Retrospective study of PD-(L)1 blockade in NSCLC without actionable genomic alterations in patients who never used tobacco

Predictive biomarkers of response to immune checkpoint inhibitors (ICI) are poorly defined in patients with non-small cell lung cancer (NSCLC) without a history of tobacco use and lacking actionable genomic alterations (AGA). A retrospective analysis of never smoking patients with metastatic, AGA-negative NSCLC treated with ICI-based regimens across multiple independent cohorts investigated potential predictive biomarkers. Among 741 patients, the objective response rate (ORR) was 23.2%, the median progression-free survival (mPFS) was 4.5 months, and the median overall survival (mOS) was 16.8 months. PD-L1 ≥ 90% and tumor mutational burden ≥ 90^th percentile were independently and significantly associated with improved ORR, mPFS, and mOS (all p<0.01). PD-(L)1 plus CTLA-4 combinations outperformed chemoimmunotherapy and PD-(L)1 monotherapy in terms of mPFS and mOS. Transcriptomic analysis revealed enrichment of innate and adaptive immune pathways in responders. High tumor-infiltrating lymphocyte density was also associated with superior ORR and PFS. The authors conclude that this analysis demonstrated how combination therapies may improve ICI outcomes in patients with AGA-negative NSCLC and no history of tobacco exposure, and identified predictive biomarkers of response to ICIs in these patients.