Myocarditis Surveillance in Patients with Advanced Melanoma on Combination Immune Checkpoint Inhibitor Therapy: The Memorial Sloan Kettering Cancer Center Experience

Abstract

This letter to the editor describes myocarditis screening among patients undergoing combination immune checkpoint inhibitor therapy, in light of the consensus document from the Checkpoint Inhibitor Safety Working Group.

The consensus document from the Checkpoint Inhibitor Safety Working Group identified monitoring strategies as a key information gap in the realm of immune checkpoint inhibitor (ICI)‐associated myocarditis [1]. Given its potentially fulminant course, experts have proposed screening algorithms using serial troponin (Tn) and/or electrocardiogram (ECG) for early detection of subclinical disease and prompt initiation of therapy to potentially mitigate cardiac morbidity and mortality [2], [3], [4].

We evaluated screening troponin I (TnI) and ECG in 76 asymptomatic patients with advanced melanoma undergoing combination ICI therapy with ipilimumab and nivolumab. Baseline and weekly TnI/ECG were obtained until the second dose, corresponding to the typical timing of onset, for a maximum of four samples. Outcomes of interest were myocarditis, major adverse cardiac events (MACE), and all‐cause mortality.

The median age was 65 years (interquartile range 57–70), with 45 (59.2%) male patients. The prevalence of coronary artery disease, hypertension, hypercholesterolemia, and diabetes mellitus was 10.5% (n = 8), 40.8% (n = 31), 34.2% (n = 26), and 13.2% (n = 10), respectively. Thirty‐one (40.3%) patients had previously received ICI therapy, one (1.3%) with doxorubicin and three (3.9%) mediastinal radiation. Over half (n = 49, 64.5%) developed noncardiac immune‐related adverse events, of which 37 received corticosteroids at some point during the course of combination ICI therapy.

Over a median of 198 days, none of the 76 patients developed clinical or subclinical myocarditis or MACE. All deaths (n = 17, 22.4%) were cancer related. Additionally, none had elevated TnI levels (>0.64 ng/mL) or ECG abnormalities. Minimally detectable nondiagnostic TnI levels (≥0.01 ng/mL and <0.06 ng/mL) were seen in 13 (17%) patients only after adoption of a higher sensitivity assay (Table 1). At the time of detectable TnI, all remained asymptomatic and hemodynamically stable, and complementary testing not limited to serial TnI/ECGs did not identify any obvious acute cardiac and/or systemic pathology. At follow‐up, 11 patients had undetectable TnI, and two had nontrending levels. There was no association between detectable TnI and all‐cause mortality. Twelve of 13 received further ICIs without cardiac events, and one discontinued ICI therapy because of disease progression.

Table 1. Detectable troponin I case description.

^aReceived additional ICI dose after detectable TnI.

^bWeekly levels at 0.02 ng/mL.

^cWeekly levels at 0.02 ng/mL until day 21 check.

Abbreviations: CAD, coronary artery disease; CCa, coronary calcium on chest computed tomography; CKD, chronic kidney disease; ECG, electrocardiogram; HL, hyperlipidemia; HTN, hypertension; ICI, immune checkpoint inhibitor; TnI, troponin I.

This is the first report on myocarditis screening among patients undergoing combination ICI therapy. Despite inclusion of a higher‐risk cohort, none of our patients developed myocarditis. We also demonstrated that ICIs can be safely continued in asymptomatic, hemodynamically stable patients with minimally detectable TnI levels after careful consideration of the clinical context. Likewise, the study by Sarocchi et al. of 59 patients undergoing serial TnI checks during nivolumab monotherapy had one patient with presumed subclinical myocarditis who tolerated continued ICI therapy without cardiac events [5]. These minor nondiagnostic TnI levels could cloud diagnostic judgment, initiate unnecessary downstream testing and treatments, and interfere with the course of potentially life‐saving cancer treatment. As more institutions adopt higher sensitivity assays, there is a trend toward increased Tn detection at a loss of discriminatory capacity, without improvement in short‐term cardiovascular outcomes [6], [7].

Our study is reflective of the low prevalence of ICI‐associated myocarditis and, therefore, low screening yield. However, it is possible that a larger study with improved risk stratification and patient selection could prove some utility for TnI/ECG screening.

Disclosures

Michael A. Postow: Bristol‐Myers Squibb, Merck, Array BioPharma, Novartis, Incyte, NewLink Genetics, Aduro (C/A), Bristol‐Myers Squibb, Merck (H), RGenix, Infinity, Bristol‐Myers Squibb, Merck, Array BioPharma, Novartis, AstraZeneca (other—institutional support); Margaret K. Callahan: Merck, Moderna, AstraZeneca, InCyte (C/A), Bristol‐Myers Squibb (RF, E—family member); Paul B. Chapman: Pfizer (RF), Merck, Immunocore, Cell Medica, Takeda Millennium (C/A); Alexander N. Shoushtari: Bristol‐Myers Squibb, Castle Biosciences, Immunocore (C/A), AstraZeneca, Bristol‐Myers Squibb, Immunocore (RF); Tomas G. Neilan: Parexel, Intrinsic Imaging (C/A); Michael G. Fradley: Novartis (C/A); Jedd D. Wolchok: Adaptive Biotech, Advaxis, Amgen, Apricity, Array BioPharma, Ascentage Pharma, Beigene, Bristol‐Myers Squibb, Celgene, Chugai, Elucida, Eli Lilly & Co., F Star, Genentech, Imvaq, Janssen, MedImmune, Merck, Neon Therapeutics, Ono, Polaris Pharma, Polynoma, Psioxus, Puretech, Recepta, Trienza, Sellas Life Sciences, Surface Oncology, Syndax (C/A), Bristol‐Myers Squibb, MedImmune, Merck Pharmaceuticals, Genentech (RF), Potenza Therapeutics, Tizona Pharmaceuticals, Adaptive Biotechnologies, Elucida, Imvaq, Beigene, Trieza (OI), Linneaus (IP). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board