IMMUNOPHENOTYPIC CORRELATES AND OUTCOMES TO FIRST-LINE PEMBROLIZUMAB AMONG PATIENTS AGED 80 YEARS OR OLDER WITH PD-L1-HIGH (≥50%) NON-SMALL CELL LUNG CANCER

Background: Aging is associated with increased levels of systemic inflammation and altered immunosurveillance in cancer. It is currently unclear whether older age correlates with a distinct immunophenotype or impacts clinical outcomes to first-line pembrolizumab in patients with advanced non-small cell lung cancer (NSCLC) and a PD-L1 TPS of ≥50%. Patients and Methods: In this multicenter retrospective analysis, we analyzed the impact of age (<80y vs ≥80y) on clinical outcomes in patients who received pembrolizumab as first-line treatment for NSCLC with a PD-L1 TPS of ≥50% and without sensitizing EGFR/ALK alterations. Multiplexed immunofluorescence (mIF) was performed in a separate cohort to explore tumor immunophenotype. The Cancer Genome Atlas and Stand Up To Cancer databases were also interrogated to identify differences in tumor immune cell subsets. Results: In a cohort of 669 patients with PD-L1 TPS ≥50% who received first-line pembrolizumab, compared to patients <80y (N=558), patients ≥80y (N=111) had no difference in objective response rate (ORR 43.0% vs 43.9%; P=0.92) or median progression-free survival (mPFS 6.4 vs 7.3 months; P=0.26). However, patients ≥80y had a shorter median overall survival (mOS 24.8 vs 15.0 months; P=0.016), and this result remained significant after adjusting for confounding factors (P=0.048). Among those who experienced disease progression on pembrolizumab, patients ≥80y were significantly less likely to receive any second-line systemic therapy compared to patients <80y (27.9% vs 55.5%; P<0.001). Among 480 patients with nonsquamous NSCLC profiled by mIF, there was no difference in median CD8+ T cells, PD-1+ immune cells, or PD-1+CD8+ T cells in patients <80y (N=442) vs ≥80y (N=38). Patients ≥80y had a higher median of tumor-stroma interface-associated FOXP3+ T cells/mm2 (89.3 vs 154 cells/mm2; P=0.01). Additionally, immune cell enrichment analyses revealed that older patients had increased levels of tumor-infiltrating dendritic cells, inflammatory macrophages, and monocytes. Conclusion: In patients with NSCLC and PD-L1 ≥50%, the ORR and mPFS to first-line pembrolizumab were similar between patients <80 vs ≥80 years old. OS was shorter among patients ≥80y, potentially reflecting lower use of second-line therapy in elderly patients after progression on pembrolizumab. Distinct cellular populations in the tumor microenvironment provide insight into potential targets for combination strategies for elderly patients with NSCLC.