11] Prospective study II 528 (178 vs. 179 vs. 171) Pembrolizumab vs. Pembrolizumab vs. chemotherapy 2 mg/kg/3 weeks vs. 10 mg/kg/3 weeks vs. standard dose 528 0 0
Kalyan R et al., 2019 [3727] Retrospective study NR 252 (117 vs. 135) Non-ICI vs. ICI (Nivolumab/Pembrolizumab)

0
Nivolumab (Niv)

Pembrolizumab (Pem) Standard dose vs. increasing dose (Niv < 540 mg; 540~1440 mg; > 1440 mg Pem < 600 mg; 600~1707 mg; >1707 mg) NR 93 (42 vs. 51) Arrhythmia 31 vs. 25; Cardiac-related chest pain 12 vs. 25; Valvular heart disease 4 vs. 2; Cardiomyopathy 13 vs. 20; Myopericardial disease 11; Pericardial disease 8; Myocarditis 1; Valvular-disease 2; Venous arterial thromboembolic events 8 40 (major CAE) Caroline Robert et al., 2014 [12] Prospective study
Scott N et al., 2015 [3828] Prospective study (NSCLC)III 418 (210 vs. 208) Nivolumab

vs. Dacarbazine		 3 mg/kg/2 weeks vs. standard dose 308 (153 vs. 155) 5 Hypotension 1 vs. 4 0
I 129 (33 vs. 37 vs. 59) Nivolumab 1 mg/kg vs. 3 mg/kg vs. 10 mg/kg intravenously/2 weeks in 8-week cycles for up to 96 weeks. 91 (21 vs. 25 vs. 45) 0 0 0 Jeffrey S Weber et al., 2015 [13] Prospective study
Tony S K Mok et al., 2019 III [3929370 (268 vs. 102) Nivolumab vs. ICC (Dacarbazine al) 3 mg/kg/2 weeks vs. standard dose ] Prospective study (NSCLC) III 1251 (636 vs. 615) Pembrolizumab vs. platinum-based chemotherapy 200 mg/3 weeks for up to 35 cycles vs. platinum-based chemotherapy for four to six cycles.362 (181 vs. 81) 1112 (515 vs. 597)0 1 (1 vs. 0)0 Myocarditis 1 vs. 00
1 Paolo A Ascierto et al., 2017 [14] Prospective study
Achim Rittmeyer et al., 2017 [4030] Prospective study (NSCLC)III III726 (364 vs. 362) 1187 (609 vs. 578)Ipilimumab Atezolizumab vs. Docetaxel10 mg/kg/4 doses/3 weeks vs. 3 mg/kg/4 doses/3 weeks 1200 mg/3 weeks vs. 75 mg/m2514 (286 vs. 228) 3 Hypertension 1 vs. 0; Heart arrest 1 vs. 0; Pericarditis 1 vs. 0 3
/3 weeks 886 (390 vs. 496) 0 0 0 F Stephen Hodi et al., 2016 [15] Prospective study
S.J. Antonia et al., 2017 [4131]II 142 (95 vs. 47) Nivolumab + Ipilimumab vs. Ipilimumab + placebo 1 mg/kg + 3 mg/kg/4 doses/3 weeks vs. 3 mg/kg + placebo/4 doses/3 weeks Prospective study (NSCLC) III 718 (475 vs. 234) Durvalumab vs.

Placebo140 (94 vs. 46)		 10 mg/kg/2 weeks for up

to 12 months vs.

placebo7		 Hypotension 3 vs. 0; Ventricular arrhythmia 1 vs. 0; Ventricular tachycardia 1 vs. 0; Atrial fibrillation 1 vs. 0; Myocardial infarction 1 vs. 0 5
421 (301 vs. 120) 26 (21 vs. 5) ACS 9 vs. 2; Arrhythmia 7 vs. 1; Heart failure 7 vs. 0; Cardiac arrest 2 vs. 1; Cardiogenic shock 1 vs. 0; Cardiomyopathy 1 vs. 0; Myocarditis 0 vs. 1; Pericardial effusion 2 vs. 0 NR Caroline Robert et al., 2015 [16]
Yuequan Shi et al., 2021 [Prospective study III 834 (278 vs. 277 vs. 256) 4232] Observational study (NSCLC/SCLC) NR 1905 (1162 vs. 743)

(598 vs. 455 vs. 273 vs. 176 vs. 125 vs. 81 vs. 62 vs. 34 vs. 23)Pembrolizumab vs. Pembrolizumab vs. Ipilimumab		 10 mg/kg/2 weeks/doses vs. 10 mg/kg/3 weeks/ doses vs. 3 mg/kg/3 weeks/4 doses 610 (221 vs. 202 vs. 187) 4 Hypertension ICI (Pembrolizumab/Nivolumab/Camrelizumab/Treprizumab/Tisilizumab/Atezolizumab/Durvalumab/Ipilimumab) only vs. combination therapy

 at least one dose 647 22 (22 vs. 0)3 vs. 1 vs. 0 Elevated cTnI or myocarditis 222
9 J. Weber, M. et al., 2017 [17] Prospective study III 906 (453 vs. 453) Nivolumab vs. Ipilimumab 3 mg/kg/4 doses/2 weeks vs. 10 mg/kg/4 doses/3 weeks 884 (438 vs. 446) 0 0 0
Roy S Herbst et al., 2016 [4333] Prospective study (NSCLC) II/III 991 (339 vs. 343 vs. 309) Pembrolizumab vs. Docetaxel Pem 2 mg/kg, Pem 10 mg/kg vs. Docetaxel 75 mg/m2/3 weeks 690 (215 vs. 225 vs. 250) 1 (0 vs. 1 vs. 1) Myocardial infarction 0 vs. 1 vs. 0; Acute cardiac failure 0 vs. 0 vs. 1 1 J.D. Wolchok et al., 2017 [18] Prospective study III 937 (313 vs. 313 vs. 311) Nivolumab +

Ipilimumab vs.

Nivolumab + p vs.

Martin Reck et al., 2016 [44Ipilimumab + p

p(placebo) 1 mg/kg+3 mg/kg

/3 weeks/4 doses vs. 3 mg/kg/2 weeks + placebo vs. 3 mg/kg/3 weeks/4 doses + placebo		 847 (300 vs. 279 vs. 268) 0 0 0
34] Prospective study (NSCLC) III 304 (154 vs. 150) Pembrolizumab vs. platinum-based

chemotherapy		 200 mg/3 weeks vs. standard dose 52 (45 vs. 7) 0 0 0 Jedd D Wolchok et al., 2010 [19] Prospective study II 217 (73 vs. 72 vs. 72) Ipilimumab 10 mg/kg vs. 3 mg/kg vs. 0.3 mg/kg/3 weeks/4 doses 115 (50 vs. 46 vs. 19)
H. Borghaei et al., 2015 [4535] Prospective study (NSCLC) III0 0 0
555 (278 vs. 268) Nivolumab vs. Docetaxel 3 mg/kg/2 weeks vs. 75 mg/m2/3 weeks 432 (196 vs. 236) 3 (3 vs. 0) Cardiac tamponade 1 vs. 0; Pericardial effusion 1 vs. 0

Tachycardia 1 vs. 0		 3 Ines Pires da Silva et al., 2021 [20] Retrospective study NR (Not Reported) 355 (193 vs. 162) Ipilimumab + Nivolumab/Pembrolizumab/Atezolizumab vs. Ipilimumab 3 mg/kg/3 weeks/4 doses + standard dose vs. 3 mg/kg/3 weeks/4 doses 287 (163 vs. 124) 1 (0 vs. 1) Myocarditis 0 vs. 1 1
Julie Brahmer et al., 2015 [4636] Prospective study (NSCLC) III 272 (135:137) Nivolumab vs. Docetaxel 3 mg/kg/2 weeks vs. 75 mg/m2/3 weeks. 187 (76 vs. 111) 0 0 0 Patrick Schöffski et al., 2022 [21] Retrospective study I/II 255 (134 vs. 121) LAG-3 inhibitor

Ieramilimab vs.

Ieramilimab + Spartalizumab		 Ieramilimab (escalating 1–15 mg/kg)/2 weeks or once/4 weeks vs. Ieramilimab + Spartalizumab q2w or q3w or q4w or Ieramilimab q2w + Spartalizumab q4w 159 (75 vs. 84) 0 0
D.P. Carbone et al., 2017 [4737]0
Prospective study (NSCLC) III 530 (267 vs. 263) Nivolumab vs. Chemotherapy(platinum-based) 3 mg/kg/2 weeks vs. standard dose for six cycles. 431 (188 vs. 243) 2 (2 vs. 0) Alexander M.M. et al., 2020 [22] Prospective study III 1011 (509 vs. 502) Pembrolizumab vs. placebo 200 mg/3 weeks for 18 doses 235 (190 vs. 45) 1 (1 vs. 0) Myocarditis 1 vs. 0 NR
Myocardial infarction 1 vs. 0; Pericardial effusion malignant 1 vs. 0 2 Omid Hamid et al., 2013 [23] Prospective study I 135 (57 vs. 56 vs. 22) Lambrolizumab 10 mg/kg/2 weeks vs. 10 mg/kg/3 weeks vs. 2 mg/kg/3 weeks 132 (55 vs. 55 vs. 22) 7 (2 vs. 4 vs. 1) Hypertension (2 vs. 4 vs. 1) NR
Margaret K. et al., 2018 [24] Retrospective study I 94 (53 vs. 41) Ipilimumab + Nivolumab

Nivolumab (Niv)

Ipilimumab (Ipi)		 Niv+Ipi(escalating doses)/3 weeks for four doses, followed by Niv 3 weeks for four doses, then Niv + Ipi/12 weeks for eight doses vs. Niv 1 mg/kg + Ipi

3 mg/kg/3 weeks for 4 doses, followed by Niv 3 mg/kg/2 weeks		 87 0 0 0
Ulrich Keilholz et al., 2019 [25] Prospective study I 51 Avelumab 10 mg/kg for one-hour intravenous infusion/2 weeks 39 0 0 0
Hussein A et al., 2022 [26] Retrospective study II-III 714 (355 vs. 359) Relatlimab + Nivolumab vs. Nivolumab Relatlimab 160 mg + Nivolumab 480 mg vs. Nivolumab 480 mg 504 (288 vs. 216) 0 0 0
The severity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4: life-threatening consequences; urgent intervention indicated. Grade 5: Death related to adverse events.

3. Cardiotoxicity in Lung Cancer

A total of 11 studies [27][28][29][30][31][32][33][34][35][36][37] included 5404 patients on ICIs, and 101 developed CAEs for an incidence of 0.15–37.78% in which grade 3–5 CAEs accounted for 55.4%. Commonly encountered cardiotoxicities included arrhythmia (32.7%), cardiac-related chest pain (24.8%), elevated cTnI or myocarditis (23.8%), cardiomyopathy (20.8%), pericardial disease (11.9%), and acute coronary syndrome (10.9%). One study indicated that major adverse cardiovascular events (MACEs) were dose-independent of nivolumab and pembrolizumab in lung cancer patients [27]. Those treated with a higher dose of durvalumab, particularly 10 mg/kg × 4 doses/2 weeks, were more prone to fatal adverse events such as a cardiac arrest and cardiogenic shock [31]. One patient treated with pembrolizumab at 10 mg/kg for 3 weeks underwent a myocardial infarction, which led to death (Table 2) [33].
Table 2. Cardiotoxicity in lung cancer.
 

4. Renal Cell Carcinoma

In seven studies [4838][4939][5040][5141][5242][5343][5444] comprising 1971 patients with renal cell carcinomas on ICIs, 14 developed CAEs with an incidence of 0.20–2.19% in which grade 3–5 CAEs accounted for 35.7%. Commonly encountered cardiotoxicities included hypertension (85.7%) and myocarditis (7.1%). Treatment-related hypertension was linked to a nivolumab plus ipilimumab therapy (100%). Compared with melanomas and lung cancer, the ICI therapy caused mild cardiotoxicity in renal cell carcinomas. Fatal CAEs were not found.

5. Urothelial Carcinoma

In Seven studies [5545][5646][5747][5848][5949][6050][6151] 111 of 2550 patients with urothelial carcinomas on ICIs developed CAEs with an incidence of 0.22–10.60% in which grade 3–5 CAEs accounted for 52.3%. Commonly encountered cardiotoxicities included hypertension (28.8%), arrhythmia (14.4%) and hypotension (6.3%). The fluctuation of blood pressure was linked to treatment with atezolizumab. Hypertension was observed in 21 patients and hypotension was observed in 7 after application of atezolizumab. Patients treated with 200 mg pembrolizumab for 3 weeks (maximum 35 cycles) or at 1200 mg every three weeks were more prone to fatal adverse events such as a cardiac arrest.

6. Other Types of Cancer

The most commonly encountered ICIs-related type of cardiotoxicity in hematological malignancies was hypertension [6252][6353][6454][6555]. In other cancers, such as hepatocellular carcinomas and malignant pleural mesotheliomas, the relevant research did not present many cases [6656][6757][6858][6959][7060][7161]; these were almost all case reports of myocarditis [7262][7363][7464].

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