Progression Phenotypes to anti–PD-(L)1 Therapy and Subsequent Management of Patients with Metastatic NSCLC: A Real-World Cohort Study

• Progression patterns independently predict survival outcomes in metastatic NSCLC. • Oligoprogression and acquired resistance correlate with superior PPS and PFS2. • Failure patterns and time-to-resistance help refine post-progression strategies. Progression patterns to anti–PD-(L)1 therapies in metastatic NSCLC may have prognostic and therapeutic implications, but they remain incompletely characterized. We retrospectively studied metastatic NSCLC who progressed to anti–PD-(L)1. First progression was classified as: oligoprogression (oligo-PD;≤3 lesions/organs) or systemic (systemic-PD); preexisting-lesion-only, new-lesion-only, or combined; and primary resistance (PR) or acquired (AR). Cox models determined associations between progression phenotypes and PFS1 (to first progression), PFS2 (to second progression), and post-progression survival (PPS; first progression to death). Among 179 patients, exhibited systemic-PD (62.6%), oligo-PD (37.4%), PR (48.0%) and AR (52.0%). Failure occurred as combined (51.4%), preexisting-lesion-only (26.8%), and new-lesion-only (21.8%). Progression most frequently occurred in organs involved at baseline. Oligo-PD showed longer PFS2 (HR 0.56; p =0.001) and PPS (HR 0.61; p =0.021) than systemic-PD. AR showed longer PFS2 (HR 0.27; p <0.001) and PPS (HR 0.42; p <0.001) than PR. AR predicted longer PFS2, whereas combined failure and PFS1 ≤6 months predicted shorter PFS2 and PPS. oligo-PD and AR may benefit from local ablative therapies combined with continuation of PD-(L)1 blockade, while early systemic-PD from transition of systemic therapies. Progression patterns to anti–PD-(L)1 therapy are independent predictors of survival outcomes in metastatic and recurrent NSCLC. Integrating time-to-resistance, progression and failure patterns may help refine risk stratification and guide post-progression treatment strategies.