LRP1b Loss Predicts Sensitivity to Immunotherapy in Patients with NSCLC: An Analysis of the Phase III CheckMate-026 Randomized Trial

作者：Andrew J. Armstrong, Hilary Dietz, David Balli, William J. Geese, Chunzhe Duan, Yu-Han Hung, Virginia Ip, Gerald Li, Ryon P. Graf, Neal Ready · 发表于：Clinical Cancer Research · 年份：2025 · DOI：10.1158/1078-0432.ccr-25-0952 · 被引用次数：1 · 研究领域：Protease and Inhibitor Mechanisms、Lung Cancer Treatments and Mutations、Caveolin-1 and cellular processes

PURPOSE: Low-density lipoprotein receptor-related protein 1b (LRP1b) is a cell surface receptor, commonly altered in many cancers and associated with improved responses, progression-free survival (PFS), and overall survival with immune checkpoint inhibition. EXPERIMENTAL DESIGN: LRP1b alterations were determined by whole-exome sequencing and associated with PFS and objective response rates in patients with non-small cell lung cancer (NSCLC) in a post hoc analysis of the randomized controlled phase III CheckMate-026 (CM026) trial (NCT02041533) examining chemotherapy compared with nivolumab, adjusting for tumor mutational burden (TMB) and clinical features. We separately evaluated a deidentified nationwide (US-based) NSCLC clinico-genomic database for associations of LRP1b alterations and PFS with anti-PD-1 immunotherapy. RESULTS: In the clinico-genomic database cohort of patients with NSCLC (N = 18,369), LRP1b mutations were positively associated with TP53/KRAS alterations and inversely with EGFR/RET/MET/ERBB2 alterations and significantly improved PFS with PD-1 inhibition (n = 1,569; adjusted HR, 0.86; P = 0.014). In CheckMate-026, patients with LRP1b alterations had a statistically significant improvement in objective response rate to nivolumab versus LRP1b wild-type patients (OR 3.5; 95% confidence interval, 1.71-7.13; P = 0.0006) but not with chemotherapy (OR 0.63; 95% confidence interval, 0.32-1.26; P = 0.19), adjusting for TMB, age, gender, histology, smoking, and perfor...