Clinical Outcomes and Predictors of Response to PD-(L)1 Blockade in Patients with NSCLC without Actionable Genomic Alterations Who Never Used Tobacco.
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Gariazzo Eleonora, Elkrief Arielle, Concannon Kyle, Ognissanti Daniele, Dodi Alessandra, Favorito Valentina, Di Federico Alessandro, De Giglio Andrea, Brunetti Leonardo, Santo Valentina, Pecci Federica, Aldea Mihaela, Garbo Edoardo, Alessi Joao V, LoPiccolo Jaclyn, Paoloni Francesco, Nishino Mizuki, Sholl Lynette M, Florez Narjust, Rotow Julia, Frumm Stacey M, Hong Lingzhi, Zhang Jianjun, Gibbons Don, Wang Xinan, Landi Lorenza, Cipriani Laura, Rakaee Mehrdad, Cortellini Alessio, Tiseo Marcello, Cappuzzo Federico, Ardizzoni Andrea, Awad Mark M, Heymach John V, Scalera Stefano, Maugeri-Saccà Marcello, Metro Giulio, Vokes Natalie, Schoenfeld Adam, Ricciuti Biagio
Аннотация
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 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, 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.