LRP1B loss predicts sensitivity to immunotherapy in patients with NSCLC: an analysis of the phase 3 Checkmate 026 randomized trial.

Abstract

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 (OS) with immune checkpoint inhibition (ICI). EXPERIMENTAL DESIGN LRP1b alterations were determined by whole exome sequencing (WES) and associated with PFS and objective response rates (ORR) in patients with non-small cell lung cancer (NSCLC) in post-hoc analysis of the randomized controlled phase 3 Checkmate-026 trial (CM026, NCT02041533) examining chemotherapy vs nivolumab, adjusting for tumor mutational burden (TMB) and clinical features. We separately evaluated a de-identified nationwide (US-based) NSCLC clinico-genomic database (CGDB) for associations of LRP1b alterations and progression-free survival with anti-PD-1 immunotherapy. RESULTS In the CGDB 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=1569, adjusted HR 0.86 p=0.014). In CM026, patients with LRP1b alterations had a statistically significant improvement in ORR to nivolumab vs. LRP1b wild-type (wt) patients (odds ratio 3.5; 95% CI 1.71-7.13; p=0.0006) but not with chemotherapy (odds ratio 0.63; 95% CI 0.32-1.26; p=0.19), adjusting for TMB, age, gender, histology, smoking and performance status. LRP1b mutations were associated with improved PFS with nivolumab (HR 0.66, p=0.04) but not chemotherapy (HR 1.26, p=0.25), also maintained in multivariate and TMB adjusted analysis. CONCLUSIONS LRP1b mutations are a candidate predictive biomarker for ICI vs. chemotherapy in NSCLC. Further mechanistic characterization of LRP1b and prospective validation are warranted, and might enable future clinical use.