Table 4.
Incidence of All-grades 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 | 53.96 [42.21; 64.97], 94.0% | 44.00 [31.00; 57.00], 93.0% | 20.28 [14.23; 27.06], 41.0% | 80.00 [61.00; 94.00], 95.0% |
| Blood and lymphatic system disorders | ||||
| Lymphopenia | 2.38 [0.42; 5.49], 0.0% | 6.76 [0.00; 28.48], 81.0% | 4.76 [1.32; 15.79] | 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 [0.0007; 2.08] | NR | 1.06 [0.19; 5.78] |
| 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 | 0.67 [0.20; 1.32], 0.0% | 1.68 [0.16; 4.34], 68.1% | 0.68 [0.00; 2.24], 0.0% | 3.79 [2.14; 5.79], 0.0% |
| Adrenocorticotropic hormone deficiency | 0.28 [0.05; 1.55] | NR | NR | NR |
| Autoimmune thyroiditis | 0.00 [0.00; 0.18], 0.0% | 0.32 [0.06; 1.79] | NR | 0.96 [0.01; 2.90], 35.8% |
| Hyperthyroidism | 0.88 [0.03; 2.54], 75.5% | 3.17 [1.98; 4.59], 7.4% | 3.83 [1.50; 6.97], 0.0% | 10.59 [6.18; 15.87], 40.9% |
| Hypophysitis | 2.58 [1.73; 3.57], 0.0% | 0.31 [0.00; 1.14], 0.0% | 1.64 [0.00; 8.01], 68.5% | 10.86 [6.64; 15.87], 62.8% |
| Hypopituitarism | 0.96 [0.31; 1.88], 23.4% | 0.16 [0.00; 0.88], 4.2% | 0.00 [0.00; 2.11] | 1.25 [0.18; 2.95], 0.0% |
| Hypothyroidism | 2.05 [0.53; 4.28], 74.7% | 7.09 [4.16; 10.64], 59.4% | 8.15 [4.81; 12.17], 0.0% | 16.37 [13.07; 19.95], 6.4% |
| Lymphocytic hypophysitis | 0.04 [0.00; 0.44], 0.0% | 0.00 [0.00; 01.21] | NR | 0.64 [0.18; 2.30] |
| Thyroiditis | 0.42 [0.06; 1.01], 0.0% | 1.63 [0.00; 4.96], 42.9% | NR | 5.39 [0.04; 15.93], 73.6% |
| Thyrotoxic crisis | 0.28 [0.05; 1.55] | NR | NR | NR |
| Eye disorders | ||||
| Uveitis | 0.14 [0.00; 0.97], 52.8% | 0.24 [0.00; 1.33], 0.0% | 0.04 [0.00; 2.26], 0.0% | 2.69 [0.01; 8.19], 72.1% |
| Gastrointestinal disorders | ||||
| Autoimmune colitis | 1.38 [0.31; 2.99], 44.6% | 0.64 [0.18; 2.30] | 0.56 [0.10; 3.11] | 1.41 [0.00; 4.98], 68.0% |
| 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 | 6.87 [5.31; 8.58], 20.2% | 1.88 [0.28; 4.41], 69.4% | 1.64 [0.00; 8.01], 68.5% | 11.80 [6.57; 18.16], 66.3% |
| Diarrhea | 27.74 [24.28; 31.33], 46.0% | 17.68 [12.07; 24.05], 76.4% | 11.14 [6.56; 16.63], 32.9% | 35.69 [26.65; 45.26], 72.7% |
| 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 | 0.39 [0.07; 2.18] | 0.97 [0.27; 3.47] | 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 | 8.70 [2.42; 26.80] | NR | NR |
| Pancreatitis | 0.01 [0.00; 0.35], 6.0% | 0.62 [0.07; 1.50], 0.0% | 0.26 [0.00; 1.50], 0.0% | 0.75 [0.05; 1.95], 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 | 0.86 [0.00; 3.19], 71.7% | NR | 0.00 [0.00; 2.11] | 0.36 [0.00; 1.36], 0.0% |
| Ulcerative colitis | 0.00 [0.00; 1.05] | NR | NR | NR |
| General disorders | ||||
| Infusion-related reaction | 0.75 [0.00; 2.51], 59.1% | 2.95 [0.82; 6.00], 67.7% | 0.00 [0.00; 2.11] | 1.94 [0.45; 4.11], 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 | 0.32 [0.02; 0.85], 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 | 0.29 [0.00; 0.91], 20.6% | 3.01 [0.00; 24.87], 94.2% | 0.68 [0.00; 2.24], 0.0% | 4.85 [0.44; 12.65], 87.3% |
| Hepatocellular injury | 0.15 [0.00; 0.80], 32.1% | 0.80 [0.14; 1.88], 18.8% | NR | 0.89 [0.11; 2.17], 0.0% |
| Hepatotoxicity | 0.42 [0.06; 1.01], 0.0% | 0.78 [0.00; 7.85], 65.1% | NR | 3.19 [1.74; 5.78] |
| Hyperbilirubinemia | 0.13 [0.00; 0.80], 0.0% | 0.32 [0.06; 1.79] | NR | 2.24 [1.09; 4.54] |
| Immune system disorders | ||||
| Episcleritis | NR | NR | NR | NR |
| Hypersensitivity | 0.43 [0.00; 1.58], 57.5% | 2.00 [1.09; 3.12], 0.0% | 0.56 [0.10; 3.11] | 2.88 [1.52; 5.37] |
| Infections | ||||
| Aseptic meningitis | 1.05 [0.19; 0.05.72] | 0.00 [0.00; 1.21] | 0.00 [0.00; 2.11] | 0.32 [0.06; 1.79] |
| Conjunctivitis | 0.40 [0.00; 2.37], 51.4% | NR | NR | NR |
| Encephalitis | 0.04 [0.00; 0.38], 0.0% | NR | NR | 0.32 [0.06; 1.79] |
| Investigations | ||||
| Alanine aminotransferase (increased) | 2.40 [1.01; 4.23], 63.1% | 2.58 [1.34; 4.12], 18.8% | 3.98 [1.92; 6.59], 0.0% | 18.65 [9.78; 29.43], 83.9% |
| Amylase (increased) | 0.67 [0.00; 4.30], 86.7% | 5.81 [3.49; 8.62], 0.0% | 1.12 [0.20; 6.09] | 9.31 [6.89; 12.01], 0.0% |
| Aspartate aminotransferase (increased) | 2.54 [0.97; 4.66], 68.8% | 2.84 [1.35; 4.73], 36.4% | 4.49 [2.31; 7.21], 0.0% | 17.82 [9.09; 28.51], 84.1% |
| Blood alkaline phosphatase (increased) | 0.97 [0.26; 1.99], 30.5% | 3.81 [0.62; 9.04], 83.2% | 0.00 [0.00; 14.87] | 5.53 [2.86; 8.91], 41.9% |
| Blood bilirubin (increased) | 0.17 [0.00; 1.28], 65.1% | 0.27 [0.00; 1.09], 0.0% | 3.37 [1.55; 7.16] | 3.21 [0.89; 6.59], 43.5% |
| Blood corticotropin (decreased) | 0.38 [0.00; 3.07], 74.5% | NR | NR | NR |
| Blood creatinine (increased) | 0.27 [0.00; 1.24], 57.0% | 1.11 [0.04; 3.10], 48.7% | 0.45 [0.00; 5.27], 65.7% | 3.16 [1.53; 5.20], 0.0% |
| Blood thyroid stimulating hormone (abnormal) | 0.94 [0.12; 2.26], 0.0% | 0.23 [0.00; 1.66], 0.0% | 1.12 [0.20; 6.09] | 5.62 [0.00; 23.04], 73.4% |
| Blood urea (increased) | NR | NR | NR | NR |
| Gamma-glutamyl transferase (increased) | 0.58 [0.00; 2.03], 50.4% | 0.55 [0.00; 3.93], 52.1% | NR | 2.62 [0.95; 4.85], 0.0% |
| Hepatic enzyme (increased) | 0.00 [0.00; 0.29], 0.0% | 0.34 [0.00; 1.07], 0.0% | 0.00 [0.00; 2.11] | 1.60 [0.68; 3.68] |
| Lipase (increased) | 1.60 [0.00; 5.44], 88.4% | 3.10 [0.00; 11.74], 85.4% | NR | 14.31 [11.40; 17.46], 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 | 1.12 [0.20; 6.09] | NR |
| Thyroxine (increased) | NR | NR | 1.12 [0.20; 6.09] | NR |
| Transaminases (increased) | 0.59 [0.07; 1.43], 0.0% | 0.64 [0.18; 2.30] | 0.00 [0.00; 14.87] | 2.81 [1.45; 4.52], 0.0% |
| Metabolism and nutrition disorders | ||||
| Diabetes mellitus | 0.51 [0.00; 10.95], 77.2% | 0.44 [0.00; 1.35], 0.0% | 2.38 [0.42; 12.32] | 0.96 [0.33; 2.78] |
| 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 | 0.75 [0.00; 3.53], 82.5% | 0.58 [0.10; 1.31], 0.0% | 5.57 [2.77; 9.09], 0.0% | 2.60 [1.19; 4.46], 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 | 6.23 [2.95; 10.50], 85.0% | 9.35 [5.66; 13.75], 67.3% | 7.74 [4.47; 11.68], 0.0% | 14.64 [11.70; 17.82], 0.0% |
| Arthritis | 0.00 [0.00; 0.34], 0.0% | 0.10 [0.00; 0.72], 16.3% | 1.90 [0.00; 6.85], 41.4% | 0.32 [0.06; 1.79] |
| Arthropathy | 0.00 [0.00; 1.22] | 0.32 [0.06; 1.79] | 0.00 [0.00; 4.14] | 0.64 [0.18; 2.30] |
| Hand-foot-syndrome (Palmar-plantar erythrodysesthesia syndrome) | 0.97 [0.17; 5.30] | NR | NR | NR |
| Joint swelling | NR | NR | 0.00 [0.00; 4.14] | NR |
| Muscle spasms | 0.46 [0.03; 1.21], 0.0% | 3.35 [0.84; 7.32], 78.7% | 0.67 [0.00; 9.22], 65.9% | 2.24 [1.09; 4.54] |
| Myalgia | 3.24 [1.03; 6.36], 81.4% | 4.19 [1.85; 7.24], 63.4% | 4.85 [2.01; 8.59], 0.0% | 11.90 [5.22; 20.66], 82.7% |
| Myopathy | NR | NR | NR | NR |
| Polymyalgia rheumatica | 0.30 [0.00; 1.11], 0.0% | NR | NR | NR |
| Polymyositis/ myositis | 0.10 [0.00; 0.75], 19.7% | 0.32 [0.06; 1.79] | NR | 2.13 [0.59; 7.43] |
| 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 | 0.20 [0.00; 1.25], 57.0% | NR | 1.12 [0.20; 6.09] | 0.32 [0.06; 1.79] |
| Myasthenia gravis | NR | NR | NR | NR |
| Myelitis | 0.39 [0.07; 2.18] | NR | NR | NR |
| Neuropathy | 0.63 [0.00; 10.45], 71.7% | NR | NR | 0.64 [0.18; 2.30] |
| Peripheral neuropathy | 0.43 [0.00; 1.80], 68.8% | 2.36 [0.84; 4.47], 38.5% | 0.40 [0.00; 2.33], 0.0% | 3.53 [1.15; 6.89], 40.4% |
| 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% | 0.52 [0.00; 1.79], 0.0% |
| Nephritis | 0.15 [0.00; 0.59], 0.0% | 0.12 [0.00; 0.76], 0.0% | 0.56 [0.10; 3.11] | 0.69 [0.00; 5.76], 60.2% |
| Nephrotoxicity | NR | 0.00 [0.00; 7.35] | NR | 0.32 [0.06; 1.79] |
| Renal failure | 0.10 [0.00; 1.02], 60.9% | 0.75 [0.21; 1.54], 0.0% | 0.45 [0.00; 3.39], 0.0% | 0.00 [0.00; 0.42], 0.0% |
| Respiratory, thoracic and mediastinal disorders | ||||
| Alveolitis | NR | NR | 0.00 [0.00; 2.11] | NR |
| Lung infiltration | 0.00 [0.00; 1.22] | NR | NR | 0.32 [0.06; 1.79] |
| Pneumonitis | 0.32 [0.00; 1.34], 60.4% | 1.36 [0.61; 2.34], 0.0% | 1.46 [0.10; 3.77], 0.0% | 7.50 [5.06; 10.32], 10.1% |
| Pulmonary toxicity | NR | 4.35 [0.77; 20.99] | NR | NR |
| Skin and subcutaneous tissue disorders | ||||
| Alopecia | 1.67 [0.17; 4.18], 43.3% | 1.95 [0.01; 6.02], 77% | 3.37 [1.55; 7.16] | 0.00 [0.00; 9.89] |
| Blister | NR | NR | NR | 0.00 [0.00; 18.43] |
| Dermatitis | 4.68 [0.00; 18.84], 97.0% | 2.23 [1.14; 3.62], 0.0% | NR | 1.92 [0.88; 4.12] |
| Eczema | 0.11 [0.00; 0.85], 18.6% | 2.10 [0.99; 3.57], 0.0% | 4.48 [0.00; 22.04], 74.9% | 2.88 [1.52; 5.37] |
| Erythema | 1.63 [0.64; 2.96], 47.9% | 4.00 [1.94; 6.68], 42.5% | 4.74 [2.38; 7.72], 0.0% | 4.79 [0.55; 12.34], 82.0% |
| Neutrophilic dermatosis | NR | NR | 1.12 [0.20; 6.09] | NR |
| Night sweats | 2.04 [0.14; 5.37], 0.0% | 0.00 [0.00; 8.57] | 1.12 [0.20; 6.09] | 5.26 [2.51; 8.74], 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 | 3.84 [0.00; 19.48], 75.2% | NR | NR |
| Pruritus | 24.88 [19.61; 30.53], 79.3% | 22.53 [14.42; 31.78], 87.0% | 21.40 [17.03; 26.10], 0.0% | 33.73 [27.64; 40.10], 42.6% |
| Rash | 20.54 [16.04; 25.42], 75.0% | 18.10 [10.83; 26.65], 86.0% | 13.47 [9.86; 17.50], 0.0% | 30.68 [15.64; 48.07], 92.3% |
| Rash erythematous | 1.13 [0.00; 4.24], 69.3% | 1.12 [0.38; 3.24] | NR | 1.06 [0.19; 5.78] |
| Rash generalized | 1.26 [0.00; 4.73], 72.3% | 0.64 [0.18; 2.30] | 1.12 [0.20; 6.09] | 2.56 [1.30; 4.96] |
| Rash macular | 0.32 [0.06; 1.80] | 0.64 [0.18; 2.30] | NR | 2.34 [1.01; 4.13], 0.0% |
| Rash maculo-papular | 5.26 [1.03; 12.10], 93.1% | 16.08 [2.73; 36.78], 97.7% | 3.89 [0.65; 8.97], 61.2% | 20.29 [8.42; 35.55], 91.8% |
| Rash papular | 1.26 [0.46; 2.37], 0.0% | 1.68 [0.70; 3.03], 0.0% | 1.12 [0.20; 6.09] | 2.24 [1.09; 4.54] |
| Rash pruritic | 2.41 [1.05; 4.21], 58.3% | 0.32 [0.06; 1.79] | NR | 1.84 [0.62; 3.55], 4.5% |
| Skin exfoliation | NR | NR | NR | NR |
| Skin hypopigmentation | 0.22 [0.00; 1.23], 47.1% | 2.24 [1.09; 4.54] | 1.18 [0.00; 9.48], 0.0% | 3.51 [0.34; 9.23], 76.2% |
| Skin reactions | NR | NR | NR | NR |
| Toxic skin eruption | 0.00 [0.00; 0.42], 36.3% | 0.32 [0.06; 1.79] | 2.38 [0.42; 12.32] | NR |
| Urticaria | 0.35 [0.00; 1.98], 0.0% | NR | 9.52 [3.77; 22.07] | 0.00 [0.00; 18.43] |
| Vitiligo | 2.39 [0.79; 4.65], 63.7% | 9.13 [5.06; 14.12], 73.3% | 7.69 [4.89; 10.99], 0.0% | 8.61 [6.06; 11.50], 8.0% |
| Vascular disorders | ||||
| Thromboembolic event | 0.34 [0.00; 1.50], 63.0% | 0.49 [0.07; 1.17], 0.0% | 1.12 [0.31; 4.00] | 0.79 [0.00; 3.46], 61.0% |
NR, not reported.