Ki-67 expression stratifies PD-L1-high NSCLC for immune checkpoint inhibitor plus chemotherapy: a real-world biomarker validation.

BACKGROUND: For patients with programmed death-ligand 1 (PD-L1)-high non-small cell lung cancer (NSCLC), both immune checkpoint inhibitor (ICI) monotherapy and ICI plus chemotherapy are first-line options, yet optimal subgroups for each remain undefined. We evaluated Ki-67 expression as a biomarker for treatment stratification. METHODS: We retrospectively analyzed 334 advanced PD-L1-high NSCLC cases (2018-2024). Patients were stratified by Ki-67 expression, and outcomes with ICI monotherapy versus ICI-chemotherapy were compared using propensity score matching and multivariable Cox models. RESULTS: After propensity score matching, in the Ki-67 > 30% cohort (n = 166), ICI-chemotherapy was associated with a higher ORR versus ICI monotherapy (32/83, 38.6% vs. 17/83, 20.5%; P = 0.01) and with longer PFS (9.9 vs. 8.4 months; HR 0.51, 95% CI 0.37-0.72; P < 0.001) and OS (22.1 vs. 16.5 months; HR 0.47, 95% CI 0.32-0.70; P < 0.001). In the Ki-67 ≤ 30% cohort (n = 78), ORR was identical (9/39, 23.1%), and no improvement was observed for PFS (8.3 vs. 9.1 months; HR 1.59, 95% CI 0.98-2.59; P = 0.06) or OS (15.7 vs. 20.3 months; HR 1.47, 95% CI 0.85-2.54; P = 0.16). Patients receiving ICI-chemotherapy had more grade ≥ 3 adverse events (40/157, 25.5% vs. 24/177, 13.6%), predominantly hematologic (30/157, 19.1% vs. 3/177, 1.7%). CONCLUSION: Ki-67 expression may represent a potential predictive biomarker for identifying PD-L1-high NSCLC patients more likely to benefit from chemo-immunotherapy, though its clinical utility requires confirmation in prospective, randomized studies.