Preexisting autoantibodies as predictor of immune-related adverse events for advanced solid tumors treated with immune checkpoint inhibitors.
Authors: Daban Arthur , Gonnin Cecile , Vano Yann-Alexandre , Phan Letuan , lillo-Lelouet Agnes , le Beller Christine , Pouchot Jacques , Fabre Elizabeth , Weiss Laurence , Tartour Eric , Oudard Stephane , Dragon Durey Marie-Agnès , Simonaggio Audrey 
Published: June 2022

2523

Background: Immune checkpoint inhibitors (ICIs), used alone or as a combination are standard of care in many cancers. Generally well tolerated, they can generate immune-related adverse events (irAEs). No biomarkers are available to identify patients who are more likely to develop irAEs. The aim of this study was to assess the association between preexisting autoantibodies, occurrence of irAEs and survival outcomes. Methods: We performed a prospective study including 221 patients receiving ICIs for advanced solid tumors between May 2015 and July 2021. Autoantibodies testing (anti-neutrophil cytoplasmic, anti-nuclear, thyroid peroxidase and thyroglobulin) was performed before ICIs initiation. The associations among preexisting autoantibodies, the occurrence, the severity, the delay of irAEs and the survival outcomes, including progression-free survival (PFS) and overall survival (OS) were analyzed. Statistical analyses were performed with T-test, Cox regression models, univariate and multivariate analyses and Kaplan-Meier’s method. Results: Of the 221 patients, 151 (68%) were men, the median age was 66,5 (range 21-90) years and 103 (81%) had an ECOG-PS of 0 or 1. Seventy-three percent (n=162) received an anti-PD-(L)1 in monotherapy, 27% (n=59) an anti-PD-(L)1 in combination, for a renal cell carcinoma in 45% (n=99) and a lung carcinoma in 41% (n=90). In total, 129 (58%) patients had preexisting antibodies. IrAEs were significantly more frequent in patients with preexisting autoantibodies: 64 patients (50%) in the positive group vs. 20 patients (22%) in the negative group, OR = 3.5 (95%CI=1.8 - 6.8), p=0.00002. Median time interval between ICI initiation and irAE was shorter in the positive group vs. the negative group, 13 weeks (IQR=43weeks) vs. 28.5 weeks (IQR=12weeks) respectively (p=0.01). Twelve patients (9.4%) experienced multi toxicities in the positive group vs. two (2%) in the negative group, OR=4.5 (95%CI0.98-36), p=0.04. ICIs exposure was identical in preexisting and non-preexisting autoantibodies groups. After a median follow-up of 25 months (95%CI=19-31), median PFS and OS were significantly longer among patients experiencing irAE: 12.6 months (95%CI=11-22.7) vs 5 months (95%CI=4.2-7.0), p= 0.0003 and 30 months (95%CI= 22.7-NR) vs 21 months (95%CI=15-34.6), p= 0.016. In multivariate analyses irAEs remain statistically associated with survival outcomes. Preexisting autoantibodies were not associated with survival outcomes. Conclusions: The presence of preexisting autoantibodies is significantly associated with the occurrence of irAE in patients treated with ICIs. Earlier and multiple irAEs were observed in the presence of preexisting autoantibodies. Thus, these biomarkers could help to identify patients at risk of irAEs and would prompt us to closely monitor them.