Analysis of Reporting of Cutaneous Toxicities Associated With Immune Checkpoint Inhibitors

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.

Study Overview

• Status: Completed
• Conditions: Cutaneous Toxicity From ICI Therapy
• Intervention / Treatment: Drug: Immune checkpoint inhibitor (ICI)

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 2214

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21215
      • Sidney Kimmel Comprehensive Care Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients treated with an immune checkpoint inhibitor for cancer.

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Cutaneous toxicity; Patients who reported a cutaneous immune related adverse event following ICI initiation with appropriate chronology that indicates drug toxicity.

Drug: Immune checkpoint inhibitor (ICI); 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).; Other Names: Ipilimumab (Yervoy, L01XC11); Nivolumab (Opdivo, L01XC17); Pembrolizumab (Keytruda, L01XC18); Durvalumab (Imfinzi, L01XC28); Avelumab (Bavencio, L01XC31); Atezolizumab (Tecentriq, L01XC32); Cemiplimab (Libtayo, L01XC33)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Investigators: Principal Investigator: Shawn Kwatra, MD, Johns Hopkins University

Publications and helpful links

General Publications

• Le TK, Brown I, Goldberg R, Taylor MT, Deng J, Parthasarathy V, Bordeaux ZA, Alphonse MP, Kwatra MM, Naranbhai V, Gusev A, Alhariri J, LeBoeuf NR, Reynolds KL, Cappelli LC, Naidoo J, Brahmer JR, Kang S, Semenov YR, Kwatra SG. Cutaneous Toxicities Associated with Immune Checkpoint Inhibitors: An Observational, Pharmacovigilance Study. J Invest Dermatol. 2022 Nov;142(11):2896-2908.e4. doi: 10.1016/j.jid.2022.04.020. Epub 2022 May 20.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 1, 2008
• Primary Completion (ACTUAL): August 31, 2020
• Study Completion (ACTUAL): August 31, 2020

Study Registration Dates

• First Submitted: May 19, 2021
• First Submitted That Met QC Criteria: May 19, 2021
• First Posted (ACTUAL): May 24, 2021

Study Record Updates

• Last Update Posted (ACTUAL): May 24, 2021
• Last Update Submitted That Met QC Criteria: May 19, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Nivolumab; Durvalumab; Pembrolizumab; Avelumab; Immune Checkpoint Inhibitors; Ipilimumab; Atezolizumab; Cemiplimab
• Other Study ID Numbers: JH IRB00210048

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes