Circulating receptor activator of nuclear factor kappa-B ligand (RANKL) levels predict response to immune checkpoint inhibitors in advanced non-small cell lung cancer (NSCLC)

• Published in: Journal for immunotherapy of cancer 2024-06, Vol.12 (6), p.e009432
• Main Authors: Iuliani, Michele, Simonetti, Sonia, Cristofani, Leonardo, Cavaliere, Silvia, Cortellini, Alessio, Russano, Marco, Vincenzi, Bruno, Tonini, Giuseppe, Santini, Daniele, Pantano, Francesco
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; B7-H1 Antigen - blood; Biomarkers; Biomarkers, Tumor - blood; Carcinoma, Non-Small-Cell Lung - blood; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Cell death; Disease; Female; Humans; Immune Checkpoint Inhibitor; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunotherapy biomarkers; Ligands; Lung Cancer; Lung Neoplasms - blood; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Male; Medical prognosis; Metabolism; Metastasis; Middle Aged; Patients; Plasma; Prognosis; RANK Ligand - blood; Sample size
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2024-009432

BackgroundReceptor activator of nuclear factor kappa-B ligand (RANKL) can directly promote tumor growth and indirectly support tumor immune evasion by altering the tumor microenvironment and immune cell responses. This study aimed to assess the prognostic significance of soluble RANKL in patients with advanced non-small cell lung cancer (NSCLC) receiving programmed cell death 1 (PD1)/programmed death-ligand 1 (PDL1) checkpoint inhibitor therapy.MethodsPlasma RANKL levels were measured in 100 patients with advanced NSCLC without bone metastases undergoing monotherapy with PD1/PDL1 checkpoint inhibitors. To establish the optimal cut-off value, we used the Cutoff Finder package in R. Survival curves for four distinct patient groups, according to their RANKL and PDL1 levels (high or low), were generated using the Kaplan-Meier method and compared with the log-rank test. The Cox regression model calculated HRs and 95% CIs for overall survival (OS) and progression-free survival (PFS).ResultsThe optimal RANKL cut-off was established at 280.4 pg/mL, categorizing patients into groups with high or low RANKL levels. A significant association was observed between increased RANKL concentrations and decreased survival rates at 24 months, only within the subgroup expressing high levels of PDL1 (p=0.002). Additionally, low RANKL levels in conjunction with elevated PDL1 expression correlated with improved PFS (median 22 months, 95% CI 6.70 to 50 vs median 4 months, 95% CI 3.0 to 7.30, p=0.009) and OS (median 26 months, 95% CI 20 to not reached vs median 7 months, 95% CI 6 to 13, p=0.003), indicating RANKL’s potential as an indicator of adverse prognosis in these patients. Multivariate analysis identified RANKL as an independent negative prognostic factor for both PFS and OS, regardless of other clinicopathological features.ConclusionThese results highlight the prognostic and predictive value of RANKL specifically in patients with high PDL1 expression.