This phase 1b/2a study evaluates the safety, feasibility, and efficacy of combining dupilumab (anti-IL-4Rα) and cemiplimab (anti-PD-1) in patients with early-stage, resectable NSCLC. Phase 1b focuses on safety and feasibility, using a 3+3 design to monitor dose-limiting toxicities (DLTs), while Phase 2a assesses the major pathological response (MPR) rate with a Simon's two-stage minimax design. Secondary endpoints include event-free survival, overall survival, and translational objectives such as deep immune monitoring from patient samples, with the trial expected to enroll 24 patients at CHUM over five years.

Inclusion Criteria:

• Histological confirmation of NSCLC is required before treatment (however, patients with a smoking history and radiographic findings suggestive of NSCLC may consent prior to biopsy to combine research and diagnostic procedures.
• Age ≥ 18 years.
• ECOG performance status 0-1
• Determined to be a surgical candidate for tumor resection by a multidisciplinary team.
• Women of childbearing potential and men must use approved contraception during the study and for 4 months post-treatment. Pregnancy or suspected pregnancy must be reported immediately.
• Adequate organ and marrow function.
• Pre-treatment biopsies are mandatory, and tumors must be T1b or larger (>1cm) and amenable to biopsy as determined by a multidisciplinary team.
• Patients must consent to provide blood at designated study time points.
• Patients must consent to core needle biopsies (at least 3 samples, as deemed safe by the performing surgeon/radiologist) prior to treatment initiation

Exclusion Criteria:

• History of autoimmune disorders or use of immunomodulatory drugs (including dupilumab) within 2 months prior to treatment initiation.
• Active autoimmune disease requiring systemic treatment in the past year, excluding replacement therapies like thyroxine or insulin.
• Use of immunosuppressive drugs or systemic steroids within 7 days prior to treatment, except chronic steroids ≤10mg prednisone or equivalent.
• No smoking history or confirmed tissue or ctDNA evidence of actionable driver alterations (e.g. EGFR mutation, ALK, or ROS1 rearrangements)
• Prior chemotherapy or radiotherapy for another primary tumor, or prior locoregional therapy to the target lesion. Therapy for a different cancer is acceptable.
• Metastatic disease where surgery would not have curative intent.
• Uncontrolled illness, including active infections requiring antibiotics, symptomatic heart failure, unstable angina, or psychiatric/social conditions impeding study compliance.
• Pregnancy or nursing, due to potential harm to the fetus or infant.
• Progressive malignancy requiring active treatment, except for certain stable cancers treated with curative intent
• HIV infection with detectable viral load or not on a stable HAART regimen
• Active Hepatitis B or C (PCR-detectable)
• History of allogeneic hematopoietic or solid organ transplantation.
• Documented hypersensitivity to protein therapeutics.
• Any condition, therapy, or abnormality that may interfere with trial results, patient participation, or their best interest as per the investigator's judgment.