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.