The Efficacy of First-Line Pembrolizumab Monotherapy in Patients with Metastatic NSCLC Aged ≥70 Years with High PD-L1 (TPS ≥ 50%) Expression: A Multicenter Real-World Study

<b>Introduction:</b> Elderly patients with metastatic non-small-cell lung cancer (NSCLC) are underrepresented in clinical trials evaluating immune checkpoint inhibitors (ICIs). This study assesses the efficacy of first-line pembrolizumab monotherapy in patients with metastatic NSCLC aged ≥70 years with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥ 50%. <b>Materials and Methods:</b> We retrospectively analyzed 381 patients with metastatic NSCLC without oncogenic driver mutations treated with pembrolizumab monotherapy between 2017 and 2023 at three academic centers in Central and Southeastern Europe. Clinical outcomes, including median time on treatment (mToT) and overall survival (mOS), were compared between patients aged ≥70 and <70 years. <b>Results:</b> Of 381 patients, 149 (39.1%) were aged ≥70. No significant differences in mToT (12.7 vs. 14.3 months; <i>p</i> = 0.125) or mOS (18.2 vs. 27.4 months; <i>p</i> = 0.124) were observed between older and younger groups. Good ECOG PS (0-1) was independently associated with longer mToT and mOS in older patients. Additionally, a history of smoking was linked to improved outcomes compared to never-smokers, suggesting potential immunogenic effects. Older patients were significantly less likely to receive second-line therapy after progression (<i>p</i> = 0.04). <b>Conclusions:</b> First-line pembrolizumab monotherapy is effective across all age groups and provides similar treatment efficacy in patients with metastatic NSCLC and a PD-L1 TPS ≥ 50%. Patients older than 70 with a smoking history and ECOG PS 0-1 derive the most benefit from this treatment modality. The adaptation of this treatment strategy for elderly patients is especially important, since only a minority of them are capable of receiving second-line therapy.