Lessons to be Learnt from Real-World Studies on Immune-Related Adverse Events with Checkpoint Inhibitors: A Clinical Perspective from Pharmacovigilance

Abstract

The advent of immune checkpoint inhibitors (ICIs) caused a paradigm shift both in drug development and clinical practice; however, by virtue of their mechanism of action, the excessively activated immune system results in a multitude of offtarget toxicities, the so-called immune-related adverse events (irAEs), requiring new skills for timely diagnosis and a multidisciplinary approach to successfully manage the patients. In the recent past, a plethora of large-scale pharmacovigilance analyses have characterized various irAEs in terms of spectrum and clinical features in the real world. This review aims to summarize and critically appraise the current landscape of pharmacovigilance studies, thus deriving take-home messages for oncologists. A brief primer to study design, conduction, and data interpretation is also offered. As of February 2020, 30 real-world postmarketing studies have characterized multiple irAEs through international spontaneous reporting systems, namely WHO Vigibase and the US FDA Adverse Event Reporting System. The majority of studies investigated a single irAE and provided new epidemiological evidence about class-specific patterns of irAEs (i.e. anti-cytotoxic T-lymphocyte antigen 4 [CTLA-4] versus anti-programmed cell death 1 [PD-1] receptor, and its ligand [PD-L1]), kinetics of appearance, co-occurrences (overlap) among irAEs, and fatality rate. Oncologists should be aware of both strengths and limitations of these pharmacovigilance analyses, especially in terms of data interpretation. Optimal management (including rechallenge), predictivity of irAEs (as potential biomarkers of effectiveness), and comparative safety of ICIs (also in terms of combination regimens) represent key research priorities for next-generation real-world studies.

Immune checkpoint inhibitors-related myocarditis in patients with cancer: an analysis of international spontaneous reporting systems

“…The results showed that the prevalence of myocarditis was 1.14% and the median time of onset was 34 days (interquartile range: 21 to 75 days). In addition, a recent review by Raschi et al [ 4 ] summarized several real-world studies (that are focused on irAEs with checkpoint inhibitors) described both rapid (median 16.5 days in combination regimens) and late myocarditis-related events (median 178 days). Taken together, assessing the marketing safety of target drugs by mining the real-world data reported in pharmacovigilance databases is of great significance, and we can fully understand the safety profiles of target drugs by signal detection.…”

“…And most ADRs reports come from America and Europe, while there are few data from Asia or Africa. Secondly, although ROR, PRR, and IC are called quantification signal detection approaches, they are only simple indicators of potential safety issues and cannot quantitatively calculate the incidence (occurrence rates) and the risk of ADRs [ 4 , 13 ]. Thirdly, although the pharmacovigilance databases are recognized as an important tool to assess the post-marketing safety of drugs by data mining algorithm and the signal detected by data mining methods indicates that the target drug and the target ADR are statistically correlated, it does not mean that the target drug and the target ADR have a biological causal relationship, which needs to be further observed and verified through several large-scale clinical trials [ 4 , 12 ].…”

“…Immune checkpoint inhibitors (ICIs), such as cytotoxic Tlymphocyte-associated protein-4 (CTLA-4), programmed cell death-1 (PD-1), and programmed death-ligand 1 (PD-L1) inhibitors that can inhibit the co-inhibitory immune checkpoint pathways have completely changed the treatment landscape of various malignant tumors [1]. However, with the applications of ICIs increasing, immune-related adverse events (irAEs) associated with ICIs can be induced [2][3][4]. These irAEs may affect any body system and organ, such as skin, lung, liver, gastrointestinal tract, and so on [5][6][7].…”

Pre-Existing Cardiovascular Conditions as Clinical Predictors of Myocarditis Reporting with Immune Checkpoint Inhibitors: A VigiBase Study

“…The retrospective case-control design of our study and the statistical tests of association used to assess reporting differences of myocarditis versus other ICI-related ADRs were tailored to the VigiBase context, and could not provide conclusions as to the causal nature of the association found between the independent and dependent variables. Lastly, instead of querying VigiBase to generate hypotheses, as has been widely done in pharmacovigilance studies on ICIs through disproportionality analysis [ 38 ], we used VigiBase to test a hypothesis. Due to the limitations inherent to the data source mentioned above, our findings do not as yet allow drawing definitive conclusions but should rather be interpreted as supporting a hypothesis that deserves further investigation.…”

Influenza Vaccination and Myo-Pericarditis in Patients Receiving Immune Checkpoint Inhibitors: Investigating the Likelihood of Interaction through the Vaccine Adverse Event Reporting System and VigiBase

“…In the recent past, analysis of the spontaneous reporting systems (SRSs) has attracted considerable interest among clinicians for the accurate and timely characterization of drug-and vaccine-related risks occurring in the real world, where comorbidities and polypharmacotherapy exist. By offering a global epidemiological perspective, these pharmacovigilance studies have been pursued to test the hypothesis of potential associations, including refusing the likelihood of interactions [3,16,17], especially for rare, unexpected, and delayed AEs, such as MP.…”