Genetic prediction of colitis in non-small cell lung cancer patients on immune checkpoint inhibitor therapy.

Immune checkpoint inhibitors (ICIs) are a remarkable advancement in cancer therapeutics; however, a substantial proportion of patients develop severe immune-related adverse events (irAEs). Understanding and predicting irAEs is the key to advancing precision immuno-oncology. Immune-mediated colitis (IMC) is a significant complication from ICI and can have life-threatening consequences. Genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) may predispose to IMC, but the link is poorly understood. We developed and validated polygenic risk scores for CD (PRS CD ) and UC (PRS UC ) in cancer-free individuals and assessed the role of each of these PRSs on IMC in a cohort of 1,316 patients with non-small cell lung cancer (NSCLC) who received ICIs. Prevalence of all-grade IMC in our cohort is 4% (55 cases), and for severe IMC, 2.5% (32 cases). The PRS UC predicted the development of all-grade IMC (HR=1.34 per standard deviation [SD], 95% CI=1.02-1.76, P =0.04) and severe IMC (HR=1.62 per SD, 95% CI=1.12-2.35, P =0.01). PRS CD was not associated with IMC or severe IMC. This is a first study to demonstrate the potential clinical utility of a PRS for ulcerative colitis in identifying NSCLC patients receiving ICI at high risk of developing IMC, where risk reduction and close monitoring strategies could help improve overall patient outcomes.