Stratifying ICI-P Risk in Non-Small Cell Lung Cancer with Genetic and Radiographic Markers

Immune checkpoint inhibitors (ICIs) have significantly changed our treatment approach in non-small cell lung cancer. But their benefits can be offset by immune-related adverse events—particularly ICI-associated pneumonitis (ICI-P), a potentially life-threatening toxicity. While relatively rare, ICI-P remains difficult to predict.

New data presented at the 2025 American Thoracic Society International Conference proposes a novel approach: combining radiographic markers and a key genetic polymorphism to stratify risk more accurately.

Connecting MUC5B Genotype to Radiographic Abnormalities

Led by researchers at MD Anderson Cancer Center, the study focused on rs35705950-T, a well-characterized variant in the MUC5B promoter known to predispose individuals to interstitial lung disease (ILD) and interstitial lung abnormalities (ILAs), both of which are implicated in ICI-P susceptibility.

Using two independent non-small cell lung cancer cohorts (GEMINI and LONESTAR), investigators evaluated 24 ICI-P cases and 48 matched controls. All patients had received ICIs with or without radiotherapy and underwent genotyping and baseline CT evaluation for ILAs.

Key findings included:

• Genetic Risk: Carriers of rs35705950-T had a 4.6-fold increased risk of developing ICI-P (OR 4.6, 95 percent CI: 1.5–15.8), rising to 5.4-fold in non-Hispanic White patients (OR 5.4, 95 percent CI: 1.7–19.5).
• Radiographic Risk: ILAs were found in 47 percent of ICI-P cases versus 15 percent of controls, corresponding to a 4.9-fold increase in ICI-P risk (OR 4.9, 95 percent CI: 1.7–14.6).
• Mechanistic Link: Mediation analysis indicated that the polymorphism’s effect on ICI-P risk was entirely mediated by ILAs (p = 0.02), suggesting ILAs function as the critical phenotypic bridge between genetic susceptibility and clinical toxicity.

Implications for Risk Stratification

These findings support a layered model for risk prediction: genetic predisposition (rs35705950-T) increases the likelihood of radiographic ILAs, which elevate the risk of pneumonitis. Importantly, there was no direct effect of the MUC5B variant on ICI-P in the absence of ILAs, underscoring the central role of subclinical interstitial changes visible on imaging.

A composite scoring system integrating this genetic and imaging data could identify patients likely to develop ICI-P before therapy begins. Such a tool could prompt pre-treatment radiologic screening in genetically predisposed patients, guide more intensive monitoring protocols, and influence decision-making on ICI use in marginal cases.

Reference:

Soto F, Suresh A, Altan M, Sheshadri A. Integrating genetic and radiographic markers to predict immune checkpoint inhibitor pneumonitis risk in non small cell lung cancer. Am J Respir Crit Care Med. 2025;211:A1072–A1072. doi:10.1164/ajrccm.2025.211.Abstracts.A1072