Three-Year Overall Survival Outcomes and Correlative Analyses in Patients With NSCLC and High (50%–89%) Versus Very High (≥90%) Programmed Death-Ligand 1 Expression Treated With First-Line Pembrolizumab or Cemiplimab

• Published in: JTO clinical and research reports Vol. 5; no. 9; p. 100675
• Main Authors: Ricciuti, Biagio, Elkrief, Arielle, Lin, Jessica, Zhang, Jianjun, Alessi, Joao V., Lamberti, Giuseppe, Gandhi, Malini, Di Federico, Alessandro, Pecci, Federica, Wang, Xinan, Makarem, Maisam, Murilo Hidalgo Filho, Cassio, Gorria, Teresa, Saini, Arushi, Pabon, Cindy, Lindsay, James, Pfaff, Kathleen L., Welsh, Emma L., Nishino, Mizuki, Sholl, Lynette M., Rodig, Scott, Kilickap, Saadettin, Rietschel, Petra, McIntyre, Debra AG, Pouliot, Jean-Francois, Altan, Mehmet, Gainor, Justin F., Heymach, John V., Schoenfeld, Adam J., Awad, Mark M.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.09.2024; Elsevier
• Subjects: Biomarkers; Cemiplimab; Long-term outcomes; PD-L1; Pembrolizumab; PD-L1; Long-term outcomes; Biomarkers; Pembrolizumab; Cemiplimab
• ISSN: 2666-3643; 2666-3643
• DOI: 10.1016/j.jtocrr.2024.100675

Responses to first-line programmed cell death protein 1 inhibition vary among patients with metastatic NSCLC and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) greater than or equal to 50%. We previously reported improved clinical outcomes to first-line programmed cell death protein 1 inhibition in patients with metastatic NSCLC with a PD-L1 TPS of greater than or equal to 90% versus 50% to 89% in a pilot study. Here, we report the three-year survival with first-line pembrolizumab and cemiplimab in two large independent cohorts of patients with PD-L1 TPS greater than or equal to 90% versus 50% to 89% and characterize genomic and immunophenotypic differences between these PD-L1 expression groups, which were largely unknown. We analyzed three-year outcomes of the following two independent cohorts: (1) a multicenter cohort of patients from four academic centers in the United States treated with pembrolizumab and (2) EMPOWER-Lung 1, randomized, phase III trial comparing first-line cemiplimab with chemotherapy. Tumor genomic profiling and multiplexed immunofluorescence were performed to evaluate genomic and immunophenotypic correlates of very high PD-L1 expression. At three years of follow-up, progression-free survival (hazard ratio [HR], 0.69; p < 0.001) and overall survival (HR, 0.70; p < 0.01) to first-line commercial pembrolizumab were significantly improved in patients with a PD-L1 TPS greater than or equal to 90% versus 50% to 89%. In the EMPOWER-Lung 1, patients assigned to the cemiplimab arm with a PD-L1 TPS greater than or equal to 90% also had significant improvements in progression-free survival (HR, 0.53; p < 0.0001) and overall survival (HR, 0.63; p = 0.007) compared with those with a PD-L1 of 50% to 89%. Tumor genomic profiling of 553 NSCLC samples revealed that mutations in STK11 and SMARCA4 were significantly more frequent in tumors with a PD-L1 TPS of 50% to 89% compared with those with a PD-L1 TPS greater than or equal to 90% (Q < 0.15), whereas BRCA2 was enriched in NSCLC samples with a PD-L1 TPS greater than or equal to 90% (Q < 0.15). Multiplexed immunofluorescence on 93 NSCLC samples identified higher intratumoral CD8+PD1+ T cells (p = 0.02) in tumors with PD-L1 TPS greater than or equal to 90% versus 50% to 89%. Pembrolizumab and cemiplimab were found to have long-term survival benefit and favorable genomic and immunophenotypic profile in patients with advanced NSCLC with PD-L1 TPS greater than or equal to 90% compared with TPS 50% to 89%.