Clinical outcomes and predictors of response to PD-(L)1 blockade in patients with NSCLC without actionable genomic alterations who never used tobacco

Purpose: Predictive biomarkers of response to immune checkpoint inhibitors (ICI) remain poorly defined in patients with non-small cell lung cancer (NSCLC) without a history of tobacco use and lacking actionable genomic alterations (AGA). We aimed to identify clinical and molecular predictors of response to ICI-based regimens in patients who have never smoked and lack AGA. Experimental design: We retrospectively analyzed patients with metastatic, AGA-negative NSCLC who never smoked, treated with ICI-based regimens across multiple independent cohorts. Tumor-infiltrating lymphocyte (TIL) densities were quantified using a machine learning-based algorithm, and immune cells biomarkers were assessed with multiplexed immunofluorescence. Transcriptomic correlates of ICI response were analyzed in the SU2C cohort. Results: Among 741 patients with AGA-negative NSCLC and no history of tobacco use, objective response rate (ORR) was 23.2%, median progression-free survival (mPFS) 4.5 months, and median overall survival (mOS) 16.8 months. PD-L1≥90% and TMB≥90th percentile were independently and significantly associated with improved ORR, mPFS, and mOS (all p<0.01). PD-(L)1+CTLA-4 combinations outperformed chemo-immunotherapy and PD-(L)1 monotherapy in terms of mPFS and mOS. Transcriptomic analysis revealed enrichment of innate and adaptive immune pathways in responders, including increased MHC class I/II antigen presentation and T-cell activity. High TIL density was also associated with superior ORR and PFS. Multiplexed immunophenotyping confirmed higher immune cell infiltration in patients who experienced durable clinical benefit. Conclusions: We demonstrated how combination therapies may improve ICI outcomes in patients with AGA-negative NSCLC and no history of tobacco exposure. Very high PD-L1, TMB, and immune-enriched phenotypes may guide treatment personalization.