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 AGAs. Experimental Design: We retrospectively analyzed patients with metastatic, AGA-negative NSCLC who never smoke treated with ICI-based regimens across multiple independent cohorts. Tumor-infiltrating lymphocyte (TIL) densities were quantified using a machine learning–based algorithm, and immune cell biomarkers were assessed with multiplexed immunofluorescence. Transcriptomic correlates of ICI response were analyzed in the Stand Up To Cancer cohort. Results: Among 741 patients with AGA-negative NSCLC and no history of tobacco use, the objective response rate (ORR) was 23.2%, median progression-free survival (mPFS) was 4.5 months, and median overall survival (mOS) was 16.8 months. PD-L1 ≥90% and tumor mutational burden (TMB) ≥90th percentile were independently and significantly associated with improved ORR, mPFS, and mOS (all P <0.01). PD-(L)1 + CTLA-4 com-binations outperformed chemoimmunotherapy and PD-(L)1 mon-otherapy 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 presenta-tion and T-cell activity. High TIL density was also associated with superior ORR and PFS. Multiplexed immunophenotyping con-firmed 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.
Clinical Outcomes and Predictors of Response to PD-(L)1 Blockade in Patients with NSCLC without Actionable Genomic Alterations Who Never Used Tobacco / Gariazzo, E., Elkrief, A., Concannon, K., Ognissanti, D., Dodi, A., Favorito, V., Di Federico, A., De Giglio, A., Brunetti, L., Santo, V., Pecci, F., Aldea, M., Garbo, E., Alessi, J.V., Lopiccolo, J., Paoloni, F., Nishino, M., Sholl, L.M., Florez, N., Rotow, J., et al.. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - 32:16(2026), pp. 3683-3693. [10.1158/1078-0432.ccr-25-4793]
Clinical Outcomes and Predictors of Response to PD-(L)1 Blockade in Patients with NSCLC without Actionable Genomic Alterations Who Never Used Tobacco
Di Federico, Alessandro;Pecci, Federica;Tiseo, Marcello;
2026-01-01
Abstract
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 AGAs. Experimental Design: We retrospectively analyzed patients with metastatic, AGA-negative NSCLC who never smoke treated with ICI-based regimens across multiple independent cohorts. Tumor-infiltrating lymphocyte (TIL) densities were quantified using a machine learning–based algorithm, and immune cell biomarkers were assessed with multiplexed immunofluorescence. Transcriptomic correlates of ICI response were analyzed in the Stand Up To Cancer cohort. Results: Among 741 patients with AGA-negative NSCLC and no history of tobacco use, the objective response rate (ORR) was 23.2%, median progression-free survival (mPFS) was 4.5 months, and median overall survival (mOS) was 16.8 months. PD-L1 ≥90% and tumor mutational burden (TMB) ≥90th percentile were independently and significantly associated with improved ORR, mPFS, and mOS (all P <0.01). PD-(L)1 + CTLA-4 com-binations outperformed chemoimmunotherapy and PD-(L)1 mon-otherapy 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 presenta-tion and T-cell activity. High TIL density was also associated with superior ORR and PFS. Multiplexed immunophenotyping con-firmed 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
