The clinical potential of HMGB1 for the risk assessment of severe checkpoint inhibitor pneumonitis: A prospective multicenter study (CS-Lung004)

Abstract

Background: Checkpoint inhibitor pneumonitis (CIP), especially graded as 3-5 or developed within 6-12 weeks, worsens the prognosis of patients with cancer. However, a risk assessment method for the disease has not been established. This was a prospective study that aimed to identify a blood biomarker to assess a risk of severe CIP.

Patients and methods: This multicenter prospective study enrolled patients with non-small cell lung cancer who were treated with anti-PD-1/PD-L1 antibodies in the first-line therapy. The potential of high mobility group box 1 (HMGB1) for Grade 3-5 CIP developed within 3 months after the first administration of anti-PD-1/PD-L1 antibody (CIP^G3-5/3months) was evaluated in the discovery cohort (December 2021-November 2022) and validation cohort (December 2022-November 2023).

Results: In the discovery and validation cohorts, 8.2 % and 6.2 % of patients experienced CIP^G3-5/3months, respectively. The HMGB1 cut-off level was set at 8.1 ng/mL by receiver operating characteristic analysis in the discovery cohort (AUC = 0.732), yielding 80.0 % sensitivity and 71.1 % specificity in the validation cohort. The incidence rate of CIP^G3-5/3months was significantly higher in patients with high HMGB1 level than in those without, both in the discovery cohort (18.2 % and 2.6 %, respectively; P = 0.028) and validation cohort (15.4 % and 1.8 %, respectively; P = 0.035). The potential of HMGB1 for assessing the risk was specific for CIP because HMGB1 serum levels were not elevated in patients with immune related adverse events other than CIP.

Conclusion: HMGB1 can be a serum biomarker that specifically assesses the risk of severe CIP.

Keywords: HMGB1; biomarker; checkpoint inhibitor pneumonitis; risk.