Toxicities with Immune Checkpoint Inhibitors: Emerging Priorities From Disproportionality Analysis of the FDA Adverse Event Reporting System

Abstract

Background Different immune-related adverse events (irAEs) were described with immune checkpoint inhibitors (ICIs), including blockers of cytotoxic T-lymphocyte associated protein 4 (CTLA4) and programmed cell death 1 or its ligand (PD1/PDL1), although their global safety is incompletely characterized.Objective To characterize spectrum, frequency and clinical features of ICI-related adverse events (AEs) reported to the FDA Adverse Event Reporting System (FAERS). Patients and MethodsAEs from FAERS (up to June 2018) recording ICIs (ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab) as suspect were extracted. Comprehensive disproportionality analyses were performed through the reporting odds ratio (ROR) with 95% confidence interval (95%CI), using other oncological drugs as comparison. An overview of systematic reviews (OoSRs) was also undertaken to identify irAEs with consistent positive associations. ResultsICIs were recorded in 47,266 reports, submitted mainly by consumers receiving monotherapy with anti-PD1/PDL1 drugs. Three areas of toxicity emerged from both disproportionality and OoSRs (33 studies):

Serious Cutaneous Toxicities with Immune Checkpoint Inhibitors in the U.S. Food and Drug Administration Adverse Event Reporting System

“…Overall, our data (a) confirmed the variegate pattern of cutaneous toxicity , including nonspecific manifestations such as rash maculopapular and pruritus, as well as serious irAEs and SCARs, thus making a timely consultation with dermatologist pivotal to minimize unnecessary drug interruption ; (b) found a differential reporting between anti‐PD1/PDL1 drugs (psoriasis, dermatitis psoriasiform, pemphigoid, and cutaneous sarcoidosis) and anti‐CTLA4 medications (acute febrile neutrophilic dermatosis and erythema nodosum) ; and (c) recorded a high proportion of death in young adults with SCARs, especially TEN (83% in adults aged 40–49), with a delayed latency as compared with recently published data on anticancer drugs (mean 46 vs. 18 days ), in keeping with immune‐related basis. This conflicts with the algorithm of drug causality for epidermal necrolysis (ALDEN), which was validated on heterogeneous drugs and suggested that late events are unlikely to be drug related ): we invite clinicians to submit complete high‐quality reports, as recommended by the Side Effect Reporting in Immuno‐Oncology (SERIO) working group .…”

“…FAERS also allows to perform disproportionality analysis, a validated concept in pharmacovigilance, to assess whether suspected drug‐induced events are differentially reported with ICIs . In this study, we carried out the so‐called disproportionality analysis by therapeutic area, (i.e., we selected reports where at least one anticancer agent was recorded, as a proxy of neoplasia).…”

“…If an imbalance exists in the proportion of cutaneous events in subjects exposed to anti‐PD1/PDL1 or anti‐CTLA4 agents (cases) as compared with individuals receiving other oncological drugs (non‐cases), an association can be hypothesized. Through this so‐called case/non‐case approach, the reporting odds ratio (ROR) with relevant 95% confidence interval (CI) was calculated and deemed significant when the lower limit of the 95% CI of the ROR >1, with at least five cases reported, to reduce the likelihood of false positives .…”

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

“…The case of oncology, and in particular immunotherapy, is not an exception, and a plethora of postmarketing DAs have documented the occurrence of various toxicities with ICIs in the real world [16,17]. Therefore, clinicians may wonder whether and how these data will impact their routine practice, especially in the era of real-world evidence and relevant debate on their complementary role with randomized controlled trials (RCTs).…”

Cyclin-dependent kinase 4/6 inhibitors and interstitial lung disease in the FDA adverse event reporting system: a pharmacovigilance assessment

“…Post-marketing monitoring is therefore crucial to timely characterize ILD and to target preventive strategies for diagnosis and management [ 8 ]. In this context, international spontaneous reporting systems, through collection of millions of worldwide reports, represent a primary source of data for safety assessment of recently marketed drugs receiving fast track designation and priority review, which deserve rigorous post-marketing monitoring [ 9 , 10 ]. In particular, the FDA Adverse Event Reporting System (FAERS) is the largest publicly available pharmacovigilance database particularly suitable to detect rare adverse events, which may escape detection and/or reporting from randomized controlled trials.…”