Table 1.
Baseline of patients characteristics
| Study | Nation | Tumors | ICI type | Patients (male/female) | Median age (years) | ECOG 0–1/ ≥ 2 | Previous therapy 0/ ≥ 1 | IrAE type (n) | irAE (n) | Non-irAE (n) |
|---|---|---|---|---|---|---|---|---|---|---|
| Ascierto 2014 [23] | Italy | Melanoma | Ipilimumab | 855 (460/395) | 61 (16–88) | 830/25 | 0/855 | Pruritus (58), rash (64), diarrhea (60), nausea (47), vomiting (15), abdominal pain (11), constipation (7), endocrine (7), liver toxicity (19), fatigue/asthenia (70) | 286 | 569 |
| Cortellini 2019 [24] | Italy | NSCLC |
Pembrolizumab or nivolumab |
559 (379/180) | 69 (24–88) | 485/74 | 116/443 | Endocrine (78), gastrointestinal (51), skin (59), pneumological (23), hepatic (10), others (46) | 231 | 328 |
| Elias 2019 [25] | USA | RCC | ICIs | 90 | NA | NA | NA | Fatigue (25), nausea (9), decreased appetite (8) | 38 | 52 |
| Freeman-Keller 2015 [14] | USA | Melanoma | Nivolumab | 148 (87/61) | NA | NA | NA | Rash (67), diarrhea/colitis/enteritis (48), vitiligo (19), hypothyroidism (16), elevated amylase/lipase (7), mucositis (9), pneumonitis (3), hyperthyroidism (2), hypophysitis (1), elevated ALT/AST (1) | 101 | 47 |
| Grangeon 2018 [26] | France | NSCLC | Anti-PD-L1 or anti-PD-1 | 270 (177/93) | 61 (32–84) | 233/17 | 16/254 | Thyroiditis (53), rashes (19), colitis (11), hepatitis (8), endocrinopathy (8), pneumonitis (6), nephritis (1), pruritus (9), arthralgia (5), mof (1), myocarditis (1), myocardial ischemia (1), psoriasis (1), irritability (1) | 124 | 146 |
| Horvat 2015 [28] | USA | Melanoma | Ipilimumab | 298 (182/116) | 65 (21–93) | 291/7 | 193/105 | Hepatotoxicity (197), dermatitis (123), diarrhea (87), hypophysitis (17), uveitis (8), other (15) | 254 | 44 |
| Study | Nation | Tumors | ICI type | Patients (male/female) | Median age (years) | ECOG 0–1/ ≥ 2 | Previous therapy 0/ ≥ 1 | IrAE type (n) | irAE (n) | Non-irAE(n) |
| Haratani 2017 [27] | Japan | NSCLC | Nivolumab | 134 (90/44) | 68 (33–85) | 116/12 | 8/126 | Rash (33), pruritus (16), vitiligo (2), pneumonitis (6), thyroiditis/hypothyroidism (10), hypophysitis (1), mucositis (3), diarrhea/colitis (10), hepatitis (5), cholangitis (2), fatigue (7), appetite loss (4), polyarthritis (1), myasthenia gravis (1) | 69 | 65 |
| Indini 2018 [29] | Germany | Melanoma | Pembrolizumab or nivolumab | 173 (107/66) | 62 (18–85) | 166/6 | 74/99 | Rash (12), pruritus (11), lichen (1), vitiligo (8), fatigue (34), fever (4), infusion-related reaction (2), decreased appetite (6), dysgeusia (2), dry mouth (2), oral mucositis (2), nausea (13), vomiting (1), gastritis (2), colitis (1), diarrhea (10), ast, alt increase (19), γgt increase (1), amylase increased (2), lipase increased (3), hyperglycemia (1), serum creatinine increase (2), acute renal failure (1), cough (5), interstitial pneumonitis (2), arthralgias (12), hypothyroidism (14), hypophysitis (2), anemia (6), thrombocytopenia (4), myasthenia with myositis (1), headache (2), paresthesia (2), peripheric sensory neuropathy (8), peripheric motor neuropathy (1), uveitis (1), conjunctivitis (1), photophobia (2) | 102 | 71 |
| Study | Nation | Tumors | ICI type | Patients (male/female) | Median age (yeaars) | ECOG0–1/ ≥ 2 | Previous therapy/ ≥ 1 | IrAE type (n) |
irAE (n) |
Non-irAE(n) |
| Kawai 2019 [30] | Japan | UC | Pembrolizumab | 30 (25/5) | 70 (26–85) | NA | 0/30 | NA | 18 | 12 |
| Masuda 2019 [31] | Japan | Gastric cancer | Nivolumab | 65 (51/14) | 66 (35–83) | 59/6 | NA | Diarrhea/colitis (5), hyperglycemia (2), pruritus (2), rash (2), type 1 dm (2), adrenal insufficiency (1), alt increased (1), ast increased (1), appetite loss (1), appetite loss (1), dry skin (1), edema limbs (1), myalgia (1), peripheral motor neuropathy (1), pneumonitis (1), QTc interval prolonged (1) | 14 | 51 |
| Okada 2018 [32] | Japan | Melanoma | Nivolumab | 15 (4/11) | NA | NA | NA | Rash (6), hypothyroidism (4), diarrhea (2), liver dysfunction (1) | 8 | 7 |
| Okamoto 2019 [33] | Japan | HNC | Nivolumab | 100 (79/21) | 65(23–81) | 95/5 | 0/100 | Dermatitis (3), interstitial lung disease (11), hypothyroidism (8), hyperthyroidism (1), adrenal insufficiency (1), liver dysfunction (4), myositis (1), rheumatoid arthritis (1), eye disorders (1), upper gastrointestinal hemorrhage (1), diarrhea (1), weight loss (1), infusion reaction (1), anemia (1), increased creatinine (1) | 30 | 70 |
| Sato 2018 [36] | Japan | NSCLC | Nivolumab | 38 (28/10) | 68.5 (49–86) | 33/5 | NA | TSH elevation (1), hypothyroidism (3), pneumonitis (5), hyperthyroidism (1), rash (1), liver dysfunction (1), hypopituitarism (1) | 11 | 27 |
| Study | Nation | Tumors | ICI type | Patients (male/female) | Median age (years) | ECOG 0–1/ ≥ 2 | Previous therapy 0/ ≥ 1 | IrAE type (n) | irAE (n) | Non-irAE(n) |
| Ricciuti 2018 [34] | Italy | NSCLC | Nivolumab | 195 (128/67) | 63(30–84) | 160/35 | 0/195 | Rash (18), psoriasis (3), pruritus (2), dry skin (2), skin desquamation (1), paronychia (1), pneumonitis (16), hyper/hypothyroidism (39), hyperprolactinemia (16), ACTH elevation (4), colitis (21), amylase increase (15), lipase increase (8), nausea/vomiting (8), constipation (1), abdominal pain (2), xerostomia (1), γ-GT (18), ALT (16), AST (16), alkaline phosphatase (16), conjunctivitis (2), uveitis (1), fatigue (38), arthritis (7), polymyalgia rheumatica (1), dermatomyositis (1), anorexia (3), anemia (1), thrombocytopenia (3), Neutropenia (1) | 85 | 110 |
| Rogado 2019 [35] | Spain | Lung cancer melanoma, HL HCC, HNC,UC RC,MCC,GBAC | Nivolumab or pembrolizumab | 106 (76/30) | 69(32–86) | 73/33 | 21/85 | Hypothyroidism (22), hyperthyroidism (3), nephritis (7), rash (3), pneumonitis (5), colitis (1), hepatitis (3), arthritis (3), hypophysitis (1), panhypopituitarism (2), suprarenal insufficiency (2), hyperthyroidism (2), ketoacidotic diabetes (1), encephalitis (1), myositis (1) | 40 | 66 |
| Shafqat 2018 [37] | USA | NSCLC, RCC, melanoma, UC HNC, Other | Nivolumab or pembrolizumab or atezolizumab | 157 (100/57) | 65 | NA | NA | Colitis (4), pneumonitis (5), hepatitis (1), endocrinopathy (21), skin toxicity (4), other (1), arthralgia/arthritis (9) | 42 | 114 |
| Study | Nation | Tumors | ICI type | Patients (male/female) | Median age(y) | ECOG 0–1/ ≥ 2 | Previous therapy 0/ ≥ 1 | IrAE type (n) | irAE (n) | Non-irAE (n) |
| Teraoka 2017 [38] | Japan | NSCLC | Nivolumab | 43 (27/16) | 70 (50–82) | 39/4 | 0/43 | Rash (12), pyrexia (6), diarrhea (4), elevated hepatic enzyme levels (1) | 19 | 24 |
| Toi 2018 [39] | Japan | NSCLC | Nivolumab or pembrolizumab | 137 (105/32) | 68 (36–88) | 134/3 | 18/119 | Skin reaction (42), pneumonitis (14), hypothyroidism (6), hyperthyroidism (1), hepatitis (6), myositis or peripheral neuropathy (5) | 66 | 71 |
| Verzoni 2019 [40] | Italy | RCC | Nivolumab | 389 (291/98) | 65 (34–85) | 350/24 | 2/387 | Cutaneous (30), endocrine (17), hepatic (7), gastro-intestinal (19), pulmonary (4) | 76 | 313 |
| VonPawel 2017 [41] | Global | NSCLC | Atezolizumab | 850 | NA | NA | NA | NA | 264 | 586 |
| Bjornhart 2019 [42] | Denmark | NSCLC | Nivolumab or pembrolizumab | 118 (55/63) | 66 (59–71) | 106/12 | 46/72 | Pneumonitis, colitis, hypophysitis, diarrhea, arthritis, uveitis, myositis, primary AI, thyroiditis, hepatitis, allergic reaction | 32 | 86 |
| Otsuka 2020 [43] | Japan | Melanoma | Nivolumab | 27 (9/18) | 69 (31–87) | NA | 23/4 | Dermatological (11), gastrointestinal (2), endocrine (4), pulmonary (4), renal (1), infusion-related reaction (1) | 16 | 12 |
| Dick 2016 [44] | Germany | Melanoma | Ipilimumab | 86 (48/38) | 59 (14–83) | NA | 22/64 | Predominantly diarrhea, autoimmune colitis, skin toxicity, infrequently hypophysitis, autoimmune hepatitis, autoimmune pancreatitis, alopecia areata | 36 | 50 |
| Study | Nation | Tumors | ICI type | Patients (male/female) | Median age(y) | ECOG 0–1/ ≥ 2 | Previous therapy 0/ ≥ 1 | IrAE type (n) | irAE (n) | Non-irAE (n) |
| Judd 2017 [45] | USA | RCC, HNSCC, UC, NSCLC, other | Nivolumab or pembrolizumab | 160 (101/59) | 65 | NA | NA | Endocrinopathy, colitis, dermatitis | 64 | 96 |
| Kim 2018 [46] | South Korea | NSCLC | Nivolumab or pembrolizumab | 58 (43/15) | 63.1 (49–68) | NA | NA | Thyroid dysfunction (19) | 19 | 39 |
| Ksienski 2018 [47] | Canada | NSCLC | Nivolumab or pembrolizumab | 271 (137/134) | NA | 187/54 | 21/250 | Hypothyroid (32), dermatitis (35), colitis (18), hyperthyroid (10), hepatitis (12), arthralgias (13), pneumonitis (17), nephritis (8), adrenal insufficiency (3), diabetes (3), hypophysitis (2), pancreatitis (1), neurologic (3), cholangitis (2), myopathy (2), myositis (1), mucositis (1), palmar plantar erythrodysesthesia (1), polymyalgia rheumatica (1), vasculitis (1), idiopathic thrombocytopenic purpra (1), myocarditis (1) | 116 | 155 |
| Lisberg 2018 [49] | USA | NSCLC | Pembrolizumab | 97 (50/47) | 65 (32–83) | NA | 13/84 | Rash (22), fatigue (9), hypothyroidism (6), fever/chills (5), anorexia (4), pneumonitis (6), pruritus (3), abdominal pain (2), worsening dyspnea (2), joint pain (2), edema (2) | 39 | 58 |
| Sugano 2020 [56] | Japan | NSCLC | Nivolumab or atezolizumab or pembrolizumab | 130 (98/32) | NA | 99/31 | NA | Interstitial lung disease (16), hypothyroidism (9), skin reaction (5), nephrotoxicity (3), encephalitis (2) | 39 | 91 |
| Study | Nation | Tumors | ICI type | Patients (male/female) | Median age (years) | ECOG 0–1/ ≥ 2 | Previous therapy 0/ ≥ 1 | IrAE type (n) | irAE (n) | Non-irAE (n) |
| Maher 2019 [50] | Global | UC | Nivolumab or atezolizumab or durvalumab or avelumab or pembrolizumab | 1747 (1328/419) | 68 (29–94) | 1572/175 | NA | NA | 268 | 1479 |
| Hua 2016 [16] | France | Melanoma | Pembrolizumab | 67 (38/29) | 57 (28–72) | NA | NA | Vitiligo (17) | 17 | 50 |
| Nakamura 2017 [17] | Japan | Melanoma | Nivolumab | 35 (18/17) | NA | NA | NA | Vitiligo (9) | 9 | 26 |
| Nakamura 2016 [52] | Japan | Melanoma | Nivolumab | 98 (52/46) | 66.5 (17–93) | 92/6 | 28/70 | Vitiligo (13), hypothyroidism (11), pruritus (10), rash (7), malaise (5) | 51 | 57 |
| Lesueur 2018 [48] | France | NSCLC | Nivolumab | 104 (67/37) | 60.3 (54.5–67.1) | 69/35 | NA | Pulmonary (4), gastrointestinal (21), dermatological (13), endocrinological (10), rheumatological (6), asthenia (19), hematological (1), others (16) | 62 | 42 |
| Minlee 2018 [51] | USA | Lung cancer, HL cutaneous cancer HNC, GC, UC reproductive cancer | Nivolumab or atezolizumab or pembrolizumab | 114 (62/52) | NA | NA | NA | Dermatitis (20) | 20 | 94 |
| Osorio 2016 [53] | USA | NSCLC | Pembrolizumab | 51 (21/30) | NA | NA | NA | Immune-related thyroid dysfunction (10) | 10 | 41 |
| Study | Nation | Tumors | ICI type | Patients (male/female) | Median age (years) | ECOG 0–1/ ≥ 2 | Previous therapy 0/ ≥ 1 | IrAE type (n) | irAE (n) | Non-irAE (n) |
| Owen 2018 [54] | USA | NSCLC | Nivolumab or pembrolizumab or atezolizumab | 91 (39/52) | 67/22 | NA | NA | Pneumonitis (9), dermatologic (6), endocrine (7), colitis (3), hepatitis (1), pancreatic insufficiency (1) | 27 | 64 |
| Yamazaki 2017 [59] | Japan | Melanoma | Nivolumab | 24 (14/10) | 63 (26–81) | 24/0 | 16/8 | Endocrine disorders (7), gastrointestinal toxicity (2), hepatotoxicity (1), pulmonary toxicity (1), skin toxicity (11) | 13 | 10 |
|
Sanlorenzo 2015 [55] |
USA | Melanoma, lung cancer, MCC, prostate cancer | Pembrolizumab | 83 (52/31) | NA | NA | NA | Macular papular eruption (24), pruritus (10), hypopigmentation (7), xerosis (2), keratosis (2), facial erythema (1) | 35 | 48 |
| Suh 2018 [57] | South Korea | NSCLC | Nivolumab/pembrolizumab | 54 (42/12) | NA | 54/0 | 0/54 | 12 | 42 | |
| Weber 2017 [58] | USA | Melanoma | Nivolumab | 576 (349/227) | 61 | 571/0 | NA | Pruritus (99), rash (73), vitiligo (45), rash maculopapular (26), diarrhea (73), colitis (6), hypothyroidism (24), hyperthyroidism (12), hypophysitis (1), AST increased (16), ALT increased (11), γ-glutamyltransferase increased (1), hepatitis (1), liver function test abnormal (1), pneumonitis (10), blood creatinine increased (3), renal failure acute (1), tubulointerstitial nephritis (1) | 255 | 321 |
NSCLC non-small cell lung cancer, UC urothelial cancer, RCC renal cell carcinoma, HL Hodgkin lymphoma, HNC head and neck carcinoma, HCC hepatocellular carcinoma, GC gastrointestinal cancer, GBAC gallbladder adenocarcinoma, MCC Merkel cell carcinoma, irAE immune-related adverse events, NA not available