Association of IL7 rs16906115 Polymorphism with Immune-Related Adverse Events in Patients with Advanced Lung Cancer Undergoing Immunotherapy

<b>Background</b>: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced non-small cell lung cancer (aNSCLC). However, immune-related adverse events (irAEs) remain a clinical challenge in this context. Genetic variants acting as cis-eQTLs may predict toxicity risk, thereby enabling personalized treatment. Specifically, the interleukin <i>7</i> (<i>IL7</i>) rs16906115 variant has recently been implicated in ICI-related toxicity in other malignancies, like melanoma, although its role in lung cancer remains less defined. We investigated the association between the <i>IL7</i> rs16906115 polymorphism, immune-related adverse events (irAEs), and survival outcomes in patients with aNSCLC receiving ICIs. <b>Methods</b>: This retrospective cohort study analyzed 153 patients with aNSCLC treated with ICIs (2018-2023) at two centers in Spain. The final analytical cohort included 124 patients with complete clinical follow-up. <i>IL7</i> rs16906115 genotyping was performed using TaqMan assays. Associations between genotypes/alleles, irAEs, and survival (PFS/OS) were evaluated using logistic regression and Kaplan-Meier analysis. A clinical-genetic predictive model was developed. <b>Results</b>: The A allele frequency was 8.5%. Carriers of the A allele (AG/AA genotypes) had significantly higher irAEs rates compared to GG homozygotes (OR = 3.77, 95% CI: 1.16-12.6, <i>p</i> = 0.0081). The association remained significant after multivariable adjustment (OR = 4.64, 95% CI: 1.50-17.2, <i>p</i> = 0.0203). Crucially, A-allele carriers exhibited significantly shorter Progression-Free Survival compared to non-carriers (median 6.6 vs. 10 months, <i>p</i> = 0.0029). The combined clinical-genetic model achieved moderate predictive performance for toxicity (AUC = 0.67, 95% CI: 0.56-0.78) compared to clinical-only models (AUC = 0.57), stratifying patients into moderate- and high-risk groups, respectively. <b>Conclusions:</b> The <i>IL7</i> rs16906115 polymorphism is a potential pharmacogenetic biomarker for predicting adverse events in aNSCLC immunotherapy. These findings identify the <i>IL7</i> rs16906115 polymorphism as a candidate biomarker, suggesting its potential utility as an exploratory tool for risk stratification that warrants further validation.