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.

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Journal
Clinical Cancer Research
Published
2026-05-18
DOI
https://doi.org/10.1158/1078-0432.ccr-25-4793
Primary Topic
Cancer Immunotherapy and Biomarkers
Type
article
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article

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

Federico Cappuzzo, Marcello Maugeri‐Saccà, Edoardo Garbo, Alessandra Dodi et al.
Clinical Cancer Research
Cancer Immunotherapy and Biomarkers
article

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

Federico Cappuzzo, Marcello Maugeri‐Saccà, Edoardo Garbo, Alessandra Dodi, Lingzhi Hong, Valentina Favorito, Leonardo Brunetti, J. Alessi, Stacey M. Frumm, Mizuki Nishino, Mehrdad Rakaee, Alessandro Di Federico, Andrea De Giglio, Jaclyn LoPiccolo, Francesco Paoloni, Eleonora Gariazzo, Don Gibbons, Daniele Ognissanti, X. Wang, N. Vokes, M Aldea, Mark M. Awad, Julia Rotow, Kyle Concannon, Adam Schoenfeld, Laura Cipriani, Valentina Santo, Federica Pecci, Jianjun Zhang, Biagio Ricciuti, Arielle Elkrief, Andrea Ardizzoni, Narjust Florez, Lorenza Landi, Lynette M. Sholl, John V. Heymach, Giulio Metro, Marcello Tiseo, Alessio Cortellini, Stefano Scalera
article en

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 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.

Clinical Cancer Research
Brigham and Women's Hospital (US), Memorial Sloan Kettering Cancer Center (US), The University of Texas MD Anderson Cancer Center (US), Harvard University (US), Università Campus Bio-Medico (IT), University of Perugia (IT), Institut Gustave Roussy (FR), Harvard University Press (US), University of Massachusetts Boston (US), IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT), GNA University (IN), NIHR Imperial Biomedical Research Centre (GB), Dana-Farber Cancer Institute (US), Dana-Farber/Harvard Cancer Center (US), Ospedale di Parma (IT), Istituti Fisioterapici Ospitalieri (IT), Tumori Foundation (US), Dana-Farber Brigham Cancer Center (US), Imperial College London (GB), University of Bologna (IT)
Good health and well-being
Openalex Percentile: Top 7%
Cancer Immunotherapy and Biomarkers
DOISourceOpenAlex
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