Placebo Immune-Related Adverse Events (irAEs): A Neglected Phenomenon in Cancer Immunotherapy Trials

Abstract

PurposeThis study aims to investigate the underexplored prevalence of placebo-reported immune-related adverse events (irAEs) in immune checkpoint inhibitor (ICI) trials. MethodsWe searched public databases for randomized clinical trials (RCTs) involving ICI versus placebo treatments in patients with malignancies. Study characteristics and irAEs occurrences were extracted for meta-analyses using a random-effects model. Main OutcomesProportions of patients reported to experience any grade and grade 3 to 5 placebo irAEs; the risk ratio (RR) of reporting 'false' irAEs in the experiment arm (defined as 'false-irAE ratio', calculated by dividing the proportion of patients documented with irAEs in the placebo arm by that in the experimental arm). Results47 RCTs with 30,119 patients were analyzed. The pooled proportion of patients reported to experience any grade and grade 3 to 5 irAEs among placebo participants was 22.85% (17.33%-29.50%) and 3.40% (2.35%-4.63%), respectively. The pooled proportion of placebo-treated patients who experienced serious irAEs was 0.67% (0.03%-1.91%). Treatment discontinuation and death due to placebo irAEs occurred in 0.69% (<0.01%-1.30%) and 0.12% (<0.01%-0.40%) of patients, respectively. The false-irAE ratio for any grade and grade 3 to 5 irAEs were 0.49 and 0.28. The false-irAE ratio was significantly higher in RCTs with control arms of placebo plus non-immunotherapy than in those with placebo alone (any grade: 0.57 vs. 0.32, P<0.001; grade 3 to 5: 0.36 vs. 0.12, P=0.009). ConclusionOur analyses of placebo-treated participants in ICI RCTs document the common occurrence of placebo irAEs. These findings are important for interpreting irAE profiles, avoiding inappropriate therapeutic interventions.