Genomic landscape of immunotherapy resistance in lung cancer

Immune checkpoint inhibitors (ICI) have emerged as an important modality in lung cancer treatment. However, studies have shown that only a fraction of patients will experience any clinical benefit when treated with ICI, and a better understanding of the mechanisms of resistance is still needed. In this study, we sought to characterize the prevalence of known mechanisms of primary and adaptive resistance in the context of the greater immunogenomic landscape in a real-world cohort of 100 non-small cell lung cancer patients treated with ICI. Targeted panel DNA sequencing and whole-transcriptome RNA sequencing were performed on a primary tumor biopsy for each patient, the clinical notes were abstracted and structured, and the digital image of the H&E was processed through a tumor-infiltrating lymphocyte (TIL) analysis pipeline. We evaluated each tumor for evidence of HLA loss of heterozygosity (LOH), mutations in the antigen presentation or interferon gamma signaling pathways, expression of alternative checkpoint molecules, and immune infiltrate exclusion. We found that over 25% of patients in the cohort showed signs of at least one of these mechanisms of ICI resistance. We evaluated the real-world progression-free survival (rwPFS) for these patients and found that the majority experienced a progression event within 6 months of treatment start. This study suggests that primary resistance to ICI affects a significant population of lung cancer patients.

This abstract is also being presented as Poster B22.