Association of <i>IL7</i> germline variants with immune-related adverse events (irAEs) in cancer patients (pts) treated with immune checkpoint inhibitors (ICIs).

12129 Background: Despite the transformative impact of ICIs on cancer treatment, their efficacy remains limited by adverse events (AEs), underscoring the need for reliable biomarkers. Here, we aimed to investigate the effect of a previously identified IL7 SNP in predicting irAEs across two clinical trials and an East Asian pan-cancer cohort. Methods: In this pooled analysis, we included 1,205 pts from the CheckMate-025 trial (CM025, NCT01668784) with renal cell carcinoma (RCC) who received either nivolumab (NIVO) or everolimus (EVE), from the BinTA-0037 (BTA-037, NCT03631706) in non-small cell lung cancer (NSCLC) treated with pembrolizumab (PEMBRO), and from the Asan ICI-treated pan-cancer cohort. The rs7816685 SNP dosages were inferred from blood and/or tumor whole exome sequencing (WES) using STITCH for CM025, and Minimac4 for Asan. For BTA-037, a surrogate SNP (rs16906062, R 2 =1.0) was extracted from tumor WES. The association between the SNP carrier status and the time to incident AEs was investigated via multivariable cause-specific Cox regression models. RNA-sequencing (RNA-seq) was performed on blood samples from the Asan cohort collected pre- and post-initiation of ICI. Blood immune cell fractions were estimated from RNA-seq data using ImmucellAI. Results: The frequency of the risk allele was 15% in CM025, 17% in BTA-037, and 24% in Asan. IL7 SNP carriers demonstrated a significantly higher risk of AEs when treated with ICI therapies in all 3 cohorts, but not with EVE (non-ICI control) (SNP´treatment P interaction =0.0012 in CM025) (Table). The SNP showed a consistent effect across different tumor types and irAE profiles, with no apparent impact on survival outcomes. RNA-seq data revealed the expression of a novel IL7 cryptic exon in carriers, and a significant increase in peripheral cytotoxic T-cell post-ICI (q=0.002). Both features were significantly correlated (R=0.29, P=1x10-11), suggesting a potential mechanistic link. Conclusions: The IL7 SNP (rs7816685) is associated with a higher risk of immune toxicity in pts treated with ICI. Overall, our findings support the use of this germline biomarker for irAE risk stratification, and pave the way for future functional studies. Adjusted hazard ratios (HRs) from multivariable Cox models adjusting for baseline covariates in each cohort. Cohort Cancer type Treatment N SNP adjusted HR for irAEs CM025 RCC NIVO 189 rs7816685 3.01 [1.59-5.68], P =0.0007 CM025 RCC EVE 193 rs7816685 0.65 [0.33-1.28], P =0.22 BTA-037 NSCLC PEMBRO 152 rs16906062 2.3 [1.16-4.6], P =0.017 Asan Pan-cancer Any ICI 671 rs7816685 1.12 [1.02-1.2], P =0.015