Association of a germline single nucleotide polymorphism (SNP) in the interleukin-7 (IL7) gene with immune-related adverse events (irAEs) in the CheckMate 025 trial.
Authors: Saad Eddy , Labaki Chris , Saliby Renee Maria , Semaan Karl , Eid Marc , Sun Maxine , Sharon Elad , Vemula Sai Vikram , Gupta Saurabh , Van Allen Eliezer Mendel , Gusev Alexander , CHOUEIRI Toni K. 
Published: June 2024

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Background: Immune checkpoint inhibitors (ICIs) have dramatically improved outcomes of patients (pts) with metastatic renal cell carcinoma (mRCC). Unfortunately, adverse events (AEs) can limit treatment efficacy and worsen patient outcomes. Recently, a germline IL7 SNP (rs16906115) was identified as a potential biomarker for prediction of irAEs. We aimed to characterize the association between a germline IL7 SNP (rs16906115) and AEs in a prospective clinical trial of patients with mRCC treated with nivolumab (NIVO) or everolimus (EVE). Methods: Whole-exome sequencing (WES) data of tumor and peripheral blood samples from CheckMate 025 (NCT01668784) were used to infer somatic alterations using the Cancer Genome Analysis pipeline, as well as SNP carrier status using the STITCH pipeline. Within each treatment arm, time to incident adverse events (AEs) were compared between carriers (SNP+) and non-carriers (SNP-) via multivariable Cox regression, controlling for age, sex and sample purity, followed by a SNP´treatment interaction term in the whole cohort. Overall survival (OS) and progression-free survival (PFS) were also assessed. Finally, a recurrent event analysis for AEs was conducted using the Andersen-Gill model, controlling for the same variables. Results: In total, 382 pts were included (NIVO: n=189, EVE: n=193), among which 56 (14.7%) were SNP+. There were no differences in clinical and pathological characteristics between SNP+ and SNP-, except for sex (SNP+ 16.1% vs. SNP- 30.1% females, P=0.046). Similarly, no differences in somatic alterations, including single nucleotide and copy number variants were seen between SNP+ and SNP-. SNP carrier status had no effect on OS nor PFS in both treatment arms (all P≥0.47). Regarding AEs, 63 pts (33.3%) in the NIVO arm experienced at least 1 grade 2+ AE, compared to 78 pts (40.4%) in the EVE arm. The most common types of grade 2+ AEs were cutaneous (21.0%), hepatobiliary (16.8%) and endocrine (15.8%) in the NIVO arm, and respiratory (30.1%), cutaneous (22.3%) and gastrointestinal (19.4%) in the EVE arm. The rate of grade 2+ AEs was significantly higher in SNP+ vs. SNP- in the NIVO arm (HR=2.91[1.48-5.72]), but not in the EVE arm (HR=0.63[0.3-1.29], SNP´treatment Pinteraction=0.002). The rate of recurrent grade 2+ AEs was also significantly higher in SNP+ vs. SNP- in the NIVO arm (HR=3.43[1.83-6.43]), whereas a trend for fewer recurrent grade 2+ AEs was seen in SNP+ vs. SNP- in the EVE arm (HR=0.46[0.17-1.25], SNP´treatment Pinteraction=0.0005). Conclusions: The IL7 SNP (rs16906115) is associated with significantly higher rates of grade 2+ AEs, including recurrent events, in pts with mRCC treated with NIVO but not with EVE, with no effect on survival outcomes. These results affirm the SNP’s predictive potential as a biomarker for irAEs to guide therapeutic decisions in pts treated with ICIs.