Safety of immune checkpoint inhibitors (ICIs) is a currently unsettled issue in clinical practice, requiring multidisciplinary expertise and heterogeneous skills of oncologists to early diagnose and timely manage immune-related adverse events (irAEs). |
In the recent past, a plethora of real-world pharmacovigilance studies have characterized epidemiological features of irAEs, namely spectrum, kinetics, co-reporting, and fatality rate. |
Considering the agnostic approval and evolving uses of different ICIs, including drug combination with targeted therapy, pharmacovigilance still plays a pivotal role in the postmarketing assessment of irAEs, thus supporting oncologists in optimal management. |
1 Introduction
2 Pharmacovigilance in Oncology: Challenges and Opportunities
3 Disproportionality Analysis: A Primer for Oncologists
Domain of clinical relevance | Concepts and proposal | Points to be considered | Specific issues for immunotherapy |
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Scientific rationale | The scientific basis must be clearly described (see text) | Timeliness is a requisite: hypothesis raised by DA to be tested by subsequent analytical pharmacoepidemiological studies | Avoid overlapping studies (redundant publication) on the same topic, unless there are key differences in the analyses (e.g. updated information in terms of events and drugs of interest) |
Choice of denominator | Usually, the entire database is used as a screening strategy to map the safety profile | Additional control drugs may be used to support the robustness of disproportionality, but the choice is arbitrary and debated | Disproportionality by therapeutic area or versus specific drug class (anti-CTLA-4 vs. anti-PD-1/PD-L1) provides clues on intraclass comparison, but distortions remain (channeling bias or confounding by disease-specific factors) |
Case definition | This aspect should be clearly defined by providing a dedicated material with search strategy for case identification | Usually, analyses are performed in terms of PTs, which can be combined to obtain the so-called SMQs | No specific definition (and reporting) in pharmacovigilance of irAEs or dedicated SMQ. Therefore, possibility of reporting false positives (e.g. pneumonitis) |
Use of case-by-case analysis | It may per se be used for standalone signal detection or may complement DA | No single method is universally accepted for causality assessment and there is no gold standard | A key added value, by characterizing spectrum, timing, and outcomes of irAEs |
Bias identification and minimization | The potential existence of biases must be a priori conceived (depending on the drug and events under investigation) | There are three sources of bias: (1) the drug-event reporting; (2) the nature of SRS; and (3) the high variability of event reporting | Indication and channeling bias are likely to occur and relevant minimization strategies should be considered; notoriety and competition bias are unlikely to occur (no specific warnings or media attention on a single irAE) |
Interpretation | Disproportion per se is not an estimate of risk; disproportionality may approach the relative risk estimate only under stringent criteria (no reporting biases and confounders) | Disproportionalities are interdependent (consider existence of competition bias and other sources of confounding) Inverse causality is highly debated | Avoid terms such as ‘association’, ‘risk’, and ‘incidence’. Avoid specific clinical recommendations in terms of risk rankings and identification of safe drugs. Higher/increased reporting can be used |
4 Methods
5 Results
Authors (year); database | Toxicity (irAEs) | Main disproportionality findings | Relative frequency (reporting proportion)a | Fatality rate | Comments/notes |
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Zhai et al. (2019); FAERS [36] | Endocrinopathies | Higher reporting with anti-CTLA-4 (vs. anti-PD-1/PD-L1), combo vs. mono, hypothyroidism and hyperthyroidism with anti-PD-1, ipilimumab and hypophysitis, combo with adrenal insufficiency | 8.6% (overall), 1.2% (hypothyroidism), 1% (adrenal insufficiency), 0.9% (hypophysitis), 0.7% (hyperthyroidism), 0.5% (diabetes mellitus) | 9.6% | Overreporting with anti-CTLA-4 monotherapy, males, NSCLC, combination; hypo/hyperthyroidism especially with anti-PD-1 and combination; adrenal insufficiency and hypophysitis with ipilimumab and combination |
Bai et al. (2020); Vigibase [37] | Thyroid dysfunction | Higher reporting of hypothyroidism, hyperthyroidism, and thyroiditis (anti-PD-1 and combo), thyrotoxic crisis with combo | 3.8% (overall), 1.8% (hypothyroidism), 1.5% (hyperthyroidism) | 0.15% (hyperthyroidism), 0.62% (thyroiditis), 0.93% (hypothyroidism), 20% for thyrotoxic crisis) | Hypo-/hyperthyroidism, and thyroiditis overreported for anti-PD-1 drug monotherapy. TTO = 46, 63, 92 combination, anti-CTLA-4, anti-PD-1, respectively). Recovered/resolved 60–78% |
Johnson et al. (2019); Vigibase [38] | Neurologic toxicity | Higher reporting of myasthenia gravis, non-infectious encephalitis/myelitis with anti-PD-1/PD-L1; Guillain–Barre syndrome and non-infectious meningitis with anti-CTLA-4. Higher reporting with combo (except myasthenia gravis) | 1.16% (peripheral neuropathy); 0.51% (noninfectious encephalitis and/or myelitis; 0.47% (myasthenia gravis); 0.15% (noninfectious meningitis) | 19.3% (myasthenia gravis); 13.2% (noninfectious encephalitis and/or myelitis) | TTO = 29 for myasthenia gravis, 61–80 for other events. Myasthenia gravis frequently overlapped with myocarditis/myositis, with a 62.5% mortality rate |
Salem et al. (2018); Vigibase [34] | Cardiovascular toxicity | Higher reporting of myocarditis, pericardial diseases, supraventricular arrhythmias, vasculitis (temporal arteritis, polymyalgia rheumatic) | 0.4% (myocarditis), 0.3% (pericardial diseases, vasculitis) | 50% (myocarditis), 21% (pericardial disease), 6% (vasculitis) | TTO = 30 (myocarditis, pericardial disease), 55 (vasculitis). Myocarditis overreported with anti-PD-1/PD-L1, and combo; pericardial diseases with anti-PD-1/PD-L1; vasculitis with anti-CTLA-4 |
Fan et al. (2019); FAERS [39] | Myocarditis | Higher reporting for all ICI monotherapies and two ICI combos | 0.7% | 51% (66% in combination) | TTO = 23, earlier for combination vs. monotherapy (16.5 vs. 32) |
Ederhy et al. (2019); Vigibase [55] | TTS | Higher reporting of TTS, especially with ipilimumab and pembrolizumab | 0.03% | 13% (1 patient) | 1333 cases of stress cardiomyopathy; TTO = 6 (median) and 76 (mean); no cases in combo; use of positive (venlafaxine/adrenaline) and negative (paracetamol) controls; 3 patients did not recover |
Nguyễn et al. (2020); Vigibase [56] | Myositis | Higher reporting with anti-PD-1/PD-L1 (vs. anti-CTLA-4) and combo; no myasthenia cases with anti-CTLA-4 | 0.6% (345 cases) | 22.3% (51.3% with myocarditis) | Median TTO = 33; 95% serious; myocarditis and myasthenia in 11.3% and 11.9%, respectively |
Oshima et al. (2018); FAERS [43] | IP | Higher proportion of IP in nivolumab + EGFR TKIs | 20,516 patients with NSCLC; 985 IP cases (18 exposed to nivolumab + EGFR TKIs) | NA | The statistically significant interaction effect supported the existence of the interaction |
Aggarwal (2019); FAERS [40] | BP | Consistent signal of BP across analyses | 37 cases with pembrolizumab, 81 with nivolumab | 7.4% (nivolumab), 2.7% (pembrolizumab) | Also literature review of case reports. Drug withdrawal in > 50% Heat map confirming and detecting signals of SJS, TEN (pembrolizumab), TEN (nivolumab) |
Jimenez et al. (2020); FAERS [57] | BDs | Signals of BDs for anti-PD-1/PD-L1, except avelumab | 99 cases with nivolumab, 43 with pembrolizumab | NA | Pemphigoid, pemphigus, and bullous dermatitis were searched linked to serious outcome |
Fang et al. (2019); FAERS [41] | Ocular AEs | Uveitis with ipilimumab, nivolumab, pembrolizumab; ocular myasthenia with nivolumab (three cases) | NA | NA | 113 ocular AEs; 68 with nivolumab |
Ali and Watson (2017); FAERS [42] | irAEs | Colitis and pneumonitis (ipilimumab and nivolumab), pneumonitis and hepatitis (pembrolizumab), endocrinopathies (all ICIs) | 2.6% (1.5% colitis, 0.5% endocrinopathies, 0.3% pneumonitis, hepatitis, 0.1% nephritis) | 18.8% (26% pembrolizumab) | TTO = 76 days (180 for nivolumab); 45.5% no concomitant drugs, except nivolumab (74% ≥ 4 drugs); 46% monotherapy; on average, irAEs persisted for 26 days after stopping ICI. 77% hospitalization |
Ji et al. (2019); FAERS [16] | irAEs | Pneumonitis, hypothyroidism, myocarditis, autoimmune hemolytic anemia for anti-PD-1; colitis, hypophysitis, adrenal insufficiency with anti-CTLA-4 | 1.05% (hypothyroidism), 0.92% (pneumonitis), 0.62% (colitis), 0.20% (hepatitis), 0.15% (myocarditis, encephalitis, myasthenia gravis), 0.14% hypophysitis | 29% (overall) | Analyses at PT and SMQ levels. Rash and hepatitis at similar rate; combo higher rate vs. monotherapy |
Raschi et al. (2019); FAERS [17] | irAEs | Pneumonitis, hypothyroidism, cholangitis, tumor pseudoprogression, and inappropriate schedule of drug administration for anti-PD-1; hypophysitis, adrenal insufficiency, hypopituitarism, and prescribed overdose with anti-CTLA-4 | 2.7% (pneumonitis), 1.6% (hypothyroidism), 1.3% (hypophysitis), 1.0% adrenal insufficiency), 0.9% (hepatitis) | 29% (overall) | Also overview of systematic review to identify toxicity priorities. No increased reporting with combination regimens. Overlap in co-reporting of endocrine, hepatobiliary, and respiratory irAEs. Also signal of potential lack of efficacy |
Authors (year); database | Toxicity (irAEs) | Fatality rate | Onset (days) | Comments/notes |
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Wang et al. (2018); Vigibase [33] | Fatal irAEs | 2% (613/31,059) 39.7% (myocarditis); 5% (colitis); 3.7% (adrenal insufficiency); 2% (hypophysitis) | 40; 40; 14.5 (ipilimumab, anti-PD-1/PD-L1, combination; Vigibase + multicenter data) | Colitis/diarrhea (70%) for anti-CTLA-4; pneumonitis (35%), hepatitis (22%) for anti-PD-1/PD-L1 monotherapy; colitis (37%), myocarditis (25%) hepatitis (22%) for combination Fatality rates: 17% (myositis), ≈ 15% (pneumonitis, hepatitis, hematological), ≈ 10% (neurological, nephritis) Myositis and myocarditis frequently co-occurred |
Raschi et al. (2019); FAERS [9] | SCARs | 2.6% (1 case), 18%, and 36% (DRESS, SJS and TEN, respectively; > 70% for TEN in subjects aged 40–59 years | Mean TTO = 46 (47 for SJS, 48 for TEN, and 40 for DRESS), 41 for combo, 45 for anti-PD-1/PD-L1, and 65 for anti-CTLA-4 | 191 SCAR cases (4618 cutaneous; SJS = 96, TEN = 66, DRESS = 39). Allopurinol and antiepileptics in 17% (10% for other anticancer drugs) Longest recorded latencies were 251, 197, and 164 (SJS, TEN, and DRESS, respectively) Also DA on cutaneous events (bullous dermatoses, especially pemphigoid, mainly reported with anti-PD-1/PD-L1) |
Anquetil et al. (2018); Vigibase [44] | Myositis | 21%; Higher with combo vs. monotherapy: 38.5% vs. 18.1%; higher in patients with concomitant myocarditis: 51.7% vs. 14.9% | Median TTO = 26 (data for 61 patients) | 180 cases (myocarditis = 29; myasthenia-like disorder = 28), 85% monotherapy Overlap with myocarditis and myasthenia gravis-like symptoms in 16% |
Wright et al. (2018); Vigibase [45] | DM | 2.8% | Median TTO = 116 (69% developed DM while receiving therapy or within 1 month after cessation, 22% developed DM between 1 and 3 months later, and 9% developed DM more than 3 months after stopping drug | 283 cases of new-onset DM (52.7% nivolumab); 17% combination; 50% with DKA; 5.6%; on corticosteroids at diagnosis; death 2.8% Maximum duration from cessation of therapy to DM onset was 247 days Co-occurrence in 21% (endocrine 8.5%) |
Vozy et al. (2019); Vigibase [46] | Hepatitis | 19% | Median TTO = 46 (34 with anti-CTLA-4; 48 with anti-PD-1/PD-L1; 41 for fatal hepatitis; no differences between monotherapies and monotherapy vs. combo) | 531 cases (85% had no co-reported drugs) Concurrent irAEs occurred in 31% (most commonly thyroiditis and dermatitis) Age > 65 years as the only independent risk factor for reporting fatal hepatitis |
Guerrero et al. (2019); Vigibase [47] | Hypophysitis | 3.3% | Median TTO = 76 | 689 cases (ipilimumab 57.5%; combination 18%); commonly reported after three doses; melanoma 81% Overlap with thyroiditis (31%), enterocolitis (19%), dermatologic manifestations (13.7%) |
Moey et al. (2020); Vigibase [58] | Pneumonitis | 17.5% (22% with pembrolizumab; 60% in lung cancer) | Median TTO = 43 (24 vs. 53, fatal and non-fatal, respectively) | 1694 cases (73% anti-PD-1 monotherapy in fatal cases). Overlap with colitis (8.1% in fatal cases) and hematotoxicity (7.4%). Fatal cases with more respiratory failure, thromboembolism and tumor progression |
Arnaud et al. (2019); Vigibase [48] | Arthritis | 4.1% | Median TTO = 81 (2.7 months) | 86 cases (82.6% anti-PD-1 monotherapy), rheumatoid arthritis (68%), autoimmune arthritis (16%) or lupus (15%). Recovered in 71% (data for 36 patients). Overlap with colitis (5.8%), thyroid diseases (4.6%) |
Raschi et al. (2019); FAERS [32] | SLE | 0.02% (among rheumatic events) | Median TTO = 196 | 4870 rheumatic events (arthralgia, n = 711), 18 cases of SLE (plus 7 cases of cutaneous SLE), only with anti-PD-1/PD-L1 No anti-TNF drugs/procainamide/hydralazine were recorded among concomitant drugs; overlap in two cases with arthralgia, arthritis and other rheumatic events |
Davis et al. (2019); Vigibase [49] | Hematological toxicities | 23% (HLH), 15% (HH), 11% (ITP) | Median TTO = 40 for HLH (23 for anti-CTLA-4, 47.5 for anti-PD-1/PD-L1), 50 for HA, 41 for ITP | 168 cases (HA = 68, ITP = 57, HLH = 26); HLH mainly with anti-CTLA-4, earlier onset (26), and higher fatality (23%) Overlap only with non-hematologic irAEs (23%) |
Noseda et al. (2019); Vigibase [50] | HLH | 26% | Median TTO = 46.9 | 38 cases (0.08% of total events), 90% ICIs as the solely suspected drug), 58% with anti-PD-1/PD-L1. Recovered in 61%. Overlap with autoimmune hepatitis and interstitial lung disease in 5% |
Tanios et al. (2019); FAERS [51] | Autoimmune hemolytic anemia | NA | NA (literature data: median TTO = 70) | 68 cases (0.21% of total events), 43 with nivolumab, 32 cases with melanoma. 26.5% with other irAEs (idiopathic thrombocytopenic purpura). Disproportionality analysis stated but not shown |
Moslehi et al. (2018); Vigibase [35] | Myocarditis | 46% (higher in combo vs. monotherapies) | Median TTO = 27 (data for 33 patients) | 101 cases (57% with anti-PD-1). Concurrent irAEs in 42% (myositis, myasthenia gravis) |
Dolladille et al. (2020); Vigibase [52] | Cardiac events | 30–27% (early and late events) | Median TTO = 21 (early cases)—178 (late cases) for Vigibase; median TTO = 14 (early cases)—104 (late cases) in three French cardio-oncology units | 437 early cases (onset < 90 days), 159 late cases (onset ≥ 90 cases); almost exclusively with anti-PD-1/PD-L1. Late cases had significantly more frequent HF (21.1% vs. 31.4%). Late cases (19) vs. early cases (19) from three French cardio-oncology units had significantly more LVSD and HF, and less frequent supraventricular arrhythmias; similar mortality (40–42%; early and late events) |
Garcia et al. (2019); FAERS [53] | Multiple sclerosis | 15.4% (two deaths) | Median TTO = 29 (30 with anti-CTLA-4, 23 with anti-PD-1/PD-L1); median time for symptom resolution was 8 weeks | 13 cases (0.03% of total events) and one additional case from a research center. History of MS was confirmed in eight patients. Three patients did not receive MS drugs while receiving ICIs. Resolution in five cases. Outcomes did not vary by comparing anti-CTLA-4 and anti-PD-1/PD-L1. All cases with other irAEs |
Zhou et al. (2019); FAERS [54] | Inflammatory bowel disease | 10% (of 38 cases) | NA | Nine cases (of 38 total cases with ICIs and metformin); 60 cases of 36,815 with anti-PD-1/PD-L1 without metformin; 11 cases of 23,572 with metformin without anti-PD-1/PD-L1 diagnosed with DM |