Germline prediction of immune checkpoint inhibitor discontinuation for immune-related adverse events

Abstract

Introduction: Immune checkpoint inhibitors (ICIs) can yield remarkable clinical responses in subsets of patients with solid tumors but can also often lead to immune-related adverse events (irAEs). Predictive features of clinically severe irAEs leading to cessation of ICIs have yet to be established. Using data from 1,327 patients with lung cancer treated with ICIs between 2009 and 2022 at four academic medical centers, we evaluated the association of a germline polygenic risk score for autoimmune disease and discontinuation of ICIs due to irAEs.

Methods: Using Cox proportional hazards model, we assessed the association between a polygenic risk score for autoimmune disease (PRS_AD) and cessation of ICI therapy due to irAEs. All models were adjusted for age at diagnosis, sex, lung cancer histology, type of therapy, recruiting center, and the first 5 principal components. To further understand the differential effects of type of therapy and disease stage on the association between PRS_AD and cessation of ICI due to irAEs, we conducted stratified logistic regression analysis by type of ICI therapy and disease stage.

Results: We found an association between PRS_AD and ICI cessation due to irAEs (HR per SD = 1.18, 95% CI = 1.02 - 1.37, P = 0.03). This association was particularly strong in patients who had ICI cessation due to irAEs within three months of therapy initiation (HR per SD = 1.38, 95% CI = 1.08 - 1.78, P = 0.01). Individuals in the top 20th percentile of PRS_AD had 7.2% ICI discontinuation for irAEs by three months, compared to 3.9% discontinuation by three months among patients in the bottom 80th percentile (log-rank P = 0.02). In addition, among patients who received combination PD-1/PD-L1 and CTLA-4 inhibitor therapy, PRS_AD had an OR per SD of 1.86 (95% CI = 1.08 - 3.51, P = 0.04).

Conclusions: We demonstrate an association between a polygenic risk score for autoimmune disease and early ICI discontinuation for irAEs, particularly among patients treated with combination ICI therapy. Our results suggest that germline genetics may be used as an adjunctive tool for risk stratification around ICI clinical decision-making in solid tumor oncology.

Figure 1:

Brief overview of GeRI study and analytical pipeline. The GeRI study is comprised of 1,328 patients with non-small cell lung cancer treated with at least one dose of immune checkpoint inhibitor (ICI) therapy. Phenotype data was manually curated from health records and each participant was provided with either a blood or saliva sample for genotyping. Genotyping was performed using Affymetrix Precision Medicine Diversity Array and imputed to 1000 genomes references panel (phase 3 v5). Association analysis between a previously published polygenic risk score for autoimmune disease (PRS_AD) and ICI cessation due to immune-related adverse events (irAEs) was conducted using the Cox proportional hazards model and Fine and Gray sub-distribution hazards models (to account for competing risks). Cumulative incidence curves were obtained by genetic risk based on PRS_AD percentile. Additionally, Cox proportional hazard models were performed to assess the association between PRS_AD and progression-free and overall survival. Kaplan-Meier survival curves and log-rank tests were performed.

Figure 2:

Cumulative incidence curves for (a) discontinuation of immune checkpoint inhibitor (ICI) therapy due to irAEs, (b) early discontinuation of ICI therapy due to irAEs, and (c) late discontinuation of ICI therapy due to irAEs across categories of polygenic risk score of autoimmune disease in the GeRI cohort. High genetic risk is defined as individuals in the >80^th percentile (top 20th percentile), whereas low/moderate genetic risk is defined as individuals in ≤80th percentile. The p-values included on each plot are the results of a log-rank test for the difference between the curves (two-sided).

Figure 2:

Cumulative incidence curves for (a) discontinuation of immune checkpoint inhibitor (ICI) therapy due to irAEs, (b) early discontinuation of ICI therapy due to irAEs, and (c) late discontinuation of ICI therapy due to irAEs across categories of polygenic risk score of autoimmune disease in the GeRI cohort. High genetic risk is defined as individuals in the >80^th percentile (top 20th percentile), whereas low/moderate genetic risk is defined as individuals in ≤80th percentile. The p-values included on each plot are the results of a log-rank test for the difference between the curves (two-sided).