Data from <i>LRP1b</i> Loss Predicts Sensitivity to Immunotherapy in Patients with NSCLC: An Analysis of the Phase III CheckMate-026 Randomized Trial

<div>AbstractPurpose:<p>Low-density lipoprotein receptor–related protein 1b (<i>LRP1b</i>) 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.</p>Experimental Design:<p><i>LRP1b</i> 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 <i>post hoc</i> 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 <i>LRP1b</i> alterations and PFS with anti–PD-1 immunotherapy.</p>Results:<p>In the clinico-genomic database cohort of patients with NSCLC (<i>N</i> = 18,369), <i>LRP1b</i> mutations were positively associated with <i>TP53/KRAS</i> alterations and inversely with <i>EGFR/RET/MET/ERBB2</i> alterations and significantly improved PFS with PD-1 inhibition (<i>n</i> = 1,569; adjusted HR, 0.86; <i>P</i> = 0.014). In CheckMate-026, patients with <i>LRP1b</i> alterations had a statistically significant improvement in objective response rate to nivolumab versus <i>LRP1b</i> wild-type patients (OR 3.5; 95% confidence interval, 1.71–7.13; <i>P</i> = 0.0006) but not with chemotherapy (OR 0.63; 95% confidence interval, 0.32–1.26; <i>P</i> = 0.19), adjusting for TMB, age, gender, histology, smoking, and performance status. <i>LRP1b</i> mutations were associated with improved PFS with nivolumab (HR, 0.66; <i>P</i> = 0.04) but not chemotherapy (HR, 1.26; <i>P</i> = 0.25), also maintained in multivariate and TMB-adjusted analyses.</p>Conclusions:<p><i>LRP1b</i> mutations are a candidate predictive biomarker for immune checkpoint inhibition versus chemotherapy in NSCLC. Further mechanistic characterization of <i>LRP1b</i> and prospective validation are warranted and might enable future clinical use.</p></div>

Duke Scholars

Author Andrew John Armstrong Medicine, Medical Oncology