Analysis of Reporting of Cutaneous Toxicities Associated With Immune Checkpoint Inhibitors

Study Overview
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Brief Summary
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Immune checkpoint inhibitors (ICIs) are associated with a wide variety of cutaneous immune-related adverse events (cirAEs). These cirAEs are reported to be the most common immune-related adverse events (irAEs) and the first to appear. This study examines the appearance of cirAEs within the World Health Organization (WHO) pharmacovigilance database, VigiBase.

Detailed Description
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ICIs have revolutionized clinical oncologic care. The ICIs that are currently FDA approved fall into three main categories: those that block the cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4; ipilimumab), block the programmed cell death protein-1 (anti-PD-1; nivolumab, pembrolizumab, cemiplimab), and block the programmed cell death ligand-1 (anti-PD-L1; atezolizumab, avelumab, durvalumab) pathway. There is a considerable diversity of cirAEs that have been reported with these ICIs in both monotherapy and combination therapy. VigiBase is the WHO pharmacovigilance database that monitors individual case safety reports associated with certain drugs. The largest database of its kind in the world, VigiBase is managed by the Uppsala Monitoring Center (UMC) in Sweden, and since its inception in 1967 has received over 19 million individual case safety reports (ICSRs) from over 130 contributing countries. In this study, the investigators examine the appearance of cutaneous immune related adverse events in the setting of immunotherapy within VigiBase.

Official Title
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Analysis of Reporting of Cutaneous Toxicities Associated With Immune Checkpoint Inhibitors

Conditions
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Cutaneous Toxicity From ICI Therapy

Intervention / Treatment
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* Drug: Immune checkpoint inhibitor (ICI)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Treated with either Ipilimumab (L01XC11), Nivolumab (L01XC17), Pembrolizumab (L01XC18), Durvalumab (L01XC28), Avelumab (L01XC31), Atezolizumab (L01XC32), and Cemiplimab (L01XC33). Developed an adverse reaction that was submitted to a pharmacovigilance center and was determined to be related to aforementioned immune checkpoint inhibitors. Adverse reaction was determined to be within the System Organ Class (SOC) Skin and subcutaneous disorder. Exclusion Criteria: Adverse event was determined not to be immune-related (for example, infectious etiology) or was a symptom (e.g., edema). Adverse event developed before the administration of ICI.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cutaneous toxicity<br>Patients who reported a cutaneous immune related adverse event following ICI initiation with appropriate chronology that indicates drug toxicity. | Drug: Immune checkpoint inhibitor (ICI)<br>* Immune checkpoint inhibitors included were targeting either PD-1, PD-L1 or CTLA-4, and had received FDA approval at the time of study (ATC classification): Ipilimumab (L01XC11), Nivolumab (L01XC17), Pembrolizumab (L01XC18), Durvalumab (L01XC28), Avelumab (L01XC31), Atezolizumab (L01XC32), and Cemiplimab (L01XC33).<br>* Other names: Cemiplimab (Libtayo, L01XC33);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cutaneous toxicity of ICIs | Number of reported adverse events associated with ICIs within the Systems Organ Class (SOC) Skin and subcutaneous disorders with one of the 7 FDA-approved ICIs Ipilimumab (L01XC11), Nivolumab (L01XC17), Pembrolizumab (L01XC18), Durvalumab (L01XC28), Avelumab (L01XC31), Atezolizumab (L01XC32), or Cemiplimab (L01XC33), alone or in any combination with each other. | From 01/01/2008 to 08/31/2020 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reporting odds ratio for monotherapy vs combination therapy | Reporting odds ratio for appearance of cirAEs, comparing the odds of appearance of cirAEs with monotherapy with PD-1, PD-L1, or CTLA-4 against combination therapy with a PD-1/PD-L1 and CTLA-4 agent. | From 01/01/2008 to 08/31/2020 | 
| Reporting odds ratio for differing monotherapy | Reporting odds ratio for appearance of cirAEs comparing monotherapy with PD1 or PD-L1 against monotherapy with CTLA-4 | From 01/01/2008 to 08/31/2020 | 
| Co-occuring irAEs | Prevalence (%) of co-occuring irAEs within other organ systems (GI, endocrine/metabolic, pulmonary, cardiac, renal, hematologic, neurologic, rheumatologic, and ophthalmologic) with cirAEs. | From 01/01/2008 to 08/31/2020 | 
| Disproportionality assessment of cirAEs with ICIs | Information component (IC), a Bayesian confidence neural network propagation method devised by the Uppsala Monitoring Center, will determine significant disproportionate signal of cirAEs associated with ICIs if >0 at the bottom of the 95% confidence interval (IC025 > 0). | From 01/01/2008 to 08/31/2020 | 
| Indication | Prevalence (%) of malignancy types (such as melanoma, pulmonary, and renal cell carcinoma) for patients receiving ICIs and developing cirAEs. | From 01/01/2008 to 08/31/2020 | 
| Time to onset | Time to onset of cirAEs after ICI administration, measured in days. | From 01/01/2008 to 08/31/2020 |