Placebo-irAEs: verwaarloosd fenomeen bij IO-studies

PURPOSE: This study aims to investigate the underexplored prevalence of placebo-reported immune-related adverse events (irAEs) in immune checkpoint inhibitor (ICI) trials. METHODS: We 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 OUTCOMES: Proportions 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). RESULTS: 47 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). CONCLUSION: Our 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.