Exploratory analysis to predict pneumonitis during durvalumab consolidation therapy for patients with locally advanced non‐small cell lung cancer from proteomic profiling of circulating extracellular vesicles

BACKGROUND: Risk factors for predicting pneumonitis during durvalumab consolidation after chemoradiotherapy (CRT) in locally advanced non‐small cell lung cancer (LA‐NSCLC) are still lacking. Extracellular vesicles (EVs) play a crucial role in intercellular communication and are potential diagnostic tools for various diseases. METHODS: We retrospectively collected predurvalumab treatment serum samples from patients treated with durvalumab for LA‐NSCLC, isolated EVs using anti‐CD9 and anti‐CD63 antibodies, and performed proteomic analyses. We examined EV proteins that could predict the development of symptomatic pneumonitis (SP) during durvalumab treatment. Potential EV‐protein biomarkers were validated in an independent cohort. RESULTS: In the discovery cohort, 73 patients were included, 49 with asymptomatic pneumonitis (AP) and 24 with SP. Of the 5797 proteins detected in circulating EVs, 33 were significantly elevated (fold change [FC] > 1.5, p < 0.05) in the SP group, indicating enrichment of the nuclear factor kappa B (NF‐κB) pathway. Patients with high levels of EV‐RELA, an NF‐κB subunit, had a higher incidence of SP than those with low levels of EV‐RELA (53.8% vs. 13.4%, p = 0.0017). In the receiver operating characteristic analysis, EV‐RELA demonstrated a higher area under the curve (AUC) than lung V20 (0.76 vs. 0.62) and was identified as an independent risk factor in the multivariate logistic regression analysis (p = 0.008, odds ratio 7.72). Moreover, high EV‐RELA was also a predictor of SP in the validation cohort comprising 43 patients (AUC of 0.80). CONCLUSIONS: Circulating EV‐RELA may be a predictive marker for symptomatic pneumonitis in patients with LA‐NSCLC treated with durvalumab.