Cheng H, Zou Y, Shah CD, et al. - In this first in human study of inhaled azacitidine, researchers assessed its safety as well as effectiveness in reversing epigenetic alterations in the bronchial epithelium secondary to chronic smoking. Researchers used azacitidine in aqueous solution to generate an aerosol suspension of 0.25 to 5 µm particle size. Patients with stage IV or recurrent NSCLC with mostly lung involvement, ≥ 1 prior systemic therapy, ECOG PS 0-1, and adequate lung function were eligible for inclusion. The participants (n = 8) were administered inhaled azacitidine daily on days 1-5 and 15-19 of 28-day cycles, at 3 escalating doses (15, 30 and 45 mg/m ² daily). No clinically significant adverse events occurred, except an asymptomatic grade 2 decreased DLCO after treatment at the highest dose in one patient, which resolved spontaneously. In cases treated at the higher doses, plasma azacitidine was only briefly identifiable. In this study, good tolerability of inhaled azacitidine was evident, and inhaled Azacitidine led to negligible plasma concentrations vs the previously documented subcutaneous administration. Based on these findings, continued development of inhaled azacitidine at non-cytotoxic doses for cases with lung-confined malignant and/or premalignant lesions is justified.