Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Immunotherapy with monoclonal antibodies (MoAbs) targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and the programmed death-1 receptor (PD-1) and its ligand PD-L1 has become standard of care for an increasing number of indications (Table 1). Therefore, an increasing number of patients will be exposed to these drugs with a chance of developing toxicities from these treatments. Depending on the immune checkpoint that is targeted, the incidence of toxicity varies. Toxicities from immune checkpoint inhibitors (ICPis) can be divided into infusion reactions and immune-related adverse events (irAEs) or adverse events of special interest (AEoSI). The latter will be the subject of these Clinical Practice Guidelines. Any organ or tissue can be involved, although some irAEs occur much more commonly than others. The most frequently occurring irAEs affect skin, colon, endocrine organs, liver and lungs. Others are very infrequent, but may be very serious, even lethal, such as neurological disorders and myocarditis.Table 1Approved indications for ICPisDrugIndicationsEMA/FDA approvalIpilimumabMetastatic melanomaEMA + FDAAdjuvant therapy stage III melanomaFDANivolumabMetastatic melanomaEMA + FDA2nd line metastatic NSCLCEMA + FDA2nd line metastatic RCCEMA + FDAClassical Hodgkin’s diseaseaEMA + FDARecurrent or metastatic SCCHNbEMA + FDALocally advanced or metastatic UCCcEMA + FDAPembrolizumabMetastatic melanomaEMA + FDA2nd line metastatic NSCLC (PD-L1 ≥ 1%)EMA + FDA1st line metastatic NSCLC (PD-L1 ≥ 50%)EMA + FDA1st line metastatic NSCLC in combination with pemetrexed + carboplatinFDAClassical Hodgkin’s diseaseEMAa + FDAdLocally advanced or metastatic UCCcFDAMSI-H or MMR deficient metastatic malignancieseFDAAtezolizumabLocally advanced or metastatic UCCcFDA2nd line metastatic NSCLCFDAAvelumabLocally advanced or metastatic UCCcFDAMetastatic Merkel cell carcinomaFDADurvalumabLocally advanced or metastatic UCCcFDAIpilimumab + nivolumabMetastatic melanomaEMA + FDAaFor the treatment of patients with cHL who have relapsed or progressed after auto-HSCT and post-transplantation brentuximab vedotin. bFor the treatment of patients with recurrent or metastatic SCCHN with disease progression on or after platinum-based therapy. cFor patients with locally advanced or metastatic UCC who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. dFor the treatment of adult and pediatric patients with cHL who are refractory or have relapsed after 3 or more lines of therapy. eFor adult and paediatric patients with unresectable or metastatic, MSI-H or dMMR that have progressed following prior treatment and who have no satisfactory alternative treatment options or with MSI-H or dMMR CRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.Auto-HSCT, autologous hematopoietic stem cell transplantation; cHL, classic Hodgkin’s lymphoma; CRC, colorectal cancer; dMMR, deficient MMR; EMA, European Medicines Agency; FDA, Food and Drug Administration; ICPi, immune checkpoint inhibitor; MMR, DNA mismatch repair; MSI-H; microsatellite instability-high; NSCLC, non-small-cell lung cancer; PD-L1, programmed death ligand 1; RCC, renal cell carcinoma; SCCHN, squamous cell carcinoma of the head and neck; UCC, urothelial carcinoma. Open table in a new tab aFor the treatment of patients with cHL who have relapsed or progressed after auto-HSCT and post-transplantation brentuximab vedotin. bFor the treatment of patients with recurrent or metastatic SCCHN with disease progression on or after platinum-based therapy. cFor patients with locally advanced or metastatic UCC who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. dFor the treatment of adult and pediatric patients with cHL who are refractory or have relapsed after 3 or more lines of therapy. eFor adult and paediatric patients with unresectable or metastatic, MSI-H or dMMR that have progressed following prior treatment and who have no satisfactory alternative treatment options or with MSI-H or dMMR CRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Auto-HSCT, autologous hematopoietic stem cell transplantation; cHL, classic Hodgkin’s lymphoma; CRC, colorectal cancer; dMMR, deficient MMR; EMA, European Medicines Agency; FDA, Food and Drug Administration; ICPi, immune checkpoint inhibitor; MMR, DNA mismatch repair; MSI-H; microsatellite instability-high; NSCLC, non-small-cell lung cancer; PD-L1, programmed death ligand 1; RCC, renal cell carcinoma; SCCHN, squamous cell carcinoma of the head and neck; UCC, urothelial carcinoma. irAEs from ipilimumab, anti-CTLA4, at a dose of 3 mg/kg, have been documented to occur in 60%–85% of patients [1.Hodi F.S. O'Day S.J. McDermott D.F. et al.Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med. 2010; 363: 711-723Crossref PubMed Scopus (11264) Google Scholar, 2.Larkin J. Chiarion Sileni V. Gonzalez R. et al.Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.N Engl J Med. 2015; 373: 23-34Crossref PubMed Scopus (5160) Google Scholar], mostly grades 1 and 2, but between 10% and 27% of patients develop grade 3 to 4 toxicities, and 2.1% ipilimumab-related deaths have been reported in the first phase III trial [1.Hodi F.S. O'Day S.J. McDermott D.F. et al.Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med. 2010; 363: 711-723Crossref PubMed Scopus (11264) Google Scholar]. The onset of these toxicities varies but usually starts within the first 8 to 12 weeks of initiation of treatment [an example of onset of adverse events (AEs) upon ipilimumab treatment is depicted in Figure 1], with skin toxicities often being the first to develop. These toxicities are dose-dependent as no grade 3 to 4 AEs were observed at a dose of 0.3 mg/kg ipilimumab, whereas these toxicities increased to 30% with a dose of 10 mg/kg [3.Wolchok J.D. Neyns B. Linette G. et al.Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study.Lancet Oncol. 2010; 11: 155-164Abstract Full Text Full Text PDF PubMed Scopus (945) Google Scholar]. In the adjuvant setting with ipilimumab 10 mg/kg followed by a maintenance dose, the recorded grade 3 to 4 irAE rate was 41.6%, and the grade 5 irAE rate 1.1% [4.Eggermont A.M. Chiarion Sileni V. Grob J.J. et al.Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy.N Engl J Med. 2016; 375: 1845-1855Crossref PubMed Scopus (966) Google Scholar]. The most frequently reported AE with anti-PD-1/PD-L1 is fatigue. Incidence of fatigue, of which the pathogenesis is poorly understood, across single drug studies, is 16%-37% for anti-PD-1 and 12%-24% for anti-PD-L1 [5.Naidoo J. Page D.B. Li B.T. et al.Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies.Ann Oncol. 2015; 26: 2375-2391Abstract Full Text Full Text PDF PubMed Scopus (917) Google Scholar]. Only in a minority of patients fatigue can be attributed to hypothyroidism. High-grade toxicities from anti-PD-1 (either nivolumab or pembrolizumab) are less common than for the CTLA4 blocking agent ipilimumab. For nivolumab, any treatment-related AE was documented in 74%–85% of patients, with 12%–20% being grade 3 and 4 [2.Larkin J. Chiarion Sileni V. Gonzalez R. et al.Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.N Engl J Med. 2015; 373: 23-34Crossref PubMed Scopus (5160) Google Scholar, 6.Robert C. Long G.V. Brady B. et al.Nivolumab in previously untreated melanoma without BRAF mutation.N Engl J Med. 2015; 372: 320-330Crossref PubMed Scopus (4054) Google Scholar, 7.Weber J.S. Hodi F.S. Wolchok J.D. et al.Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma.J Clin Oncol. 2017; 35: 785-792Crossref PubMed Scopus (747) Google Scholar] for metastatic melanoma patients, 58% and 7%, respectively, for advanced cisplatin refractory squamous non-small-cell lung cancer (NSCLC) [8.Brahmer J. Reckamp K.L. Baas P. et al.Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer.N Engl J Med. 2015; 373: 123-135Crossref PubMed Scopus (6280) Google Scholar], 69% and 10%, respectively, for metastatic cisplatin refractory non-squamous NSCLC [9.Borghaei H. Paz-Ares L. Horn L. et al.Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.N Engl J Med. 2015; 373: 1627-1639Crossref PubMed Scopus (6821) Google Scholar] and 79% and 19%, respectively, for tyrosine kinase inhibitor refractory metastatic renal cell carcinoma [10.Motzer R.J. Escudier B. McDermott D.F. et al.Nivolumab versus everolimus in advanced renal-cell carcinoma.N Engl J Med. 2015; 373: 1803-1813Crossref PubMed Scopus (4154) Google Scholar]. For pembrolizumab, the Keynote-002 study, comparing pembrolizumab at doses of 2 and 10 mg/kg to chemotherapy in ipilimumab pre-treated metastatic melanoma, showed grade 1 to 2 irAEs in 57%–60% and grade 3 to 4 toxicity in 14% of patients [11.Ribas A. Puzanov I. Dummer R. et al.Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial.Lancet Oncol. 2015; 16: 908-918Abstract Full Text Full Text PDF PubMed Scopus (1230) Google Scholar]. In the Keynote-006 study comparing pembrolizumab, given at 10 mg/kg either every 3 or 2 weeks, to ipilimumab, treatment-related toxicity was observed in 73%–80% of patients, with 10%–13.5% having grade 3 or higher AEs [12.Robert C. Schachter J. Long G.V. et al.Pembrolizumab versus ipilimumab in advanced melanoma.N Engl J Med. 2015; 372: 2521-2532Crossref PubMed Scopus (4075) Google Scholar]. In a similar design to the Keynote-002, the Keynote-010 study in cisplatin refractory NSCLC patients compared pembrolizumab (2 mg/kg) and pembrolizumab (10 mg/kg) with docetaxel. The reported treatment-related AEs for the pembrolizumab-treated groups were 63% and 66% for any AE, and 13% and 16% for grade 3 to 4 toxicities, respectively [13.Herbst R.S. Baas P. Kim D.W. et al.Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.Lancet. 2016; 387: 1540-1550Abstract Full Text Full Text PDF PubMed Scopus (4582) Google Scholar]. In the Keynote-024 study pembrolizumab given at 200 mg flat dose every 3 weeks was compared with cisplatin-based chemotherapy as first-line treatment in metastatic NSCLC patients (tumour PD-L1 expression ≥ 50%). Treatment-related toxicity was reported in 73.4% (any AE) and 26.6% of patients with a grade 3 or higher AE [14.Reck M. Rodríguez-Abreu D. Robinson A.G. et al.Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.N Engl J Med. 2016; 375: 1823-1833Crossref PubMed Scopus (6288) Google Scholar]. Combination immunotherapy has only been approved for patients with metastatic melanoma. Treatment-related AEs were observed in 95% of patients. In 55% of patients these AEs were of grade 3 or higher [2.Larkin J. Chiarion Sileni V. Gonzalez R. et al.Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.N Engl J Med. 2015; 373: 23-34Crossref PubMed Scopus (5160) Google Scholar]. The onset of grade 3 to 4 toxicities for either monotherapy with nivolumab or combination immunotherapy differs, as irAEs not only may develop earlier in combination therapy but also may start over a prolonged period of time (Figure 2). In general, irAEs occur quite early, mostly within weeks to 3 months after initiation of immune checkpoint blockers. However, the first onset of irAEs has been documented as long as 1 year after discontinuation of treatment. The role of tissue biopsy in the diagnosis of immune-therapy related toxicity is not established. Some recommendations suggest tissue biopsy in higher grade (3 and 4) toxicity [skin, gastroinstestinal (GI), liver, kidney, lung] where there is diagnostic doubt about the aetiology of the complication and management would be altered by the outcome of the biopsy procedure [15.Eigentler T.K. Hassel J.C. Berking C. et al.Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD-1 antibody therapy.Cancer Treat Rev. 2016; 45: 7-18Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar]. In general, when biopsy is carried out in such circumstances, the reporting pathologist must be apprised of the specific reasons for the biopsy procedure. Before starting treatment, patients should be assessed in terms of susceptibility to develop irAEs. This includes a work-up consisting of patient history (and family history), general physical condition, autoimmune diseases, baseline laboratory tests and radiological exams (Supplementary Table S1, available at Annals of Oncology online) [mostly computed tomography (CT) scans of the chest, abdomen/pelvis and often brain magnetic resonance imaging (MRI)]. Patients with a history of autoimmune disease, or who are being actively treated for an autoimmune disease, are at risk for worsening of their autoimmune disease while on immune checkpoint blockade [16.Menzies A.M. Johnson D.B. Ramanujam S. et al.Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab.Ann Oncol. 2017; 28: 368-376Abstract Full Text Full Text PDF PubMed Scopus (550) Google Scholar]. Similarly, patients that have had irAEs on ipilimumab are at risk of developing irAEs following anti-PD-1 treatment and vice versa [16.Menzies A.M. Johnson D.B. Ramanujam S. et al.Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab.Ann Oncol. 2017; 28: 368-376Abstract Full Text Full Text PDF PubMed Scopus (550) Google Scholar, 17.Bowyer S. Prithviraj P. Lorigan P. et al.Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy.Br J Cancer. 2016; 114: 1084-1089Crossref PubMed Scopus (96) Google Scholar]. Results from these retrospective series showed a higher rate of grade 3 to 4 toxicity in patients treated with ipilimumab following anti-PD-1 (up to 35%) and patients with grade 3 to 4 toxicity on ipilimumab followed by anti-PD-1 developed grade 3 to 4 irAEs in > 20% of cases. The time between last dose of first drug and initiation of the second drug, however, may be important, considering the long half-lives of these MoAbs. Patients should be informed of the potential AEs of immunotherapy before treatment initiation. In all cases, patients should report directly to the treating physician or team (nurse, nurse practitioner, physician). Once irAEs have developed, prompt work-up is required and action should be taken to prevent further aggravation of AEs, In many cases, especially the most severe, immunotherapy should be discontinued and immunosuppressive or immune modulating drugs including high-dose corticosteroids, and sometimes tumour necrosis factor alpha (TNFα) antagonists, mycophenolate or tacrolimus, are needed to overcome these toxicities, followed by careful tapering of immunosuppression. Long-term (> 6 weeks) treatment with immunosuppressive drugs or use of infliximab increases the chance of opportunistic infections; therefore, pneumocystis prophylaxis should be considered according to local guidelines. Importantly, so far there is no evidence that the clinical outcome of patients on ICPis is affected by the use of immunosuppressive agents for the management of immune-related toxicities [7.Weber J.S. Hodi F.S. Wolchok J.D. et al.Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma.J Clin Oncol. 2017; 35: 785-792Crossref PubMed Scopus (747) Google Scholar, 18.Horvat T.Z. Adel N.G. Dang T.O. et al.Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center.J Clin Oncol. 2015; 33: 3193-3198Crossref PubMed Scopus (713) Google Scholar]. Skin AEs are among the most frequent AEs observed by patients treated with MoAbs inhibiting either immune checkpoints CTLA4 (ipilimumab in 43%–45% of the patients) or PD-1 (nivolumab and pembrolizumab in ∼34%) [1.Hodi F.S. O'Day S.J. McDermott D.F. et al.Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med. 2010; 363: 711-723Crossref PubMed Scopus (11264) Google Scholar, 3.Wolchok J.D. Neyns B. Linette G. et al.Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study.Lancet Oncol. 2010; 11: 155-164Abstract Full Text Full Text PDF PubMed Scopus (945) Google Scholar, 19.Lacouture M.E. Wolchok J.D. Yosipovitch G. et al.Ipilimumab in patients with cancer and the management of dermatologic adverse events.J Am Acad Dermatol. 2014; 71: 161-169Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, 20.Belum V.R. Benhuri B. Postow M.A. et al.Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor.Eur J Cancer. 2016; 60: 12-25Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar] and usually develop early in the course of treatment (within the first few weeks after initiation). However, serious skin AEs are rare and do not usually require dose reductions or treatment discontinuation. One immune-related skin AE, vitiligo, seems to be associated with good clinical responses to anti-PD-1 MoAbs in patients treated for melanoma [21.Hua C. Boussemart L. Mateus C. et al.Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab.JAMA Dermatol. 2016; 152: 45-51Crossref PubMed Scopus (457) Google Scholar]. The most frequent skin AEs are rash, pruritus and vitiligo, but the latter is seen mostly in patients treated for melanoma [20.Belum V.R. Benhuri B. Postow M.A. et al.Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor.Eur J Cancer. 2016; 60: 12-25Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar]. Rash is reported in ∼24% of the patients treated with ipilimumab, in ∼15% of those receiving anti-PD-1 MoAbs and in 40% with the combination of ipilimumab and nivolumab. However, grade 3 or 4 rashes are rare, with an incidence of < 3% with monotherapy ipilimumab or anti-PD-1 and < 5% with the combination [2.Larkin J. Chiarion Sileni V. Gonzalez R. et al.Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.N Engl J Med. 2015; 373: 23-34Crossref PubMed Scopus (5160) Google Scholar, 22.Boutros C. Tarhini A. Routier E. et al.Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination.Nat Rev Clin Oncol. 2016; 13: 473-486Crossref PubMed Scopus (672) Google Scholar]. Pruritus is reported in around 25%–35% of the cases with ipilimumab, 13%–20% with anti-PD-1 and 33% with the combination, but reaches a grade 3 and 4 in < 2.5% [22.Boutros C. Tarhini A. Routier E. et al.Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination.Nat Rev Clin Oncol. 2016; 13: 473-486Crossref PubMed Scopus (672) Google Scholar]. Vitiligo is reported in about 8% of patients with melanoma treated with anti-PD-1 MoAbs [20.Belum V.R. Benhuri B. Postow M.A. et al.Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor.Eur J Cancer. 2016; 60: 12-25Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar] or with the combination of checkpoint inhibitors, but is more rarely reported with ipilimumab alone. In a small prospective study, vitiligo was found in up to 25% of patients treated with pembrolizumab [21.Hua C. Boussemart L. Mateus C. et al.Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab.JAMA Dermatol. 2016; 152: 45-51Crossref PubMed Scopus (457) Google Scholar]. It is likely that the incidence is underreported in clinical trials, due to the fact that patients are not routinely seen and systematically subjected to a full-body skin exam by a dermatologist. In this study, the occurrence of vitiligo was significantly associated with the clinical response to the drug. Development of vitiligo is predominantly observed in melanoma patients treated with ICPis but not in NSCLC or renal cancer. More rarely, other skin AEs have been reported with checkpoint inhibitors: alopecia areata, stomatitis, xerosis cutis and photosensitivity. Exacerbation of psoriasis has also been anecdotally reported with these drugs, as well as psoriasiform or lichenoid skin reactions in patients without any history of such skin disease [19.Lacouture M.E. Wolchok J.D. Yosipovitch G. et al.Ipilimumab in patients with cancer and the management of dermatologic adverse events.J Am Acad Dermatol. 2014; 71: 161-169Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, 23.Sibaud V. Meyer N. Lamant L. et al.Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies.Curr Opin Oncol. 2016; 28: 254-263Crossref PubMed Scopus (174) Google Scholar]. Histopathologically, skin reactions may be categorised into four broad groups [24.Curry J.L. Tetzlaff M.T. Nagarajan P. et al.Diverse types of dermatologic toxicities from immune checkpoint blockade therapy.J Cutan Pathol. 2017; 44: 158-176Crossref PubMed Scopus (154) Google Scholar]:•Inflammatory skin disorders, which comprise a range of changes reflecting acute, subacute or chronic inflammation of various patterns, associated with variable epidermal changes, including psoriasiform or lichenoid reactions. A lichenoid interface chronic dermatitis is a common finding [25.Shi V.J. Rodic N. Gettinger S. et al.Clinical and histologic features of lichenoid mucocutaneous eruptions due to anti-programmed cell death 1 and anti-programmed cell death ligand 1 immunotherapy.JAMA Dermatol. 2016; 152: 1128-1136Crossref PubMed Scopus (152) Google Scholar, 26.Tetzlaff M.T. Nagarajan P. Chon S. et al.Lichenoid dermatologic toxicity from immune checkpoint blockade therapy. A detailed examination of the clinicopathologic features.Am J Dermatopathol. 2017; 39: 121-129Crossref PubMed Scopus (78) Google Scholar]•Immunobullous skin lesions akin to dermatitis herpetiformis or bullous pemphigoid•Keratinocyte alteration—Grover’s disease [27.Uemura M. Faisal F. Haymaker C. et al.A case report of Grover's disease from immunotherapy-a skin toxicity induced by inhibition of CTLA-4 but not PD-1.J Immunother Cancer. 2016; 4: 55Crossref PubMed Scopus (41) Google Scholar]/acantholytic dyskeratosis•Immune-reaction mediated by alteration of melanocytes (regression of nevi, prurigo nodularis, tumoural melanosis and vitiligo). When a patient treated with a checkpoint inhibitor presents with a skin AE, the first requirement is ruling out any other aetiology of the skin problem, such as an infection, an effect of another drug or a skin condition linked to another systemic disease. Next, the severity of the skin AE needs to be evaluated by a careful and thorough physical examination of the skin including the mucosal areas, an appreciation of the general patient status (fever, enlarged lymph nodes etc.), and if needed, a biological checkup including a blood cell count, liver and kidney tests. This will help to eliminate the possibility of a dermatological emergency such as drug rash with eosinophilia and systemic symptoms (DRESS), acute febrile neutrophilic dermatosis (Sweet syndrome), Stevens-Johnson syndrome or toxic epidermal necrolysis (TEN). In such life-threatening cases (fatal cases have already been described), the treatment with checkpoint inhibitor(s) should be permanently discontinued, the patient should be hospitalised, and symptomatic treatment should be initiated immediately by a dermatologist or at a specialised dermatology unit. To gauge the severity of the skin AE, the Common Terminology Criteria for Adverse Events (CTCAE) classification is usually used. Concerning a maculopapular rash, the most frequent event with checkpoint inhibitors, the fourth version of the CTCAE classification proposes:•Grade 1: macules/papules covering < 10% the body surface area (BSA) with or without symptoms (e.g. pruritus, burning, tightness)•Grade 2: macules/papules covering 10%–30% BSA with or without symptoms (e.g. pruritus, burning, tightness); limiting instrumental activities of daily living (ADL)•Grade 3: macules/papules covering > 30% BSA with or without associated symptoms; limiting selfcare ADL•Grade 4: papulopustular rash associated with life-threatening superinfection; Stevens-Johnson syndrome, TEN and bullous dermatitis covering > 30% of BSA and requiring intensive care unit (ICU) admission. The relation with impairment in instrumental or selfcare ADL seems appropriate to evaluate the severity of the AE as well as its impact on the patient’s life. However, the fact that when > 30% BSA is involved, the rash is automatically graded 3, is subject to discussion. Indeed, when the rash is diffuse but light and not associated with any additional symptoms, a grade 2 would seem more appropriate than grade 3. The fifth version of the CTCAE classification will give a more appropriate classification for skin AEs. For grade 1 skin AEs such as rash and/or pruritus, treatment with checkpoint inhibitors can be continued (see Figures 3 and 4). Symptoms can be treated with topical emollients, oral antihista-mines and/or mild strength topical corticosteroids. In the case of grade 2 skin AEs, treatment with checkpoint inhibitors can be continued but should be checked weekly for improvement. If not resolved, treatment should be interrupted until the skin AE has reverted to grade 1. Symptomatic treatment consists of topical emollients, oral antihistamines and median-to-high strength topical steroids. Grade 3 skin AEs also require immediate interruption of checkpoint inhibition, until these are back to grade 1. Treatment includes topical emollients, oral antihistamines and high strength topical steroids [II, B]. Systemic corticosteroids 0.5–1 mg/kg can be considered, depending on the severity of the symptoms. In the rare event of grade 4 skin toxicity, treatment with checkpoint inhibitors should be interrupted, and patients should be admitted immediately and be placed under supervision of a dermatologist. Treatment consists of intravenous (i.v.) (methyl)prednisolone 1–2 mg/kg with tapering when the toxicity resolves to normal [II, B].Figure 4Schematic of body surface area (BSA).View Large Image Figure ViewerDownload Hi-res image Download (PPT) Although thyroid gland disorders have been observed quite frequently in patients treated with immunotherapies such as cytokines interleukin-2 and type I interferons, their incidence has increased considerably since the introduction of ICPis. Both hyper- and hypothyroidism have been reported, although hypothyroid disorders are more common than hyperthyroidism. The latter is often transient and may precede hypothyroidism. Still, little is known about the pathogenesis of thyroid disorders following ICPis. It is thought to be mediated by T cells and not by B cell autoimmunity. Recently, a cohort of 51 NSCLC patients treated with pembrolizumab in the Keynote-001 study was prospectively followed by thyroid-stimulating hormone (TSH), triiodothyronine and thyroxine (FT3, FT4) and anti-thyroid antibodies (Abs) measurement [28.Osorio J.C. Ni A. Chaft J.E. et al.Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer.Ann Oncol. 2017; 28: 583-589Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar]. The incidence of thyroid dysfunction requiring thyroid hormone replacement was 21% (in 80% of these patients, anti-thyroid Abs were detected), compared with 8% in patients that did not develop thyroid dysfunction. These results suggest that the pathogenesis of autoimmune thyroid disease and thyroid gland dysfunction as irAEs might have a similar pathogenesis. Thyroid dysfunction is most common upon treatment with anti-PD-1/PD-L1 or combination of anti-CTLA4 and agents blocking the PD-1/PD-L1 axis. With ipilimumab (3 mg/kg), the incidence was reported to be between 1% and 5% [1.Hodi F.S. O'Day S.J. McDermott D.F. et al.Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med. 2010; 363: 711-723Crossref PubMed Scopus (11264) Google Scholar, 2.Larkin J. Chiarion Sileni V. Gonzalez R. et al.Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.N Engl J Med. 2015; 373: 23-34Crossref PubMed Scopus (5160) Google Scholar], but higher incidence (up to 10%) has been observed with the higher doses of ipilimumab (10 mg/kg) [4.Eggermont A.M. Chiarion Sileni V. Grob J.J. et al.Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy.N Engl J Med. 2016; 375: 1845-1855Crossref PubMed Scopus (966) Google Scholar]. With anti-PD-1 (either pembrolizumab or nivolumab) or anti-PD-L1 (atezolizumab) therapy, the reported thyroid dysfunction rate varies from 5% to 10% (irrespective of tumour type) [6.Robert C. Long G.V. Brady B. et al.Nivolumab in previously untreated melanoma without BRAF mutation.N Engl J Med. 2015; 372: 320-330Crossref PubMed Scopus (4054) Google Schola