Background and Objectives

This clinical trial evaluates a novel pre‑operative therapeutic regimen in patients with early‑stage non‑small cell lung cancer (NSCLC). Standard of care alone leaves a substantial risk of recurrence, prompting the need for additional treatment. Investigators will administer inhaled azacitidine (AZA) together with a platinum‑based chemotherapy and the immune‑checkpoint inhibitor durvalumab to reduce microscopic residual disease and enhance anti‑tumor immunity. The ultimate goal is to lower lung‑cancer recurrence and improve surgical success rates.

Study Design

The study runs Phase 1 and Phase 2 concurrently, with each cycle lasting 21 days for a total of three cycles. During the first three days of each cycle, inhaled AZA is delivered via nebulizer for 20–30 minutes. On day 4, durvalumab and platinum chemotherapy are given intravenously. The primary endpoint focuses on safety and dose‑finding, while secondary assessments include efficacy based on tumor‑tissue changes and immune‑marker modulation. This design aims to capture both the direct pulmonary delivery effect of the drug and systemic immune activation.

Patient Population and Expected Benefits

Eligible participants are adults (≥18 years) with resectable early‑stage NSCLC who will undergo mandatory pre‑ and post‑treatment tissue biopsies and blood sampling. Inhaled AZA is expected to act locally in the lung, minimizing systemic toxicity while delivering epigenetic DNA‑methyltransferase inhibition. Durvalumab blocks PD‑L1 to promote immune‑cell recognition of tumor cells. If the two mechanisms act synergistically, the regimen could markedly reduce recurrence risk compared with existing neoadjuvant approaches.

Current Treatment Landscape and Differentiation

The only FDA‑approved neoadjuvant regimen for early‑stage NSCLC currently combines durvalumab with standard chemotherapy, and AZA is available solely via intravenous infusion. Inhaled AZA concentrates the drug within the lung, lowering systemic exposure and inducing direct epigenetic remodeling of pulmonary tissue. This approach offers a high‑local‑concentration effect and concurrent immune activation that are not achievable with existing therapies.

Future Outlook and Impact

Success of this trial could redefine early‑lung‑cancer treatment by establishing a new combination of inhaled epigenetic therapy and immunotherapy. Expanded neoadjuvant options would enable more personalized strategies, potentially improving long‑term survival and expanding market size. Conversely, failure would clarify the limitations of inhaled epigenetic agents and guide future research directions.