Abstract Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for advanced non-small cell lung cancer (NSCLC), yet durable responses remain limited in a subset of patients. Serum amyloid A (SAA), an acute-phase protein linked to systemic inflammation, may reflect dynamic immune responses. This retrospective study analyzed 242 advanced NSCLC patients treated with first-line chemoimmunotherapy or immunotherapy between August 2016 and December 2024. Patients were stratified by early SAA kinetics into flare-responders (initial rise followed by decline), responders (sustained decline), and non-responders. Clinical outcomes, including progression-free survival (PFS) and overall survival (OS), were evaluated using Kaplan–Meier and Cox regression analyses. In the chemoimmunotherapy cohort, SAA flare-responders demonstrated significantly prolonged median PFS (29.8 months, 95% CI: 9.95—49.65; HR: 0.31, 95% CI: 0.15–0.64; p