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

Abstract

Cutaneous toxicities frequently occurred with immune checkpoint inhibitors (ICIs), although clinical and pharmacological features are incompletely characterized. The U.S. Food and Drug Administration Adverse Event Reporting System was queried to describe ICI‐related cutaneous toxicities, focusing on severe cutaneous adverse reactions (SCARs): Stevens‐Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. As compared with other anticancer drugs, a higher proportion of death (11.3% vs. 8.7%) and serious reports (42.7% vs. 34.6%) emerged for ICIs (p < .05). A higher frequency of coreported allopurinol and antiepileptics was recorded among 2,525 total SCARs (17% vs. 10%, ICIs and anticancer agents, respectively; p < .05). Mean times to onset were 47, 48, and 40 days (SJS, TEN, and DRESS, respectively), with comparable mean latency between monotherapy and combination regimens (41 days). This immune‐related pattern advocates for long‐lasting monitoring by oncologists and dermatologists.

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

“…After full-text analysis of 36 potentially eligible studies, 30 met the inclusion criteria and were finally retained [ 9 , 16 , 17 , 32 – 58 ]. Of these 30 studies, 14 performed DAs (Table 2 ) and 16 were only based on a descriptive design (Table 3 ), mainly due to the rarity of irAEs under investigation.…”

“…Although most common irAEs were identified during preapproval clinical development, their assessment and clinical characterization in terms of spectrum, timing and outcomes were only recently investigated through real-world, large-scale pharmacovigilance analyses. In particular, the analysis of spontaneous reporting systems (SRSs) allows real-time long-term monitoring of the safety profile of medicines, and also timely identification of rare irAEs worldwide [ 9 ].…”

Oral side effects of immune checkpoint inhibitor therapy (ICIT): An analysis of 4683 patients receiving ICIT for malignancies at Massachusetts General Hospital, Brigham & Women's Hospital, and the Dana‐Farber Cancer Institute, 2011 to 2019

“…Various well known and characterized autoimmune oral mucosal conditions have been associated with ICIT, often synchronously with dermatologic changes 20 . These include conditions in which abnormal cell‐mediated immune function plays the major pathoetiologic role, such as lichenoid reactions, 21 and others that are antibody‐mediated, ie, vesiculobullous disorders like mucous membrane pemphigoid, pemphigus valgaris, 15,22‐24 erythema multiforme, 25,26 and Steven–Johnson syndrome 27‐29 . However, the incidence and characterization of ICIT‐related oral mucosal disease are largely incomplete and possibly under‐reported.…”

The value of case reports and spontaneous reporting systems for pharmacovigilance and clinical practice

“…This implies a delicate balance between timely interruption of the offender (with medical treatment) and early resumption to avoid cancer recurrence or progression. A recent example includes immune checkpoint inhibitors, which may cause a variegate spectrum of skin toxicity, including rare but serious cutaneous adverse reactions, namely Stevens–Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms 2 …”