First-in-human study of inhaled Azacitidine in patients with advanced non-small cell lung cancer

Abstract

Background: Aerosolized Azacitidine has been shown to inhibit orthotopic lung cancer growth and induce re-expression of methylated tumor suppressor genes in murine models. We hypothesized that inhaled Azacitidine is safe and effective in reversing epigenetic changes in the bronchial epithelium secondary to chronic smoking.

Patients and methods: We report the first in human study of inhaled Azacitidine. Azacitidine in aqueous solution was used to generate an aerosol suspension of 0.25-5 μm particle size. Main inclusion criteria: Stage IV or recurrent NSCLC with predominantly lung involvement, ≥1 prior systemic therapy, ECOG PS 0-1, and adequate pulmonary function. Patients received inhaled Azacitidine daily on days 1-5 and 15-19 of 28-day cycles, at 3 escalating doses (15, 30 and 45 mg/m2 daily). The primary objective was to determine the feasibility and tolerability of this new therapeutic modality. The key secondary objectives included pharmacokinetics, methylation profiles and efficacy.

Results: From 3/2015 to 2/2018, eight patients received a median number of 2 (IQR = 1) cycles of inhaled Azacitidine. No clinically significant adverse events were observed, except one patient treated at the highest dose developed an asymptomatic grade 2 decreased DLCO which resolved spontaneously. One patient receiving 12 cycles of therapy had an objective and durable partial response, and two patients had stable disease. Plasma Azacitidine was only briefly detectable in patients treated at the higher doses. Moreover, in 2 of 3 participants who agreed and underwent pre- and post-treatment bronchoscopy, the global DNA methylation in the bronchial epithelium decreased by 24 % and 79 % post-therapy, respectively. The interval between last inhaled treatment and bronchoscopy was 3 days.

Conclusions: Inhaled Azacitidine resulted in negligible plasma levels compared to the previously reported subcutaneous administration and was well-tolerated. The results justify the continued development of inhaled Azacitidine at non-cytotoxic doses for patients with lung-confined malignant and/or premalignant lesions.

Trial registration: ClinicalTrials.gov NCT02009436.

Keywords: Inhaled Azacitidine; Lung cancer.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest

None of below are relevant to this work: HC has received research funding from Genentech, Spectrum, and Array; and has received compensation as a scientific advisor to AstraZeneca, Bayer, and Takeda. MK has received compensation as a scientific advisor to Celgene and Eli Lilly. AV has received research funding from GlaxoSmithKline, BMS, Jannsen, Incyte, MedPacto, Celgene, Novartis, Curis and Eli Lilly and Company, has received compensation as a scientific advisor to Novartis, Stelexis Therapeutics, Acceleron Pharma, and Celgene, and has equity ownership in Throws Exception and Stelexis Therapeutics. BP is an employee of Merck. BH has received research funding from Astra Zeneca, Merck, Boehringer Ingelheim, BMS, Pfizer, Takeda, Guardant Health, Mirati, AbbVie, Novartis, and GlaxoSmithKline; and has received compensation as a scientific advisor to Foundation Medicine, Guardant Health, Astra Zeneca, Pfizer, Novartis, Merck, BMS, Boehringer-Ingelheim, Genentech, Spectrum, Ignyta. RPS has received compensation as a scientific advisor to Stelexis Therapeutics, Acceleron Pharma, and has ownership in Stelexis Therapeutics.

Copyright © 2021 Elsevier B.V. All rights reserved.

Figures

Figure 1.

Patient disposition (PFT, pulmonary function test).

Figure 2.

Representative case. A 57 year-old African American male with heavily pre-treated stage IV lung adenocarcinoma received 12 cycles of inhaled Azacitidine treatment. (Dx: Diagnosed; PR: partial response; PD: progression of disease; LE: lower extremity; SD: stable disease)

Figure 3.

Global methylation profile in 3 participants who underwent pre- and post-treatment bronchoscopy with paired pre- and post-treatment bronchial epithelium specimens. The Interval between last inhaled treatment and bronchoscopy was approximately 3 days. *=P