Introduction
- Baseline disruption of the interferon gamma (IFN-γ) pathway enhances tumor immune elimination post-checkpoint blockade in murine models.1 In multiple solid tumor types, mixed-effects meta-analysis has shown a significant increase in responses to immunotherapy with IFN-γ pathway mutations, including in multivariable models incorporating high versus low tumor mutational burden (TMB).2
- However, an extensive analysis of multiple co-variables and outcomes has not been conducted. In the Stand Up to Cancer-Mark Foundation (SU2C-MF) NSCLC clinical cohort, we found that non-synonymous mutations in IFN-γ pathway genes (n=26, 8%) associated with better outcomes following PD-(L)1 inhibitors (ICI), including improved radiological responses, progression-free survival, and overall survival (OS) (AACR 2024).3,4
- This association remains significant in multivariable models and using different permutation tests.4 Here, we present key and updated findings from SU2C-MF NSCLC cohort, but crucially aimed to validate these results in an independent dataset and examine predictive versus prognostic significance.