Author of

• 36050

  +

  P01 - Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics (ID 227)

  • Event: WCLC 2020
  • Type: Posters
  • Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
  • Presentations: 1
  • Moderators:
  • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall

  • 36055

    +

    P01.05 - Pilot Study of Inhaled Azacitidine in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 3500)

    00:00 - 00:00  |  Presenting Author(s): Haiying Cheng
    • Abstract
    • Slides

    Introduction
    

    Aerosolized 5-Azacitidine (5-Aza) has been shown to inhibit orthotopic lung cancer growth and induce re-expression of methylated tumor suppressor genes in murine models of NSCLC. We hypothesize that inhaled 5-Aza could be safe and effective in reversing epigenetic changes in the bronchial epithelium, most secondary to chronic smoking.

    Methods
    

    We report the first in human study of inhaled 5-Aza. Commercially available 5-Aza in aqueous solution was used to generate an aerosol suspension of a mean particle size of 1 to 5µm. Main inclusion criteria: Stage IV or recurrent NSCLC with predominantly lung involvement, ≥1 prior systemic therapy, ECOG PS 0-1, and good pulmonary function. Patients were treated with inhaled 5-Aza daily on days 1-5 and 15-19 of 28-day cycles, at 3 escalating doses (15, 30 and 45mg/m² daily). The starting dose was 15mg/m² which was derived from our preclinical studies that showed it to be a safe, non-cytotoxic and effective as a DNA demethylating dose. The primary objective was to determine the feasibility and tolerability of this new therapeutic modality. The secondary objectives included PK, methylation profiles, efficacy (RECIST 1.1), PFS and OS. The MethylFlash^TM Global DNA Methylation (5-mC) ELISA assay was used to check global methylation profiles in paired pre and post-treatment bronchial epithelium specimens.

    Results
    

    From 3/2015 to 2/2018, eight patients were treated: The median age was 70 years, 5 (62.5%) were female, 5 (62.5%) were African American, and 5 (62.5%) were active or former smokers. The mean number of prior therapies was 3. The patients received an average of 3.4 cycles of inhaled 5-Aza. No clinically significant adverse events were observed, although one patient treated at the highest dose developed an asymptomatic grade 2 decreased DLCO (defined as the dose-limiting toxicity) which resolved spontaneously. One (12.5%) patient who received 12 cycles of therapy had an objective and durable partial response, and two (25%) patients had stable diseases. All three received inhaled therapy at doses of 30 or 45 mg/m². Median PFS and OS were 1.8 and 11.6 months, respectively.

    PK analysis revealed no measurable plasma Azacitidine at the lowest dose level. At higher doses (30 or 45 mg/m²), the plasma Azacitidine concentration was measurable right following the first daily inhalation at 6.66±9.72ng/ml (0 hour post dose), and increased after the fifth daily treatment at 17.87±18.10ng/ml. The plasma level quickly decreased by 80%-90% at 2 hours post inhalation and became undetectable 4 hours afterwards. 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 approximately 3 days.

    Conclusion
    

    Inhaled 5-Aza at the doses given is well-tolerated and results in minimal systemic absorption. The results of the study justify to continue developing inhaled 5-Aza using a non-cytotoxic dose in patients with lung-confined malignant and/or premalignant lesions. Clinical trial information: NCT02009436. Supported by NIH CA154755.

    Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.