ABSTRACT
Background
Immune checkpoint inhibitors (ICI) can cause myocarditis, leaving physicians uncertain regarding the safety of restarting ICIs after recovery. This study aims to measure real-world incidence of ICI-induced myocarditis and whether re-exposure to ICI after myocarditis impacts all-cause mortality.
Methods
Adult patients with cancer treated with ICIs were identified from TriNetX network, and outcomes were compared between patients re-exposed to ICI and those who were not.
Results
Among 195,578 patients receiving ICIs, 0.6% (n=1,214) developed myocarditis. Myocarditis was associated with increased all-cause mortality (hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.25–1.66). Among those with myocarditis, 13.8% (n=168) were re-exposed to ICIs; re-exposure was associated with lower all-cause mortality (HR, 0.50; 95% CI, 0.35–0.73).
Conclusions
ICI-induced myocarditis increases mortality, while re-exposure may improve survival in selected patients.
Key Points
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Immune-checkpoint inhibitors;
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Myocarditis;
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Lymphocyte-activation gene 3 inhibitors;
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Cytotoxic T-lymphocyte-associated protein 4 inhibitors;
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Programmed cell death protein 1/programmed cell death ligand 1 inhibitors;
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Real-world data.
Immune checkpoint inhibitors (ICIs) can cause myocarditis. , Given the mortality risk, American and European guidelines recommend immediate ICI discontinuation and initiation of immunosuppressive therapy. , Uncertainty persists regarding the safety of resuming ICIs in patients who have recovered from myocarditis. Therefore, we aim to assess the incidence of ICI-induced myocarditis and outcomes of ICI re-exposure in real-world settings.
Methods
We used the TriNetX network, comprising 152 healthcare organizations aggregating deidentified data from electronic health records (EHR) (150 million patients). No ethical approval was required. No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents. We identified patients aged ≥18 years with any neoplasm who received ICIs after January 1, 2014, using diagnostic codes and prescription records ( Table ). ICI exposure was identified across participating hospitals using prescription and administration records mapped to standardized RxNorm codes. The index date was the first recorded ICI exposure. The primary outcome was the EHR-coded incidence of new-onset myocarditis occurring ≥1 day after ICI exposure. Secondary outcome was all-cause mortality. Re-exposure was defined as any ICI given 1 month to 5 years after ICI-induced myocarditis. Patients with ICI-induced myocarditis were stratified into two cohorts: those re-exposed and those not re-exposed. Hazard ratios (HR) and confidence intervals (CI) were calculated for all-cause mortality. A chi-square test compared the myocarditis incidence across different ICI classes. Propensity score matching was performed using a 1:1 greedy nearest-neighbor algorithm with a caliper of 0.1 pooled standardized mean difference. E -values were calculated to assess robustness to unmeasured confounding; higher values indicate that stronger confounders would be necessary to invalidate the observed associations. Analyses were conducted on the TriNetX platform, using R software (R Foundation for Statistical Computing, Vienna, Austria; version 3.4.4).
Table
Baseline characteristics and outcomes
| Variable | Overall patients receiving ICI ( n = 195,578) | Patients re-exposed to ICI ( n = 168) |
|---|---|---|
| Baseline characteristics | ||
| Age (y) | 68.9 ± 12.9 | 68.4 ± 12.0 |
| Male, n (%) | 105,416 (53.9) | 82 (48.8) |
| Female, n (%) | 84,098 (43.0) | 55 (32.7) |
| BMI (kg/m 2) | 27.0 ± 6.5 | 27.5 ± 7.0 |
| Race/Ethnicity | ||
| White | 132,407 (67.7) | 110 (65.4) |
| Black or African American | 15,646 (8.0) | 13 (7.7) |
| Asian | 11,343 (5.8) | 11 (6.5) |
| Other races | 36,182 (18.5) | 34 (20.2) |
| Comorbidities | ||
| Hypertension | 103,265 (52.8) | 123 (73.2) |
| Diabetes mellitus | 41,658 (21.3) | 57 (33.9) |
| Chronic kidney disease | 19,990 (13.8) | 53 (31.5) |
| Chronic lower respiratory disease | 57,304 (29.3) | 58 (34.5) |
| Overweight and obesity | 36,182 (18.5) | 49 (29.1) |
| Malignant melanoma of the skin | 24,838 (12.7) | 51 (30.3) |
| Malignant neoplasm of the bronchus and lungs | 68,648 (35.1) | 34 (20.2) |
| Malignant neoplasms of digestive organs | 37,551 (19.2) | – |
| Breast cancer | 12,321 (6.3) | – |
| Malignant neoplasm of the genital organs | 15,255 (7.8) | – |
| Metastatic cancer of unknown primary | 25,034 (12.8) | 65 (38.6) |
| Laboratory values | ||
| Hemoglobin (g/dL) | 11.9 ± 2.2 | 12.3 ± 1.9 |
| HbA1c | 6.2 ± 1.5 | 6.3 ± 1.6 |
| LDL (mg/dL) | 93.3 ± 38.1 | 86.3 ± 34.0 |
| Serum creatinine (mg/dL) | 1.4 ± 6.7 | 1.1 ± 1.1 |
| LVEF (%) | 58.7 ± 11.3 | 54.4 ± 12.7 |
| ICI— i nduced myocarditis | ||
| PD-1 and PD-L1 inhibitors (p: reference) | ||
| Nivolumab | 397/51,257 (0.8%) | – |
| Pembrolizumab | 410/87,831 (0.5%) | – |
| Cemiplimab | 25/2,967 (0.8%) | – |
| Atezolizumab | 47/16,414 (0.3%) | – |
| Durvalumab | 61/14,072 (0.4%) | – |
| Avelumab | 12/1,570 (0.8%) | – |
| Dostarlimab | 10/751 (1.3%) | – |
| Total | 962/174,862 (0.6%) | – |
| CTLA-4 inhibitors (P < .001) | ||
| Ipilimumab | 214/18,278 (1.2%) | – |
| Tremelimumab | 12/841 (1.4%) | – |
| Total | 226/19,119 (1.2%) | |
| LAG 3 inhibitors (P < .001) | ||
| Relatlimab | 26/1,475 (1.8%) | – |
| Total | 26/1,475 (1.8%) | – |
| All-cause mortality in patients with ICI—Induced myocarditis | ||
| HR: 1.44 (95% CI: 1.25-1.66), P <.01 | ||
| Various treatments used for ICI—Induced myocarditis | ||
| Steroids | 767 (63.2) | – |
| Abatacept | 65 (5.4) | – |
| Tocilizumab | 14 (1.2) | – |
| Rituximab | 10 (0.8) | – |
| Antithymocyte globulin | 0 | – |
| Infliximab | 32 (2.6) | – |
| Re-exposure to ICIs after ICI—induced myocarditis | ||
| Nivolumab | – | 73 (18.5) |
| Pembrolizumab | – | 69 (16.9) |
| Ipilimumab | – | 16 (7.4) |
| Durvalumab | – | <10 |
| Atezolizumab | – | <10 |
| Cemiplimab | – | <10 |
| Total | – | 168 (13.8) |
| All-cause mortality risk in patients re-exposed to ICIs after ICI—Induced myocarditis | ||
| HR: 0.50 (95% CI: 0.35-0.73), P <.01 | ||
|
RxNorm codes
: Ipilimumab (1094833); nivolumab (1597876); pembrolizumab (1547545); atezolizumab (1792776); avelumab (1875534); durvalumab (1919503); cemiplimab (2058826); dostarlimab (2539967); relatlimab (2596773); tremelimumab (2619313); steroids (3264, 8640, 8638, 6902); abatacept (614391); tocilizumab (612865); rituximab (121191); antithymocyte globulin (1011); infliximab (191831).
ICD-10-CM codes : Malignant melanoma of the skin (C43-C44); malignant neoplasm of the bronchus and lungs (C34); malignant neoplasms of digestive organs (C15-C26); breast cancer (C50-C50); malignant neoplasm of the genital organs (C51-C58); metastatic cancer of unknown primary (C79); myocarditis (I40.1, I40.8, I40.9, I51.4); hypertension (I10); diabetes mellitus (E08-E13); chronic kidney disease (N18); chronic lower respiratory disease (J40-J4A); overweight and obesity (E66). |
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