The predictive role of TRAIL gene expression in immune checkpoint inhibitor (ICI)-treated patients (pts).

Abstract

2637 Background: Despite FDA-approved molecular biomarkers such as PD-L1 levels, tumor mutation burden (TMB), and microsatellite instability (MSI) status, only ~30% of matched cancer pts respond to ICI. TRAIL, a protein product of TNFSF10 gene, is a member of the TNF superfamily involved in regulating immune responses and inducing apoptosis when bound to either Death Receptor 4 or 5 (DR4/5) especially in cancer cells. While TRAIL has been studied for its prognostic roles in cancer, its predictive value for pts treated with ICI remains unclear. This study investigates the association between TRAIL expression and outcomes in ICI-treated pan-cancer pts. Methods: RNA expression levels of TRAIL were assessed in a cohort of 217 pan-cancer pts treated with ICIs at the University of California San Diego (UCSD) Moores Cancer Center. RNA transcripts were normalized using an internal housekeeping gene profile of 735 tumors and 35 histologies. Transcript abundances were percentile-ranked (0–100) and categorized as high (≥75th percentile) or low ( < 75th percentile). Associations between TRAIL expression and overall survival (OS) and progression-free survival (PFS) were analyzed. Statistical significance was defined as p-value ≤ 0.05. Results: Among the 217 ICI-treated pts, the median age was 61.9 years, and 56.2% were female. The most common cancer types were colorectal (24.9%), breast (8.8%), ovarian (8.3%), pancreatic (7.4%), and lung (6.5%) cancers. FDA-approved ICI biomarkers favorable rates were PD-L1 ≥1% in 40.1%, TMB-high (≥10 mut/Mb) in 11.5%, and MSI-high in 4.8%. Based on the ICI type used, 91.7% received anti-PD-(L)1 while 7.8% received anti-CTLA-4 with anti-PD-1. Pts with high TRAIL expression (24%) had similar PD-L1, TMB, MSI profiles (p > 0.05). Pts with high levels of TRAIL expression achieved better OS (HR = 0.41, 95%CI:0.25-0.69, p = 0.0004) and PFS (HR = 0.67, 95%CI:0.47-0.96, p = 0.027). After adjusting for age, sex, cancer type, PD-L1 IHC level (≥1% vs. < 1%), TMB (≥10 mut/Mb vs. < 10mut/Mb), MSI status (stable vs. unstable), KRAS, TP53 and CDKN2A/B alteration status and immune checkpoints genes expression, overall survival remained significantly associated with better survival in TRAIL high pts compared to TRAIL low pts (HR = 0.38, 95%CI:0.19-0.76, p = 0.006). However, no difference was found between both groups in regard to progression-free survival (HR = 0.68, 95%CI:0.42-1.10, p = 0.11). Conclusions: High TRAIL expression is associated with improved overall survival in ICI-treated pan-cancer pts, independent of cancer type or other predictive biomarkers. These findings suggest TRAIL as a potential biomarker for ICI benefit. Larger studies in diverse and real-world settings are warranted to validate these findings.