Table 5.
Incidence of grade ≥3 Potential Immune-Related Adverse Events (irAEs) in Advanced Melanoma presented as % with 95% confidence interval, and I2 for the % of heterogeneity for the FDA approved doses (I2 not reported if the outcome was obtained from one study).
| irAEs | Ipilimumab | Nivolumab | Pembrolizumab | Nivolumab +Ipilimumab |
|---|---|---|---|---|
| Number of studies | 10 | 7 | 4 | 5 |
| Overall incidence | 11.95 [10.17; 13.85], 7.0% | 4.00 [1.00; 7.00], 70.0% | 1.65 [0.33; 3.59], 0.0% | 32.00 [16.00; 49.00], 93.0% |
| Blood and lymphatic system disorders | ||||
| Lymphopenia | 0.00 [0.00; 1.80] | 2.20 [0.00; 24.35], 87% | 0.00 [0.0000; 0.0838] | NR |
| Cardiac disorders | ||||
| Pericarditis | 0.00 [0.00; 1.05] | 0.37 [0.07; 2.08] | NR | NR |
| Ventricular arrhythmia | 0.00 [0.00; 7.71] | 0.37 [0.07; 2.08] | NR | 0.00 [0.00; 3.93] |
| Endocrine disorders | ||||
| Acute adrenocortical insufficiency | 0.10 [0.00; 0.58], 0.0% | 0.00 [0.00; 1.21] | 0.00 [0.00; 2.11] | 0.32 [0.06; 1.79] |
| Adrenal insufficiency | 0.00 [0.00; 0.16], 0.0% | 0.77 [0.07; 1.97], 25.2% | 0.68 [0.00; 2.24], 0.0% | 1.13 [0.22; 2.48], 0.0% |
| Adrenocorticotropic hormone deficiency | 0.00 [0.00; 1.05] | NR | NR | NR |
| Autoimmune thyroiditis | 0.00 [0.00; 0.18], 0.0% | 0.00 [0.00; 1.21] | NR | 0.36 [0.00; 1.36], 0.0% |
| Hyperthyroidism | 0.04 [0.00; 0.38], 0.0% | 0.00 [0.00; 0.22], 0.0% | 0.00 [0.00; 0.61], 0.0% | 0.52 [0.00; 1.73], 0.0% |
| Hypophysitis | 1.21 [0.61; 1.97], 0.0% | 0.15 [0.00; 0.87], 0.0% | 0.68 [0.00; 3.10], 19.1% | 2.48 [0.72; 4.97], 34.0% |
| Hypopituitarism | 0.63 [0.07; 1.55], 36.0% | 0.08 [0.00; 0.71], 0.0% | 0.00 [0.00; 2.11] | 0.43 [0.00; 1.71], 0.0% |
| Hypothyroidism | 0.00 [0.00; 0.00], 0.0% | 0.00 [0.00; 0.00], 0.0% | 0.00 [0.00; 0.36], 0.0% | 0.00 [0.00; 0.54], 0.0% |
| Lymphocytic hypophysitis | 0.00 [0.00; 0.20], 0.0% | 0.00 [0.00; 01.21] | NR | 0.32 [0.06; 1.79] |
| Thyroiditis | 0.00 [0.00; 0.22], 0.0% | 0.00 [0.00; 0.15], 0% | NR | 0.00 [0.00; 0.41], 0.0% |
| Thyrotoxic crisis | 0.28 [0.05; 1.55] | NR | NR | NR |
| Eye disorders | ||||
| Uveitis | 0.02 [0.00; 0.70], 49.4% | 0.00 [0.00; 0.22], 0.0% | 0.00 [0.00; 0.36], 0.0% | 0.42 [0.00; 3.95], 70.1% |
| Gastrointestinal disorders | ||||
| Autoimmune colitis | 0.81 [0.17; 1.75], 10.2% | 0.32 [0.06; 1.79] | 0.56 [0.10; 3.11] | 1.19 [0.00; 5.54], 77.8% |
| Autoimmune pancreatitis | 0.00 [0.00; 0.22], 0.0% | 0.32 [0.06; 1.79] | NR | 0.17 [0.00; 2.18], 62.6% |
| Colitis | 4.69 [3.06; 6.59], 43.8% | 0.33 [0.00; 1.00], 0.0% | 0.34 [0.00; 4.92], 66.7% | 9.02 [5.12; 13.76], 51.8% |
| Diarrhea | 4.50 [3.03; 6.21], 37.5% | 0.52 [0.00; 1.60], 30.6% | 0.00 [0.00; 0.30], 0.0% | 5.52 [2.24; 9.89], 58.4% |
| Enterocolitis | 0.03 [0.00; 0.51], 0.0% | NR | 0.00 [0.00; 2.11] | 0.36 [0.00; 1.36], 0.0% |
| Frequent bowel movements | 0.00 [0.00; 1.48] | 0.00 [0.00; 1.83] | NR | NR |
| Gastrointestinal perforation | 0.32 [0.02; 0.83], 0.0% | 0.10 [0.00; 0.72], 16.3% | 1.12 [0.31; 4.00] | 0.63 [0.02; 1.79], 0.0% |
| Gastrointestinal toxicity | NR | 4.35 [0.77; 20.99] | NR | NR |
| Pancreatitis | 0.01 [0.00; 0.35], 6.0% | 0.46 [0.02; 1.28], 0.0% | 0.00 [0.00; 0.67], 0.0% | 0.20 [0.00; 1.08], 0.0% |
| Peritonitis | 0.13 [0.00; 0.80], 0.0% | 0.32 [0.06; 1.79] | NR | 0.32 [0.06; 1.79] |
| Rectal hemorrhage | 0.10 [0.00; 0.65], 0.0% | NR | 0.00 [0.00; 2.11] | 0.14 [0.00; 0.95], 0.0% |
| Ulcerative colitis | 0.00 [0.00; 1.05] | NR | NR | NR |
| General disorders | ||||
| Infusion-related reaction | 0.00 [0.00; 0.33], 0.0% | 0.00 [0.00; 0.17], 0.0% | 0.00 [0.00; 2.11] | 0.00 [0.00; 0.00], 0.0% |
| Hepatobiliary disorders | ||||
| Acute hepatic failure | 0.13 [0.00; 1.55], 58.5% | NR | NR | NR |
| Acute hepatitis | 0.00 [0.00; 0.29], 0.0% | NR | NR | 0.32 [0.06; 1.79] |
| Autoimmune hepatitis | 0.23 [0.00; 0.71], 0.0% | 0.64 [0.18; 2.30] | 0.22 [0.00; 2.22], 48.5% | 1.62 [0.52; 3.18], 0.0% |
| Hepatitis | 0.08 [0.00; 0.47], 0.0% | 0.95 [0.00; 10.35], 85.5% | 0.00 [0.00; 0.67], 0.0% | 3.45 [0.32; 8.92], 80.5% |
| Hepatocellular injury | 0.01 [0.00; 0.41], 22.7% | 0.51 [0.04; 1.33], 0.0% | NR | 0.63 [0.02; 1.79], 0.0% |
| Hepatotoxicity | 0.24 [0.00; 0.77], 9.7% | 0.00 [0.00; 0.61], 0.0% | NR | 2.56 [1.30; 4.96] |
| Hyperbilirubinemia | 0.13 [0.00; 0.80], 0.0% | 0.00 [0.00; 1.21] | NR | 0.00 [0.00; 1.21] |
| Immune system disorders | ||||
| Episcleritis | NR | NR | NR | NR |
| Hypersensitivity | 0.00 [0.00; 0.07], 0.0% | 0.11 [0.00; 0.59], 0.0% | 0.00 [0.00; 2.11] | 0.00 [0.00; 1.21] |
| Infections | ||||
| Aseptic meningitis | 1.05 [0.19; 5.72] | 0.00 [0.00; 1.21] | 0.00 [0.00; 2.11] | 0.32 [0.06; 1.79] |
| Conjunctivitis | 0.00 [0.00; 0.11], 0.0% | NR | NR | NR |
| Encephalitis | 0.04 [0.00; 0.38], 0.0% | NR | NR | 0.32 [0.06; 1.79] |
| Investigations | ||||
| Alanine aminotransferase (increased) | 0.27 [0.01; 0.75], 0.0% | 0.38 [0.01; 1.09], 0.0% | 0.00 [0.00; 0.30], 0.0% | 8.94 [5.29; 13.32], 45.4% |
| Amylase (increased) | 0.01 [0.00; 0.67], 35.3% | 1.51 [0.34; 3.26], 0.0% | 0.00 [0.00; 4.14] | 3.12 [1.31; 5.48], 22.4% |
| Aspartate aminotransferase (increased) | 0.11 [0.00; 0.58], 14.9% | 0.12 [0.00; 0.67], 0.0% | 0.00 [0.00; 0.30], 0.0% | 7.01 [3.53; 11.38], 52.4% |
| Blood alkaline phosphatase (increased) | 0.04 [0.00; 0.48], 17.9% | 0.00 [0.00; 0.32] | 0.00 [0.00; 14.87] | 0.19 [0.00; 0.99], 0.0% |
| Blood bilirubin (increased) | 0.00 [0.00; 0.01], 0.0% | 0.00 [0.00; 0.16], 0.0% | 0.00 [0.00; 2.11] | 0.01 [0.00; 1.00], 29.1% |
| Blood corticotropin (decreased) | 0.15 [0.00; 1.51], 47.6% | NR | NR | NR |
| Blood creatinine (increased) | 0.00 [0.00; 0.01], 0.0% | 0.00 [0.00; 0.25], 0.0% | 0.00 [0.00; 0.36], 0.0% | 0.13 [0.00; 1.45], 0.0% |
| Blood thyroid stimulating hormone (abnormal) | 0.06 [0.00; 0.78], 0.0% | 0.00 [0.00; 0.02], 0.0% | 0.00 [0.00; 4.14] | 0.00 [0.00; 1.02], 0.0% |
| Blood urea (increased) | NR | NR | NR | NR |
| Gamma-glutamyl transferase (increased) | 0.03 [0.00; 0.48], 0.0% | 0.00 [0.00; 0.22], 0.0% | NR | 0.50 [0.00; 1.92], 0.0% |
| Hepatic enzyme (increased) | 0.00 [0.00; 0.29], 0.0% | 0.10 [0.00; 072], 16.3% | 0.00 [0.00; 2.11] | 0.96 [0.33; 2.78] |
| Lipase (increased) | 0.29 [0.00; 2.29], 82.7% | 2.22 [0.01; 6.83], 65.6% | NR | 9.22 [6.81; 11.91], 0.0% |
| Liver function test (abnormal) | 0.00 [0.00; 0.09], 0.0% | 0.64 [0.07; 1.63], 17.8% | NR | 0.36 [0.00; 1.36], 0.0% |
| Thyroxine free (decreased) | NR | NR | 0.00 [0.00; 4.14] | NR |
| Thyroxine (increased) | NR | NR | 0.00 [0.00; 4.14] | NR |
| Transaminases (increased) | 0.00 [0.00; 0.34], 0.0% | 0.32 [0.06; 1.79] | 0.00 [0.00; 14.87] | 2.44 [1.18; 4.08], 0.0% |
| Metabolism and nutrition disorders | ||||
| Diabetes mellitus | 0.51 [0.00; 10.95], 77.2% | 0.08 [0.00; 0.73], 0.0% | 2.38 [0.42; 12.32] | 0.64 [0.18; 2.30] |
| Diabetic ketoacidosis | 0.00 [0.00; 0.16], 0.0% | 0.11 [0.00; 0.94], 35.4% | NR | 0.36 [0.00; 1.36], 0.0% |
| Hyperglycemia | 0.00 [0.00; 0.29], 0.0% | 0.44 [0.04; 1.12], 0.0% | 0.99 [0.00; 4.29], 32.9% | 1.61 [0.52; 3.18], 0.0% |
| Hyperlipasemia | 0.00 [0.00; 1.05] | NR | NR | NR |
| Type 1 diabetes mellitus | 0.00 [0.00; 1.48] | NR | 2.38 [0.42; 12.32] | 1.06 [0.19; 5.78] |
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 0.29 [0.01; 0.82], 9.4% | 0.00 [0.00; 0.04], 0.0% | 0.04 [0.00; 1.27], 0.0% | 0.00 [0.00; 0.52], 0.0% |
| Arthritis | 0.00 [0.00; 0.34], 0.0% | 0.10 [0.00; 0.72], 16.3% | 0.00 [0.00; 1.03], 0.0% | 0.32 [0.06; 1.79] |
| Arthropathy | 0.00 [0.00; 1.22] | 0.00 [0.00; 1.21] | 0.00 [0.00; 4.14] | 0.32 [0.06; 1.79] |
| Hand-foot-syndrome (Palmar-plantar erythrodysesthesia syndrome) | 0.00 [0.00; 3.60] | NR | NR | NR |
| Joint swelling | NR | NR | 0.00 [0.00; 4.14] | NR |
| Muscle spasms | 0.00 [0.00; 0.19], 0.0% | 0.00 [0.00; 0.33], 0.0% | 0.00 [0.00; 1.26], 0.0% | 0.64 [0.18; 2.30] |
| Myalgia | 0.00 [0.00; 0.05], 0.0% | 0.00 [0.00; 0.08], 0.0% | 0.40 [0.00; 2.33], 0.0% | 0.01 [0.00; 0.56], 0.0% |
| Myopathy | NR | NR | NR | NR |
| Polymyalgia rheumatica | 0.13 [0.00; 0.80], 0.0% | NR | NR | NR |
| Polymyositis/ myositis | 0.00 [0.00; 0.34], 0.0% | 0.32 [0.06; 1.79] | NR | 1.06 [0.19; 5.78] |
| Rhabdomyolysis | 0.00 [0.00; 3.89] | NR | NR | 1.06 [0.19; 5.78] |
| Nervous system disorders | ||||
| Guillain-Barre syndrome | 0.00 [0.00; 0.09], 0.0% | 0.11 [0.00; 0.94], 35.4% | NR | 0.36 [0.00; 1.36], 0.0% |
| Lethargy | 0.00 [0.00; 0.27], 0.0% | NR | 0.00 [0.00; 4.14] | 0.32 [0.06; 1.79] |
| Myasthenia gravis | NR | NR | NR | NR |
| Myelitis | 0.39 [0.07; 2.18] | NR | NR | NR |
| Neuropathy | 0.00 [0.00; 0.63], 0.0% | NR | NR | 0.32 [0.06; 1.79] |
| Peripheral neuropathy | 0.00 [0.00; 0.06], 0.0% | 0.00 [0.00; 0.41], 0.0% | 0.00 [0.00; 0.36], 0.0% | 0.02 [0.00; 0.67], 0.0% |
| Renal and urinary disorders | ||||
| Acute renal failure | 0.31 [0.02; 0.80], 0.0% | 0.04 [0.00; 0.44], 0.0% | 0.26 [0.00; 1.50], 0.0% | 0.32 [0.00; 1.46], 0.0% |
| Nephritis | 0.15 [0.00; 0.59], 0.0% | 0.12 [0.00; 0.76], 0.0% | 0.00 [0.00; 2.11] | 0.03 [0.00; 1.57], 16.7% |
| Nephrotoxicity | NR | 0.00 [0.00; 7.35] | NR | 0.32 [0.06; 1.79] |
| Renal failure | 0.05 [0.00; 0.76], 50.9% | 0.30 [0.00; 0.89], 0.0% | 0.00 [0.00; 1.26], 0.0% | 0.00 [0.00; 0.42], 0.0% |
| Respiratory, thoracic, and mediastinal disorders | ||||
| Alveolitis | NR | NR | 0.00 [0.00; 0.0211] | NR |
| Lung infiltration | 0.00 [0.00; 1.22] | NR | NR | 0.32 [0.06; 1.79] |
| Pneumonitis | 0.07 [0.00; 0.44], 0.0% | 0.00 [0.00; 0.25], 0.0% | 0.27 [0.00; 1.85], 0.0% | 0.81 [0.08; 2.01], 0.0% |
| Pulmonary toxicity | NR | 0.00 [0.00; 14.31] | NR | NR |
| Skin and subcutaneous tissue disorders | ||||
| Alopecia | 0.00 [0.00; 0.09], 0.0% | 0.00 [0.00; 0.20], 0.0% | 0.00 [0.00; 2.11] | 0.00 [0.00; 9.89] |
| Blister | NR | NR | NR | 0.00 [0.00; 18.43] |
| Dermatitis | 0.00 [0.00; 0.26], 0.0% | 0.00 [0.00; 0.33]. 0.0% | NR | 0.00 [0.00; 1.21] |
| Eczema | 0.00 [0.00; 0.02], 0.0% | 0.00 [0.00; 0.36], 0.0% | 0.00 [0.00; 2.84], 0.0% | 0.00 [0.00; 121] |
| Erythema | 0.00 [0.00; 0.17], 0.0% | 0.00 [0.00; 0.23], 0.0% | 0.00 [0.00; 0.32], 0.0% | 0.14 [0.00; 0.95], 0.0% |
| Neutrophilic dermatosis | NR | NR | 0.00 [0.00; 4.14] | NR |
| Night sweats | 0.00 [0.00; 1.27], 0.0% | 0.00 [0.00; 8.57] | 0.00 [0.00; 4.14] | 0.00 [0.00; 0.50],0.0% |
| Pemphigoid | 0.00 [0.00; 0.34], 0.0% | 0.00 [0.00; 1.21] | NR | 0.32 [0.06; 1.79] |
| Photosensitivity reaction | NR | 0.00 [0.00; 0.12], 0.0% | NR | NR |
| Pruritus | 0.05 [0.00; 0.39], 0.0% | 0.00 [0.00; 0.22], 0.0% | 0.00 [0.00; 0.88], 21.9% | 0.57 [0.01; 1.65], 0.0% |
| Rash | 0.49 [0.10; 1.05], 0.0% | 0.06 [0.00; 0.55], 0.0% | 0.22 [0.00; 2.52], 51.3% | 2.98 [1.22; 5.28], 21.5% |
| Rash erythematous | 0.00 [0.00; 0.29], 0.0% | 0.00 [0.00; 1.41] | NR | 0.00 [0.00; 3.93] |
| Rash generalized | 0.04 [0.00; 0.66], 0.0% | 0.00 [0.00; 1.21] | 0.00 [0.00; 4.14] | 0.32 [0.06; 1.79] |
| Rash macular | 0.32 [0.06; 1.80] | 0.00 [0.00; 1.21] | NR | 0.17 [0.00; 2.18], 0.0% |
| Rash maculo-papular | 0.03 [0.00; 0.36], 0.0% | 0.43 [0.00; 2.05], 66.3% | 0.02 [0.00; 0.88], 0.0% | 2.14 [0.00; 6.83], 81.0% |
| Rash papular | 0.00 [0.00; 0.34], 0.0% | 0.00 [0.00; 0.36],0.0% | 0.00 [0.00; 4.14] | 0.00 [0.00; 1.21] |
| Rash pruritic | 0.00 [0.00; 0.22], 0.0% | 0.00 [0.00; 1.21] | NR | 0.00 [0.00; 0.38], 0.0% |
| Skin exfoliation | NR | NR | NR | NR |
| Skin hypopigmentation | 0.00 [0.00; 0.34], 0.0% | 0.00 [0.00; 1.21] | 0.00 [0.00; 1.36], 0.0% | 0.00 [0.00; 0.38], 0.0% |
| Skin reactions | NR | NR | NR | NR |
| Toxic skin eruption | 0.00 [0.00; 0.42], 36.3% | 0.32 [0.06; 1.79] | 0.00 [0.00; 8.38] | NR |
| Urticaria | 0.00 [0.00; 5.13] | NR | 0.00 [0.00; 8.38] | 0.00 [0.00; 18.43] |
| Vitiligo | 0.00 [0.00; 0.14], 0.0% | 0.00 [0.00; 0.03], 0.0% | 0.00 [0.00; 0.30], 0.0% | 0.00 [0.00; 0.04], 0.0% |
| Vascular disorders | ||||
| Thromboembolic event | 0.19 [0.00; 0.91], 0.0% | 0.49 [0.07; 1.17], 0.0% | 0.00 [0.00; 2.11] | 0.79 [0.00; 3.46], 61.0% |
NR, not reported.