PET/CT-guided management of immune checkpoint blockade and multi-modal profiling following treatment in long-term responders with metastatic lung cancer in the National Network Genomic Medicine Lung Cancer Germany (nNGM)

BACKGROUND: The optimal duration of immune checkpoint blockade (ICB) in lung cancer remains undefined. Indefinite treatment in long-term responders increases health care burden, exposes patients to avoidable toxicities, and is not supported by any clinical or 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 National Network Genomic Medicine Lung Cancer Germany (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 tumor-infiltrating lymphocyte 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 versus 82 months, hazard ratio 0.35 (95% confidence interval 0.18-0.67), P = 0.002], despite substantially shorter treatment duration (27 versus 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) versus 17% (B). Tumors that occurred after treatment exhibited features of acquired resistance, whereas SPLC displayed characteristics of primary resistance, including low programmed death ligand 1 expression, low tumor mutational burden, 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.