Potential Biomarker of PD-L1 Expression Phenotypes in Tumor and Immune Cells for Combined PD-1 and CTLA-4 Blockade Therapies in Advanced NSCLC.

8524 Background: Pembrolizumab-based chemo-immunotherapies (Pembro) and nivolumab plus ipilimumab-based immunotherapies with or without 2 cycles of chemotherapies (Nivo+Ipi) have improved survival in patients with advanced NSCLC compared to the conventional chemotherapy. However, biomarkers to support appropriate choice in these immunotherapies remain unclear. Methods: From 2019 to 2023, this multicenter, observational study retrospectively reviewed advanced NSCLC patients who received first-line Pembro or Nivo+Ipi and had evaluable PD-L1 expression status on tumor cells (tumor proportion score [TPS], 22C3) and immune cells (immune cell [IC] score, SP142). Survival curve comparisons between treatments were conducted using restricted mean survival time (RMST) estimation in place of Log-rank test, when the proportional hazard assumption was not met. Additionally, the genomic and expression profiles associated with TPS and IC score were assessed using whole-exome sequencing and RNA sequencing in available NSCLC samples. Results: A total of 198 patients were included (Pembro/Nivo+Ipi: 137/61). In the Pembro cohort, patients with high TPS (≥ 50%) had significantly longer progression-free survival (PFS) than those with low TPS (< 50%) (median PFS [mPFS, months]: 8.1 vs. 7.1, P = 0.02; hazard ratio [HR] = 0.59 [0.38–0.92]), while no significant difference in PFS was observed based on IC score (high vs. low: mPFS 7.4 vs. 6.8, P = 0.11, HR = 0.72 [0.49–1.07]). In the Nivo+Ipi cohort, PFS did not significantly differ by TPS (high vs. low: mPFS 4.0 vs. 4.0, P = 0.26; HR = 0.51 [0.16–1.68]), whereas patients with high IC score (≥ 1) had significantly longer PFS than those with low IC score (= 0) (mPFS: 7.7 vs. 2.8, P = 0.04; HR = 0.53 [0.28–0.98]). A durable PFS benefit of Nivo+Ipi over Pembro was observed only in patients with low TPS/high IC score (mPFS: 12.4 vs. 6.6; Schoenfeld individual test: P < 0.05; RMST Nivo+Ipi /RMST Pembro [2 years] = 1.5, P = 0.049, Table). Sequence analyses revealed that tumors with low TPS/high IC score had significantly higher tumor mutational burden (TMB) than other tumors (median TMB: 18.2 vs. 1.9 [/mb]; P < 0.001) and showed distinct enrichment in antigen presentation and T-cell receptor signaling pathways. Conclusions: Nivolumab plus ipilimumab-based immunotherapies demonstrated superior durable response compared to pembrolizumab-based chemo-immunotherapies in patients with low TPS/high IC score. PD-L1 phenotypes based on TPS and IC score could guide the optimal selection of immunotherapies for advanced NSCLC patients. Efficacy comparison in patients with low TPS (< 50%)/high IC score (≥ 1). Treatments mPFS (months) PFS rate at 2 years RMST at 2 years RMST Nivo+Ipi /RMST Pembro at 2 years P value Pembrolizumab-based chemo-immunotherapies 6.6 6% 8.5 1.5 [1.0–2.3] 0.049 Nivolumab plus ipilimumab-based immunotherapies 12.4 41% 12.9