Table 3.
Details concerning patients with ICI associated myocarditis (n: 122) or pericardial disorders (n: 95) collected from VigiBase (last accessed: 01/2018).
| Myocarditis | Pericardial disorders | |||
|---|---|---|---|---|
| Characteristics | n (%) | Data available, n (%) | n (%) | Data available, n (%) |
| Reporting region | 122 (100.0) | 95 (100.0) | ||
| Americas | 58 (47.5) | 47 (49.4) | ||
| Europe | 49 (40.2) | 38 (40.0) | ||
| Australia | 2(1.6) | 1 (1.1) | ||
| Asia | 13 (10.7) | 9(9.5) | ||
| Reporters | 119 (97.5) | 94 (98.9) | ||
| Healthcare professional | 101 (84.9) | 77 (81.9) | ||
| Non-healthcare professional | 18 (15.1) | 17 (18.1) | ||
| Reporting year | 122 (100.0) | 95 (100.0) | ||
| 2018 | 35 (28.7) | 13 (13.7) | ||
| 2017 | 72 (59.0) | 49 (51.6) | ||
| 2016 | 8(6.6) | 15 (15.8) | ||
| 2015 | 5(4.1) | 13 (13.7) | ||
| 2013–2014 | 2(1.6) | 5(5.3) | ||
| Gender | 117 (95.9) | 95 (100.0) | ||
| Male | 78 (66.7) | 57 (60.0) | ||
| Female | 39 (33.3) | 38 (40.0) | ||
| Age at onset, mean ± SD, years | 66.4 ± 12.7 | 99 (81.1) | 59.5 ± 11.8 | 81 (85.3) |
| [min-max] | [20–90] | [22–82] | ||
| Suspected Drugs* | 122 (100.0) | 95 (100.0) | ||
| Only ICI | 114 (93.4) | 88 (92.6) | ||
| ICI + 1 other drug | 4(3.3) | 4(4.2) | ||
| ICI + ≥2 other drugs | 4(3.3) | 3(3.2) | ||
| Drugs | 122 (100.0) | 95 (100.0) | ||
| Monotherapy with Anti PD-1/PD-L1 | 84 (68.9) | 74 (77.9) | ||
| - Nivolumab | 58 (47.5) | 42 (44.2) | ||
| - Pembrolizumab | 22 (18.0) | 21 (22.1) | ||
| - Atezolizumab | 2 (1.6) | 9 (9.5) | ||
| - Avelumab | 1 (0.8) | 1 (1.1) | ||
| - Durvalumab | 1 (0.8) | 1 (1.1) | ||
| Monotherapy with Anti CTLA-4 | 6(4.9) | 13 (13.7) | ||
| - Ipilimumab | ||||
| Combination therapy | 32 (26.2) | 8 (8.4) | ||
| - Nivolumab + Ipilimumab | 30 (24.6) | 8 (8.4) | ||
| - Pembrolizumab + Ipilimumab | 1 (0.8) | 0 (0.0) | ||
| - Tremelimumab + Durvalumab | 1 (0.8) | 0 (0.0) | ||
| Drug dosing | ||||
| Ipilimumab | 23 (62.7) | 12 (57.1) | ||
| - 1–3 mg/kg | 19 (73.1) | 11 (91.7) | ||
| - 5 mg/kg | 1 (3.8) | 1 (8.3) | ||
| - 10 mg/kg | 3 (11.5) | 0 (0.0) | ||
| Nivolumab | 49 (55.7) | 38 (76.0) | ||
| - 1–2 mg/kg | 16 (32.7) | 7 (18.4) | ||
| - ≥ 3 mg/kg | 33 (67.3) | 31 (81.6) | ||
| Pembrolizumab | 11 (47.8) | 16 (76.2) | ||
| - 2 mg/kg | 6 (54.5) | 4 (25.0) | ||
| - 3 mg/kg | 5 (45.5) | 12 (75.0) | ||
| Number of ICI administration before onset, median [IQR], | 1 (1–2.75) | 21 (17.2) | 2(1–6) | 9(9.5) |
| [min-max] | [1–8] | [1–10] | ||
| Time to irAE onset, days: | 44 (36.1) | 28 (29.5) | ||
| Median, [IQR] | 30 [18–60] | 30 [8.5–90] | ||
| [min-max] | [1–240] | [0–330] | ||
| Severe AE | 102 (83.6) | 122 (100.0) | 77 (81.0) | 95 (100.0) |
| Death | 61 (50.0) | 122 (100.0) | 20 (21.1) | 95 (100.0) |
| Malignant Neoplasm Progression | 8(6.6) | 122 (100.0) | 11 (11.6) | 95 (100.0) |
| Indications** | 103 (84.4) | 87 (91.6) | ||
| Malignant melanoma | 42 (40.7) | 16 (18.4) | ||
| Lung cancer | 33 (32.1) | 49 (56.3) | ||
| Renal cell carcinoma | 11 (10.7) | 6 (7.0) | ||
| Gastrointestinal cancer | 5(4.9) | 1 (1.1) | ||
| Mesothelioma | 4(3.9) | 1 (1.1) | ||
| Hematologic cancer and lymphoma | 2(1.9) | 3(3.5) | ||
| Thymic cancer | 2 (1.9) | 0 (0.0) | ||
| Urothelial cancer | 2 (1.9) | 2(2.3) | ||
| Malignant neoplasm non specified | 2 (1.9) | 2 (2.3) | ||
| Squamous cell carcinoma of head and neck | 0 (0.0) | 2 (2.3) | ||
| Glioblastoma | 0 (0.0) | 1 (1.1) | ||
| Breast cancer | 0 (0.0) | 4(4.6) | ||
| Concurrent irAE | 122 (100.0) | 95 (100.0) | ||
| None (lone) | 36 (29.5) | 35 (36.8) | ||
| Gastro-intestinal disorders (any) | 19 (15.6) | 10 (10.5) | ||
| - Hepatitis / hepatic failure / Abnormal liver enzymes | 13 (10.7) | 6 (6.3) | ||
| - Colitis / diarrhea / gastroenteritis / enteritis / Dehydration | 9 (7.4) | 4 (4.2) | ||
| - Gastro-intestinal bleeding | 1 (0.8) | 0 (0.0) | ||
| - Electrolyte disorders | 1 (0.8) | 1 (1.1) | ||
| Endocrino-metabolic disorders (any) | 6 (4.9) | 6 (6.3) | ||
| - Hypophysitis | 3 (2.5) | 0 (0.0) | ||
| - Thyroid disorders | 3 (2.5) | 5(5.3) | ||
| - Adrenal insufficiency | 1 (0.8) | 3 (3.2) | ||
| - Diabetes mellitus | 1 (0.8) | 0 (0.0) | ||
| Pulmonary disorders (any) | 16 (13.1) | 38 (40.0) | ||
| - Pneumonitis / Pneumonia | 13 (10.7) | 8 (8.4) | ||
| - Pleural effusion | 3 (2.5) | 22 (23.2) | ||
| - Respiratory failure / respiratory disorder | 2(1.6) | 4(4.2) | ||
| - Pulmonary embolism | 0 (0.0) | 4 (4.2) | ||
| - Pulmonary hypertension | 0 (0.0) | 1 (1.1) | ||
| Cardiovascular disorders (any) | 49 (40.2) | 14 (14.7) | ||
| - Arrhythmia | 23 (18.9) | 6 (6.3) | ||
| - Cardiac failure or shock / pulmonary edema | 19 (15.6) | 3 (3.2) | ||
| - Cardiac arrest | 11 (9) | 4 (4.2) | ||
| - Myocardial infarction / coronary artery disease | 5 (4.1) | 1 (1.1) | ||
| - Myocarditis | --- | 4 (4.2) | ||
| - Pericarditis / pericardial effusion / cardiac tamponade | 4 (3.3) | --- | ||
| - Vasculitis | 1 (0.8) | 0 (0.0) | ||
| Renal disorders (any) | 4 (3.3) | 8 (8.4) | ||
| - Nephritis | 2 (1.6) | 1 (1.1) | ||
| - Acute kidney injury / renal failure | 2 (1.6) | 7 (7.4) | ||
| Hematologic disorders (any) | 2 (1.6) | 0 (0.0) | ||
| - Leukopenia | 1 (0.8) | 0 (0.0) | ||
| - Thrombocytopenia | 1 (0.8) | 0 (0.0) | ||
| Musculoskeletal disorders (any) | 34 (27.9) | 5(5.3) | ||
| - Myositis / Rhabdomyolysis | 31 (25.4) | 3 (3.2) | ||
| - Arthralgia / Rheumatoid arthritis / Joint inflammation | 3(2.5) | 3 (3.2) | ||
| Neurologic disorders (any) | 15 (12.3) | 1 (1.1) | ||
| - Myasthenia gravis | 13 (10.7) | 1 (1.1) | ||
| - Encephalitis / Meningitis | 2(1.6) | 0 (0.0) | ||
| - Stroke (ischemic or hemorrhagic) | 1 (0.8) | 0 (0.0) | ||
| Dermatologic disorders (any) | 3 (2.5) | 3(3.2) | ||
| - Unspecified rash / Purpura / Pruritis | 1 (0.8) | 3(3.2) | ||
| - Steven Johnson Syndrome | 1 (0.8) | 0 (0.0) | ||
| - Pemphigus | 1 (0.8) | 0 (0.0) | ||
| - Lichen planus | 1 (0.8) | 0 (0.0) | ||
Other concomitant reported suspected medications for myocarditis were carboplatin (n: 3), axitinib (n: 1), bendamustine (n: 1), cetuximab (n: 1), cisplatin (n: 1), cyclophosphamide (n: 1), dabrafenib (n: 1), etinostat (n: 1), etoposide (n: 1), gemcitabine (n: 1), niraprib (n: 1), obinutuzumab (n: 1), paclitaxel (n: 2), temozolomide (n: 1), trametinib (n: 1).
Other concomitant reported suspected medications for pericardial disorders were paclitaxel (n: 3), carboplatin (n: 2), dabrafenib (n: 1), etinostat (n: 1), niraprib (n: 1), temozolomide (n: 1), trametinib (n: 1).
Of the 42 ICI-associated myocarditis cases in melanoma patients, 6 were treated with anti-CTLA-4 monotherapy, 15 with anti-PD-1 or anti-PD-L1 monotherapy, and 21 with a combination of an anti-CTLA-4 plus an anti-PD-1 or an anti-PD-L1 therapy. Of the 33 ICI-associated myocarditis cases in lung cancer patients, 27 were treated with anti-PD-1 or anti-PD-L1 monotherapy, and 6 were treated with a combination of an anti-CTLA-4 plus an anti-PD-1 or anti-PD-L1 therapy. Of the 16 ICI-associated pericardial disorders in melanoma patients, anti-CTLA-4 monotherapy, anti-PD-1 or anti-PDL-L1 monotherapy, and combination therapy were used in 4, 8, 4 patients, respectively. In total, 49 cases of ICI-associated pericardial disorders was seen in lung cancer patients of which 48 were treated with anti-PD-1 or anti-PD-L1 monotherapy, and 1 with combination therapy.
Abbreviations: CTLA-4, cytotoxic T-lymphocyte-associated protein 4; ICI, immune checkpoint inhibitor; IQR, interquartile range; irAE, immune related adverse event; [min-max], minimum-maximum; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1; SD, standard deviation