BACKGROUND: The optimal duration of immune checkpoint blockade (ICB) in lung cancer remains undefined. Indefinite treatment in long-term responders increases healthcare burden, exposes patients to avoidable toxicities, and is not supported by any clinical and biological rationale or translational data. Prospective strategies to determine the optimal duration of immunotherapy in lung cancer are urgently needed.

PATIENTS AND METHODS: In this retrospective cohort study, 455 patients from 21 nNGM centers with ≥2 years of disease control on first-line ICB-based therapy were grouped into PET/CT-guided discontinuation (cohort A, n=126) or continued ICB without PET/CT (cohort B, n=329), and assessed for overall survival (OS). Matched pre- and post-ICB tumor samples from cohort A patients with persistent or progressive disease were analyzed by comprehensive genomic profiling, histological TIL quantification, and spatial transcriptomics to explore mechanisms of late resistance.

RESULTS: After a median follow-up of 55 months, cohort A showed significantly longer OS (median not reached vs. 82 months; HR 0.35 [0.18-0.67], p = 0.002), despite substantially shorter treatment duration (27 vs. 45 months; p < 0.001). Discontinuation was either PET-driven (A) or resulted from immune-related toxicity, progression, or patients' choice (B). Systematic re-biopsies in cohort A revealed a high incidence of second primary lung cancers (SPLC, 28%). All progression events were managed exclusively with local (ablative) treatments in 53% (A) vs. 17% (B). Post-treatment tumors exhibited features of acquired resistance, whereas SPLC displayed characteristics of primary resistance, including low PD-L1 expression, low TMB, and immunologically cold tumor microenvironments.

CONCLUSIONS: A structured discontinuation strategy appears to provide a safe approach for long-term ICB responders, enabling earlier detection of resistance before generalized progression. A confirmatory prospective non-inferiority randomized trial within the nNGM is underway.