To investigate the clinical features, management strategies, and outcomes of metastatic non–small cell lung cancer (NSCLC) patients exhibiting atypical responses (AR) during PD-1/PD-L1 inhibitor therapy. We conducted a retrospective review of 926 patients with metastatic NSCLC treated with PD-1/PD-L1 inhibitors at three academic centers. Tumor responses were evaluated using RECIST version 1.1. AR was identified in 56 patients (6.1%), with a median onset of 2 months after initiating therapy. Patients with metastases in three or more organs at baseline were at higher risk for developing AR (p = 0.038). The most frequent sites of disease progression were the lymph nodes (33.8%) and lungs (29.7%). Most patients with AR (78.2%) had only one or two progressing lesions, predominantly arising from pre-existing tumors (89.1%). Survival outcomes did not differ significantly between AR and typical responders (TR). Importantly, receipt of local therapy targeting progressive lesions was independently associated with improved progression-free survival (p = 0.025). Atypical response is a notable phenomenon in metastatic NSCLC patients receiving PD-1/PD-L1 inhibitors and is associated with survival comparable to typical response patterns. Targeted local interventions for progressing lesions, without halting ongoing immunotherapy, may provide additional clinical benefit.
