The use of immune checkpoint inhibitors (ICIs) has transformed the treatment landscape for a number of tumour types over the past decade. Targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4; ipilimumab), programmed cell death protein 1 (PD1; nivolumab, pembrolizumab), and programmed death-ligand 1 (PD-L1; atezolizumab, avelumab, or durvalumab), as monotherapy or in combination, activates the immune system to recognise and target cancer cells via a T-cell-mediated immune response and can lead to improved survival in the metastatic setting in a number of malignancies, as well as improved recurrence-free survival when utilised in multi-modality radical treatment paradigms in melanoma and non-small cell lung cancer (NSCLC).1,2 The systemic activation of T-cells can also lead to auto-immune toxicity, affecting any body system; most commonly skin, gastrointestinal, liver and endocrine toxicities.3
As discussed by Findlay and colleagues, ICI-related myocarditis is rare but potentially fatal. Its true incidence remains unknown but data from a single cancer registry study from the USA suggests a prevalence of 1.14% with fatality rates as high as 50%.4,5 Data suggest that myocarditis is an early ICI-toxicity, typically seen within the first three months of starting treatment, and is more common in patients treated with combination anti-CTLA-4 and anti-PD1 blockade. The prevalence of myocarditis in patients treated with chemotherapy and anti-PD1 or tyrosine kinase Inhibitors (TKI) and anti-PD1 combinations has not been described.
The presenting symptoms can be non-specific including: dyspnoea, fatigue and myalgia.6 Patients can also present with a new arrhythmia or conduction abnormality. Other toxicities, such as myositis, rhabomyolysis, vasculitis or myasthenia gravis may occur concurrently.4,7 A high index of suspicion is required. An electrocardiogram (ECG) is often, but not exclusively, abnormal. Other investigations, such as troponin and brain natriuretic peptides (BNP), can be helpful. In patients with symptoms suggestive of myocarditis, or in patients with ECG changes and raised troponins, we suggest urgent echocardiogram, cardiology review and consideration of high-dose corticosteroids.8 In patients with vague symptoms and a normal troponin, further investigations such as a BNP and echocardiogram are warranted. Importantly, ICI-cardiotoxicity is not limited to myocarditis. Other less frequently occurring cardiotoxicity has also been reported, including pericardial disease, vasculitis and non-inflammatory left ventricular dysfunction.9
Our current understanding of the underlying pathophysiology of ICI-associated cardiotoxicity is limited. Pre-clinical models suggest a critical role for both CTLA-4 and PD1 in downregulating excessive immune responses in the myocardium and preventing inflammatory injury.10 ICIs abrogate this protective measure of the heart. Another proposed mechanism suggests that the tumour itself may activate the clonal expansion of a T-cell population, which cross-reacts with the same cardiac antigens presented on major histocompatability (MHC) class I complexes on cardiomyocytes.9 A better understanding of the underlying pathophysiology of ICI-associated cardiotoxicity could suggest bespoke investigations and new treatment paradigms.
Despite increasing awareness of ICI cardiotoxicity, many unanswered questions remain. A pertinent issue is the unknown true incidence. Secondary to this is the uncertain reliability of our currently available diagnostic tests. Blood-based biomarkers, such as troponin and BNP, have the advantage of being easily accessible, thereby allowing for monitoring with serial measurements, without requiring expert cardiology interpretation. Troponin is considered more specific for myocarditis than BNP, which is primarily a marker of left ventricular (LV) strain rather than myocardial inflammation, and can be elevated due to other cardiac comorbidities and the underlying malignancy itself. Case series of ICI-associated myocarditis reported variable blood biomarker results. One series (n=30) reported a rate of 47% of troponin-I elevation and 100% of BNP,11 whereas, in another series (n=44), 79% of cases had troponin (I or T) or creatinine kinase (CK) elevation.6 In a case-control study that included 35 cases of ICI-induced myocarditis, troponin-T was elevated in 94% of cases and natriuretic peptides in 66%. Higher levels of serum cardiac troponin-T, but not natriuretic peptides, were associated with a greater risk of major cardiovascular events, defined as the composite of cardiovascular death, cardiogenic shock, cardiac arrest, and haemodynamically significant complete heart block.5 It is possible that the differing degree of severity of myocarditis may have contributed to variability of troponin levels between different studies. Moreover, troponin-T and CK, as opposed to troponin-I, may have been elevated due to concurrent myositis.
Cardiac arrhythmias can occur if the conduction system is affected. In a case series that included 44 cases of ICI-associated myocarditis, ECG abnormalities were detectable in 89% of cases. Complete heart block was evident in 36% of cases, and was associated with the more severe and fatal cases of ICI-myocarditis.6 If ICI-myocarditis is suspected, imaging with an echocardiogram to assess for wall motion abnormalities is often performed. However, a normal left ventricular ejection fraction (LVEF) does not rule out ICI-myocarditis with 51% of ICI-myocarditis cases having LVEF of >50%. Other lesser regional wall-motion abnormalities have been reported in ICI-induced myocarditis and, therefore, in such cases ICI-cardiotoxicity should still be suspected.5,10 The utility of cardiac magnetic resonance imaging (MRI) is limited by its availability, with only 26% of patients having had cardiac MRI during the course of their investigations.6 Moreover, the cardiac MRI’s sensitivity remains questionable, with only a third of suspected ICI-myocarditis cases having detectable oedema.5 Further prospective evaluation of the sensitivity and specificity of our current tools for the diagnosis of ICI-associated cardiotoxicity is warranted.
Another pertinent issue is the limited evidence available to help us risk stratify patients. Treatment with a combination of anti-CTLA-4 (ipilimumab) and anti-PD1 (nivolumab) antibodies is the most established risk factor for the development of ICI-induced myocarditis, which, when compared with single agent nivolumab, is estimated to be associated with a 4.7-fold risk increase.4 A recent study suggested that ICI-associated myocarditis is more common in population groups that are otherwise regarded as low-risk for general myocarditis, such as female patients and patients 75 years or older.12 In view of the paucity of established risk factors, the low incidence of ICI-induced myocarditis, the uncertainties relating to the reliability of our diagnostic tools and the lack of prospective data, surveillance strategies for the detection of ICI-myocarditis cannot be recommended.
Currently, immunosuppression with high-dose corticosteroids remains the first-line treatment for ICI-associated myocarditis. There are sparse data relating to treatment options in steroid-refractory cases. Current guidelines suggest that other immunosuppressants, such as infliximab, should be considered,8 however, these approaches are largely extrapolated from the treatment of other more common ICI toxicities, such as colitis. Two recent case reports suggested new novel immunosuppressive strategies. One report suggested the use of alemtuzumab, a monoclonal antibody that binds to CD52, leading to complement-mediated, rapid cytolytic induction of immunosuppression.13 Another case report described the use of CTLA-4 agonist, abatacept. This antibody inhibits CD28-B7-mediated T-cell co-stimulation, upstream of CTLA-4 and the PD1 pathways, leading to rapid global T-cell anergy, thereby reversing immune activation by ICIs.14 Further research and validation of these approaches is required with careful consideration of risk-benefit and, in particular, cost-effectiveness, given the expense of these proposed treatments.
An evolving field
Over the past two years, new combinations of ICIs with cytotoxic chemotherapy and targeted molecular therapies have been licensed for the treatment of metastatic NSCLC and renal cell carcinoma.15,16 In particular, the combination of anti-PD-L1, avelumab, and TKI, axitinib, showed superior efficacy to what was, until recently, the standard of care, sunitinib.17 It is now well documented that anti-angiogenesis TKIs are associated with cardiotoxicity, including: QT-prolongation, left ventricular dysfunction, congestive heart failure, acute coronary syndromes and myocardial infarction (MI).18,19 Therefore, the combination of TKIs with ICIs has the potential for increased cardiotoxicity. Indeed, the preliminary results of avelumab and axitinib combination included a grade 5 myocarditis case among the included 55 patients.20
ICIs are rapidly becoming ubiquitous in oncology. As a consequence of this it is expected that an increasing number of cancer patients will present with ICI toxicity, with the most severe of cases most likely to present in Accident & Emergency departments and acute medical units of general hospitals. It is, therefore, paramount that frontline physicians are aware of both common and rare ICI toxicities. ICI-induced myocarditis can become rapidly fatal. Therefore, in cancer patients treated with ICIs, who present with non-specific symptoms, especially in cases with new ECG abnormalities, prompt initiation of high-dose corticosteroids may prove life-saving. Reassuringly, there is evidence to suggest that immunosuppression for the treatment of ICI-related toxicity does not compromise oncological efficacy outcomes.21 Therefore, such concerns should not preclude initiation of steroids in suspected cases of ICI-related cardiotoxicity.
Conflicts of interest
AG: none declared. NY: reports non-financial support from MSD, non-financial support from Roche, personal fees from Roche, outside the submitted work.
1. Weber J, Mandala M, Del Vecchio M et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 2017;377:1824–35. https://doi.org/10.1056/NEJMoa1709030
2. Antonia SJ, Villegas A, Daniel D et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 2017;377:1919–29. https://doi.org/10.1056/NEJMoa1709937
3. Wang Y, Zhou S, Yang F et al. Treatment-related adverse events of PD-1 and PD-L1 inhibitors in clinical trials: a systematic review and meta-analysis. JAMA Oncol 2019;5:1008–19. https://doi.org/10.1001/jamaoncol.2019.0393
4. Johnson DB, Balko JM, Compton ML et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 2016;375:1749–55. https://doi.org/10.1056/NEJMoa1609214
5. Mahmood SS, Fradley MG, Cohen JV et al. Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol 2018;71:1755–64. https://doi.org/10.1016/j.jacc.2018.02.037
6. Atallah-Yunes SA, Kadado AJ, Kaufman GP et al. Immune checkpoint inhibitor therapy and myocarditis: a systematic review of reported cases. J Cancer Res Clin Oncol 2019;145:1527–57. https://doi.org/10.1007/s00432-019-02927-x
7. Moslehi JJ, Salem JE, Sosman JA et al. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet 2018;391:933. https://doi.org/10.1016/S0140-6736(18)30533-6
8. Brahmer JR, Lacchetti C, Schneider BJ et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2018;36:1714–68. https://doi.org/10.1200/JCO.2017.77.6385
9. Lyon AR, Yousaf N, Battisti NML et al. Immune checkpoint inhibitors and cardiovascular toxicity. Lancet Oncol 2018;19:e447–e458. https://doi.org/10.1016/S1470-2045(18)30457-1
10. Hu JR, Florido R, Lipson EJ et al. Cardiovascular toxicities associated with immune checkpoint inhibitors. Cardiovasc Res 2019;115:854–68. https://doi.org/10.1093/cvr/cvz026
11. Escudier M, Cautela J, Malissen N et al. Clinical features, management, and outcomes of immune checkpoint inhibitor-related cardiotoxicity. Circulation 2017;136:2085–7. https://doi.org/10.1161/CIRCULATIONAHA.117.030571
12. Zamami Y, Niimura T, Okada N et al. Factors associated with immune checkpoint inhibitor-related myocarditis. JAMA Oncol 2019; online first. https://doi.org/10.1001/jamaoncol.2019.3113
13. Esfahani K, Buhlaiga N, Thebault P et al. Alemtuzumab for immune-related myocarditis due to PD-1 therapy. N Engl J Med 2019;380:2375–6. https://doi.org/10.1056/NEJMc1903064
14. Salem JE, Allenbach Y, Vozy A et al. Abatacept for severe immune checkpoint inhibitor-associated myocarditis. N Engl J Med 2019;380:2377–9. https://doi.org/10.1056/NEJMc1901677
15. Gandhi L, Rodriguez-Abreu D, Gadgeel S et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 2018;378:2078–92. https://doi.org/10.1056/NEJMoa1801005
16. Socinski MA, Jotte RM, Cappuzzo F et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 2018;378:2288–301. https://doi.org/10.1056/NEJMoa1716948
17. Motzer RJ, Penkov K, Haanen J et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1103–15. https://doi.org/10.1056/NEJMoa1816047
18. Orphanos GS, Ioannidis GN, Ardavanis AG. Cardiotoxicity induced by tyrosine kinase inhibitors. Acta Oncol 2009;48:964–70. https://doi.org/10.1080/02841860903229124
19. Touyz RM, Herrmann J. Cardiotoxicity with vascular endothelial growth factor inhibitor therapy. NPJ Precis Oncol 2018;2:13. https://doi.org/10.1038/s41698-018-0056-z
20. Choueiri TK, Larkin J, Oya M et al. Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial. Lancet Oncol 2018;19:451–60. https://doi.org/10.1016/S1470-2045(18)30107-4
21. Horvat TZ, Adel NG, Dang TO et al. Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol 2015;33:3193–8. https://doi.org/10.1200/JCO.2015.60.844