Pulmonary Rehabilitation Modifies Functional Decline During First-Line Immune Checkpoint Inhibitor Therapy for Advanced Non-Small Cell Lung Cancer

Background Immune checkpoint inhibitors (ICIs) have improved survival in advanced NSCLC; yet the trajectory of objective physical performance during immunotherapy remains poorly characterized. Pulmonary rehabilitation (PR) has not been evaluated in this setting in randomized trials. Research Question Does supervised pulmonary rehabilitation modify functional capacity and multidimensional physical performance during first-line immunotherapy for advanced NSCLC? Study Design and Methods In this randomized controlled trial, patients with stage IV NSCLC initiating first-line ICI-based therapy were randomized 1:1 to supervised PR or usual care for 8 weeks. The primary outcome was change in 6-minute walk distance (6MWD). Secondary outcomes included multidimensional physical performance, symptom burden, and health-related quality of life. Exploratory outcomes included inflammatory biomarkers and oncologic endpoints. Results Of 148 individuals screened, 48 were randomized (PR, n=24; usual care, n=24). At 8 weeks, supervised PR significantly improved 6-minute walk distance compared with usual care (adjusted mean difference, 25.8 m; 95% CI, 10.1–41.5 m; p=.002). Significant between-group differences favoring PR were observed in lower-extremity performance (SPPB), quadriceps strength, fine motor dexterity, respiratory symptom burden (CAT), anxiety, and depressive symptoms. Participants receiving usual care demonstrated decline across multiple functional domains despite stable ECOG performance status. No between-group differences were observed in inflammatory biomarkers. Exploratory analyses demonstrated a trend toward longer progression-free survival (median, 15.0 vs 10.0 months) in the pulmonary rehabilitation group; however, the study was not powered to detect differences in survival outcomes. Interpretation Among patients receiving first-line ICI-based therapy for advanced NSCLC, early functional deterioration occurred despite stable ECOG performance status, indicating that oncologic stability does not necessarily reflect physiologic stability. Supervised PR modified functional trajectories during active treatment in this randomized trial, supporting early rehabilitation as an integral component of immunotherapy care rather than a survivorship intervention.