Serum RNASE3 and TREM2 biomarker set predicts clinical response to benralizumab in nasal polyps

In the OSTRO Ph3 study, which enrolled patients with severe, uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP), addition of benralizumab to standard-of-care treatment reduced Nasal Polyp Score (NPS) compared with placebo. Enhanced treatment effects were observed in subgroups with comorbid asthma or higher baseline blood eosinophils (bEos), however, there is a need to better understand the molecular drivers determining clinical response to benralizumab in CRSwNP. Serum samples (n=224) from the OSTRO study were analysed using Olink proteomics. The eosinophil protein RNASE3 (Eosinophil cationic protein) and the non-eosinophil protein TREM2 (Triggering receptor expressed on myeloid cells 2) were significantly reduced by benralizumab and high baseline levels were predictive of NPS reduction in the benralizumab arm. K-means clustering was used to separate patients into RNASE3_TREM2 high (n=134) and low (n=90) groups based on baseline biomarker levels. The RNASE3_TREM2 high group had a higher odds ratio (OR=4.2; p<0.05) for NPS response than the comorbid asthma (OR=2.7), >150≤300 bEos/μL (OR=3.6) and >300 bEos/μL (OR=2.1) groups. In a joint interaction model, the RNASE3_TREM2 high group remained predictive even when adjusting for clinical characteristics. Additionally, the RNASE3_TREM2 high group exhibited a significant negative prognostic relationship in the placebo group. In conclusion, in CRSwNP, serum RNASE3 and TREM2 levels are associated with enhanced efficacy of benralizumab as well as poorer outcomes with standard-of-care treatment.