Table S1- Frequency of adverse effects of immune checkpoint inhibitors (ICPI).
Immune-related adverse effects
ICPI Affected organ or system of (Frequency) (Trade name) the human body Adverse reactions observed Very Common Uncommon Rare Very rare Unknown common
Sepsis, septic shock, urinary tract infection, respiratory tract Infections and infestations X infection
Neoplasms benign, Tumour pain X
malignant and unspecified
(including cysts and Paraneoplastic syndrome X
polyps)
Anaemia, lymphopenia X Blood and lymphatic Ipilimumaba Haemolytic anaemia, thrombocytopenia, eosinophilia, neutropenia X system disorders (Yervoy) [1] Histiocytosis haematophagic X
Hypersensitivity X Immune system disorders Anaphylactic reaction X
Hypopituitarism (including hypophysitis), hypothyroidism X
Adrenal insufficiency, secondary adrenocortical insufficiency, Endocrine disorders X hyperthyroidism, hypogonadism
Autoimmune thyroiditis, thyroiditis X
Metabolism and nutrition Decreased appetite X
disorders Dehydration, hypokalemia X Hyponatremia, alkalosis, hypophosphatemia, tumour lysis X syndrome, hypocalcaemia
Confusional state X Psychiatric disorders Mental status changes, depression, decreased libido X
Peripheral sensory neuropathy, dizziness, headache, lethargy X
Guillain-Barré syndrome, meningitis (aseptic), autoimmune
central neuropathy (encephalitis), syncope, cranial neuropathy, Nervous system disorders X brain oedema, peripheral neuropathy, ataxia, tremor, myoclonus,
dysarthria
Myasthenia gravis X
Blurred vision, eye pain X
Uveitis, vitreous haemorrhage, iritis, eye oedema, blepharitis,
Eye disorders reduced visual acuity, foreign body sensation in eyes, X
conjunctivitis
Vogt-Koyanagi-Harada syndrome, serous retinal detachment X
Cardiac disorders Arrhythmia, atrial fibrillation X
Hypotension, flushing, hot flush X
Vasculitis, angiopathy, peripheral ischaemia, orthostatic Vascular disorders X hypotension
Temporal arteritis X
Dyspnea, cough X Respiratory, thoracic and Respiratory failure, acute respiratory distress syndrome, lung mediastinal disorders X infiltration, pulmonary oedema, pneumonitis, allergic rhinitis
Gastrointestinal disorders Diarrhoea, vomiting, nausea X Gastrointestinal haemorrhage, colitis, constipation,
gastroesophageal reflux disease, abdominal pain, mucosal X
inflammation
Gastrointestinal perforation, large intestine perforation, intestinal
perforation, peritonitis, gastroenteritis, diverticulitis, pancreatitis, X enterocolitis, gastric ulcer, large intestinal ulcer, stomatitis,
oesophagitis, ileus
Proctitis X
X Hepatobiliary disorders Abnormal hepatic function
Hepatic failure, hepatitis, hepatomegaly, jaundice X
Rash, pruritus X
Dermatitis, erythema, vitiligo, urticaria, eczema, alopecia, night X sweats, dry skin
Skin and subcutaneous Toxic epidermal necrolysis, leukocytoclastic vasculitis, skin X tissue disorders exfoliation, hair colour changes
Erythema multiforme, psoriasis, drug reaction with eosinophilia X and systemic symptoms (DRESS)
Pemphigoid X
Arthralgia, myalgia, musculoskeletal pain, muscle spasms X Musculoskeletal and Polymyalgia rheumatica, myositis, arthritis, muscular weakness X connective tissue disorders Polymyositis X
Renal failure, glomerulonephritis, autoimmune nephritis, renal Renal and urinary disorders X tubular acidosis, haematuria Proteinuria X
Reproductive system and Amenorrhea X breast disorders
Fatigue, injection site reaction, pyrexia X General disorders and Chills, asthenia, oedema, pain, influenza-like illness X administration site Multi-organ failure, systemic inflammatory response syndrome, conditions X infusion related reaction
Infections and infestations Pneumonia X
Anaemia X
Thrombocytopaenia, lymphopaenia X Blood and lymphatic Neutropaenia, leukopaenia, eosinophilia X system disorders Immune thrombocytopenic purpura, haemolytic anaemia, pure X red cell aplasia, haemophagocytic lymphohistiocytosis
Infusion-related reaction X
Pembrolizumab b Immune system disorders Sarcoidosis X
(Keytruda) [2] Solid organ transplant rejection X
Hypothyroidism X
Endocrine disorders Hyperthyroidism X
Adrenal insufficiency, hypophysitis, thyroiditis X
Decreased appetite X Metabolism and nutrition Hyponatraemia, hypokalaemia, hypocalcaemia X disorders Type 1 diabetes mellitus X
Psychiatric disorders Insomnia X Headache X
Dizziness, neuropathy peripheral, lethargy, dysgeusia X
Nervous system disorders Epilepsy X
Encephalitis, Guillain-Barré syndrome, myelitis, myasthenic X syndrome, meningitis (aseptic)
Dry eye X
Eye disorders Uveitis X
Vogt-Koyanagi-Harada syndrome X
Cardiac arrhythmia (including atrial fibrillation) X
Cardiac disorders Pericardial effusion, pericarditis X
Myocarditis X
Vascular disorders Hypertension X
Respiratory, thoracic and Dyspnoea, cough X
mediastinal disorders Pneumonitis X
Diarrhoea, abdominal pain, nausea, vomiting, constipation X
Colitis, dry mouth X Gastrointestinal disorders Pancreatitis, gastrointestinal ulceration X
Small intestinal perforation X
Hepatobiliary disorders Hepatobiliary disorders X
Rash, pruritus X
Severe skin reactions, erythema, dry skin, vitiligo, eczema, Skin and subcutaneous X alopecia, dermatitis acneiform tissue disorders Lichenoid keratosis, psoriasis, dermatitis, papule, hair colour X changes Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema X nodosum
Musculoskeletal pain, arthralgia X Musculoskeletal and Pain in extremity, myositis, arthritis X connective tissue disorders Tenosynovitis X
Nephritis, acute kidney injury X Renal and urinary disorders Nephritis X
General disorders and Fatigue, asthenia, oedema, pyrexia X
administration site Influenza-like illness, chills X conditions
Upper respiratory tract infection X
Infections and infestations Pneumonia, bronchitis X
Aseptic meningitis X
Neoplasms benign,
malignant and unspecified Histiocytic necrotising lymphadenitis (Kikuchi lymphadenitis) X (including cysts and Nivolumab b polyps) (Opdivo) [3] Neutropaenia X Blood and lymphatic Eosinophilia X system disorders Haemophagocytic lymphohistiocytosis X
Infusion related reaction, hypersensitivity X
Immune system disorders Anaphylactic reaction X
Solid organ transplant rejection, sarcoidosis X Hypothyroidism, hyperthyroidism X
Adrenal insufficiency, hypopituitarism, hypophysitis, thyroiditis, X Endocrine disorders diabetes mellitus
Diabetic ketoacidosis X
Hypoparathyroidism X
Decreased appetite X Metabolism and nutrition Dehydration, metabolic acidosis X disorders Tumour lysis syndrome X
Peripheral neuropathy, headache, dizziness X
Polyneuropathy, autoimmune neuropathy (including facial and X Nervous system disorders abducens nerve paresis)
Guillain-Barré syndrome, demyelination, myasthenic syndrome, X encephalitis
Uveitis, blurred vision, dry eye X Eye disorders Vogt-Koyanagi-Harada syndrome X
Tachycardia, pericardial disorders X
Cardiac disorders Arrhythmia (including ventricular arrhythmia), atrial fibrillation, X myocarditis
Hypertension X Vascular disorders Vasculitis X
Pneumonitis, dyspnoea, cough X Respiratory, thoracic and Pleural effusion X mediastinal disorders Lung infiltration X
Gastrointestinal disorders Diarrhoea, nausea X Colitis, stomatitis, vomiting, abdominal pain, constipation, dry X mouth
Pancreatitis, gastritis X
Duodenal ulcer X
Hepatitis X Hepatobiliary disorders Cholestasis X
Rash, pruritus X
Skin and subcutaneous Vitiligo, dry skin, erythema, alopecia X
tissue disorders Erythema multiforme, psoriasis, rosacea, urticaria X
Toxic epidermal necrolysis, Stevens-Johnson syndrome X
Musculoskeletal pain, arthralgia X
Musculoskeletal and Polymyalgia rheumatica, arthritis X
connective tissue disorders Sjogren’s syndrome, myopathy, myositis (including polymyositis), X rhabdomyolysis
Tubulointerstitial nephritis, renal failure (including acute kidney Renal and urinary disorders X injury)
General disorders and Fatigue X
administration site Pyrexia, oedema (including peripheral oedema) X
conditions Pain, chest pain X
Infections and infestations Urinary tract infection X
Atezolizumab Blood and lymphatic Thrombocytopenia X (Tecentriq) [4] system disorders
Immune system disorders Infusion-related reaction X Hypothyroidism X
Endocrine disorders Hyperthyroidism, diabetes mellitus, adrenal insufficiency X
Hypophysitis X
Metabolism and nutrition Decreased appetite X
disorders Hypokalaemia, hyponatraemia, hyperglycemia X
Nervous system disorders Guillain-Barré syndrome, meningoencephalitis X
Myasthenic syndrome X
Eye disorders Uveitis X
Vascular disorders Hypotension X
Cardiac disorders Myocarditis X
Respiratory, thoracic and Dyspnoea, cough X
mediastinal disorders Pneumonitis, hypoxia, nasal congestion, nasopharyngitis X
Diarrhoea, vomiting, nausea X
Gastrointestinal disorders Abdominal pain, colitis, dysphagia, oropharyngeal pain X
Pancreatitis X
Aspartate aminotransferase increased or alanine aminotransferase Hepatobiliary disorders X increased, hepatitis
Skin and subcutaneous Rash, pruritus X
tissue disorders Psoriasis X
Musculoskeletal and Arthralgia, back pain, musculoskeletal pain X
connective tissue disorders Myositis X
Renal and urinary disorders Nephritis X
Pyrexia, fatigue, asthenia X General disorders and
administration site Influenza like illness, chills X
conditions
Anaemia X Blood and lymphatic Lymphopenia X system disorders Thrombocytopenia, eosinophilia X
Drug hypersensitivity, hypersensitivity anaphylactic reaction, Immune system disorders X Type I hypersensitivity
Hypothyroidism X
Adrenal insufficiency, hyperthyroidism, thyroiditis, autoimmune Endocrine disorders thyroiditis, adrenocortical insufficiency acute, autoimmune X
hypothyroidism, hypopituitarism
Avelumab b, c Metabolism and nutrition Decreased appetite X (Bavencio) [5] disorders Type 1 diabetes mellitus X
Headache, dizziness, neuropathy peripheral X Nervous system disorders Guillain-Barré Syndrome X
Eye disorders Uveitis X
Cardiac disorders Myocarditis X
Hypertension, hypotension X Vascular disorders Flushing X
Respiratory, thoracic and Cough, dyspnoea X
mediastinal disorders Pneumonitis X
Gastrointestinal disorders Nausea, diarrhoea, constipation, vomiting, abdominal pain X Dry mouth X
Colitis, autoimmune colitis, enterocolitis, ileus X
Pancreatitis X
Autoimmune hepatitis, acute hepatic failure, hepatic failure, Hepatobiliary disorders X hepatitis
Rash, pruritus, rash maculo-papular, dry skin X
Rash pruritic, erythema, rash generalized, psoriasis, rash Skin and subcutaneous erythematous, rash macular, rash papular, dermatitis exfoliative, tissue disorders X erythema multiforme, pemphigoid, pruritus generalized, eczema,
dermatitis
Back pain, arthralgia X Musculoskeletal and Myalgia X connective tissue disorders Myositis X
Renal and urinary disorders Tubulo-interstitial nephritis X
General disorders and Fatigue, pyrexia, oedema peripheral X
administrative site Asthenia, chills, influenza like illness X
conditions Systemic inflammatory response syndrome X
Upper respiratory tract infections, pneumonia X Infections and infestations Dental and oral soft tissue infections, oral candidiasis, influenza X
Durvalumabd Hypothyroidism X
(Imfinzi) [6] Hyperthyroidism X Endocrine disorders Adrenal insufficiency, type 1 diabetes mellitus X
Hypophysitis/hypopituitarism, diabetes insipidus X Myasthenia gravis, meningitis X Nervous System Disorders Noninfective encephalitis, Guillain-Barre syndrome X
Cardiac disorders Myocarditis X
Cough/productive cough, pneumonitis X Respiratory, thoracic and Dysphonia X mediastinal disorders Interstitial lung disease X
Diarrhoea, abdominal pain X Gastrointestinal disorders Colitis X
Aspartate aminotransferase increased or alanine aminotransferase Hepatobiliary disorders X increased
Hepatitis X
Rash, pruritus X Skin and subcutaneous Dermatitis, night sweats X tissue disorders Pemphigoid X
Myalgia X Musculoskeletal and Myositis X connective tissue disorders Polymyositis X
Blood creatinine increased, dysuria X Renal and urinary disorders Nephritis X
General disorders and Pyrexia X
administration site Peripheral oedema X conditions
Immune system disorders Infusion-related reaction X Sjogren’s syndrome, immune thrombocytopenic purpura, X vasculitis
Solid organ transplant rejection X
Hypothyroidism, hyperthyroidism X
Endocrine disorders Type 1 diabetes mellitus, adrenal insufficiency, hypophysitis, X thyroiditis
Paraneoplastic encephalomyelitis, chronic inflammatory
demyelinating polyradiculoneuropathy, encephalitis, meningitis, Nervous system disorders X Guillain-Barre syndrome, central nervous system inflammation,
neuropathy peripheral, myasthenia gravis
Eye disorders Keratitis X Cemiplimab Cardiac disorders Myocarditis, pericarditis X (Libtayo) [7] Respiratory, thoracic and Pneumonitis, dyspnoea, X mediastinal disorders
Gastrointestinal disorders Diarrhoea, X
Stomatitis X
Hepatobiliary disorders Hepatitis X
Skin and subcutaneous Rash, pruritus X skin disorders
Arthralgia, musculoskeletal pain, arthritis X Musculoskeletal and Muscular weakness, polymyalgia rheumatica X connective tissue disorders Myositis X
Renal and urinary disorders Nephritis X General disorders and
administration site Fatigue X
conditions a-Patients with advanced melanoma, b-Monotherapy, c-Results from a phase I study in solid tumors, d-Patients with locally advanced unresectable non-small cell lung cancer.
[1] Summary of product characteristics Yervoy. Available online: https://www.ema.europa.eu/en/documents/product-information/yervoy-epar-product-information_en.pdf (accessed on 20 September 2020) [2]Summary of product characteristics Keytruda. Available online: https://www.ema.europa.eu/en/documents/product-information/keytruda-epar-product information_en.pdf (accessed on 20 September 2020) [3] Summary of product characteristics Opdivo. Available online: https://www.ema.europa.eu/en/documents/product-information/opdivo-epar-product-information_en.pdf (accessed on 20 September 2020) [4] Summary of product characteristics Tecentriq. Available online: https://www.ema.europa.eu/en/documents/product-information/tecentriq-epar-product-information_en.pdf (accessed on 20 September 2020) [5] Summary of product characteristics Bavencio. Available online: https://www.ema.europa.eu/en/documents/product-information/bavencio-epar-product-information_en.pdf (accessed on 20 September 2020) [6] Summary of product characteristics Imfinzi. Available online: https://www.ema.europa.eu/en/documents/product-information/imfinzi-epar-product-information_en.pdf (accessed on 20 September 2020) [7] Summary of product characteristics Libtayo. Available online: https://www.ema.europa.eu/en/documents/product-information/libtayo-epar-product-information_en.pdf (accessed on 20 September 2020)