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 they also commonly cause immune-related adverse events (irAEs). The predictive features of clinically severe irAEs leading to cessation of ICIs have yet to be established. Given the similarities between irAEs and autoimmune diseases, we sought to investigate the association of a germline polygenic risk score for autoimmune disease and discontinuation of ICIs due to irAEs.

Methods: The Genetics of immune-related adverse events and Response to Immunotherapy (GeRI) cohort comprises 1302 patients with non-small cell lung cancer (NSCLC) who received ICI therapy between 2009 and 2022 at four academic medical centers. We used a published polygenic risk score for autoimmune diseases (PRS_AD) in the general population and validated it in the All of Us. We then assessed the association between PRS_AD and cessation of ICI therapy due to irAEs in the GeRI cohort, using cause-specific and Fine-Gray subdistribution hazard models. To further understand the differential effects of type of therapy on the association between PRS_AD and cessation of ICI due to irAEs, we conducted a stratified analysis by type of ICI therapy.

Results: Using a competing risk model, we found an association between PRS_AD and ICI cessation due to irAEs (HR per SD=1.24, p=0.004). This association was particularly strong in patients who had ICI cessation due to irAEs within 3 months of therapy initiation (HR per SD=1.40, p=0.005). Individuals in the top quintile of PRS_AD had 4.8% ICI discontinuation for irAEs by 3 months, compared with 2% discontinuation by 3 months among patients in the bottom quintile (log-rank p=0.03). In addition, among patients who received combination programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors and cytotoxic T-lymphocyte associated protein 4 (CTLA4) inhibitors, ICI discontinuation for irAEs by 3 months occurred in 4 of the 13 patients (30.8%) with high PRS_AD genetic risk (top quintile) versus 3 of 21 patients (14.3%) with low PRS_AD genetic risk (bottom quintile).

Conclusions: We demonstrate an association between a polygenic risk score for autoimmune disease and early ICI discontinuation for irAEs. 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.

Keywords: Genetic; Immune Checkpoint Inhibitor; Immune related adverse event - irAE; Lung Cancer.

Figure 1. Brief overview of the GeRI study and the analytical pipeline. The GeRI study comprises 1302 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 provided either a blood or saliva sample for genotyping. Genotyping was performed using the Affymetrix Precision Medicine Diversity Array and imputed to the 1,000 genomes reference panel (phase 3 version 5). We used a published polygenic risk score for autoimmune diseases (PRS_AD) in the general population and validated it in the All of Us. Next, association analysis between the PRS_AD and ICI cessation due to immune-related adverse events (irAEs) was conducted using the Cox proportional hazards model and Fine-Gray subdistribution hazards models (to account for competing risks) in the GeRI study. Cumulative incidence curves were obtained by genetic risk based on PRS_AD percentile. GeRI, Genetics of immune-related adverse events and Response to Immunotherapy.

Figure 2. Cumulative incidence curves for (a) overall discontinuation of immune checkpoint inhibitor (ICI) therapy due to immune-related adverse events (irAEs) and (b) early discontinuation of ICI therapy due to irAEs (≤3 months) across categories of polygenic risk score of autoimmune disease (PRS_AD) in the Genetics of immune-related adverse events and Response to Immunotherapy (GeRI) study. PRS_AD quintiles were categorized into low (Q1), average (Q2–Q4), and high genetic risk (Q5). The p values included on each plot are the results of a log-rank test for the difference between the curves (two-sided). Due to few individuals having cessation after the first dose due to irAEs, the numbers at risk (at time 0) do not match the total number in the study.