Inclusion Criteria:
1. Ability of participant to understand this study, and participant willingness to sign a written informed consent.
2. Stated willingness to comply with all study procedures / study intervention regimen and availability for the duration of the study
3. Males and females age ≥ 18 years
4. Histologically or cytologically confirmed unresectable Stage III NSCLC
5. Completion of definitive concurrent chemoradiation (CRT) within 6 weeks prior to enrollment/registration
6. MRD-positive status confirmed by a validated circulating tumor DNA (ctDNA) assay within 6 weeks following chemoradiation
7. Eastern Cooperative Oncology Groug (ECOG) Performance Status (PS): 0 - 2 (Appendix A)
8. Availability of archival tumor tissue for tumor-informed ctDNA assay, or eligibility for a validated plasma-only ctDNA panel if tumor tissue is unavailable.
9. Patients with a prior or concurrent malignancy are eligible provided the malignancy is not expected to interfere with study treatment, safety assessment, or interpretation of study endpoints, in the opinion of the treating investigator
10. Females of childbearing potential must have a negative serum or urine pregnancy test 48 hours prior to initiating treatment.
11. Females of child-bearing potential and males with partners of child-bearing potential must agree not to donate sperm, to practice sexual abstinence or to use the forms of contraception listed in Child-Bearing Potential/Pregnancy section for the duration of study participation and :
* Females: for 6 months after the last dose of the study medication.
* Males: for 3 months after the last dose of the study medication.
12. Adequate organ function, defined as follows:
* Leukocytes \> 1.5 × 10⁹/L
* Absolute Neutrophil Count (ANC) \> 1.5 × 10⁹/L Note: Patients with benign neutropenia may be eligible with ANC 1000-1500 if deemed safe by the treating physician.
* Platelets \> 100 × 10⁹/L
* Hemoglobin ≥ 9 g/dL
* Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min (Cockcroft-Gault)
* Total bilirubin ≤ 1.5 × ULN or direct bilirubin ≤ 1 × ULN
* AST and ALT ≤ 2.5 × ULN (≤ 5 × ULN if liver metastases present)
Exclusion Criteria:
1. Prior neoadjuvant chemotherapy.
2. Concurrent or planned use of other anti-neoplastic or investigational agents during study participation.
3. Absence of post-chemoradiation ctDNA results
4. Radiographic evidence of disease progression on CT and/or PET/CT imaging within 6 weeks following completion of definitive concurrent chemoradiation
5. Presence of known sensitizing genomic alterations, including EGFR mutations or ALK rearrangements..
6. Diagnosed with a psychiatric illness or is in a social situation that would limit compliance with study requirements
7. Currently pregnant or breastfeeding
8. Has a known allergic reaction to any excipient contained in the study drug formulation
9. Patients with a prior or concurrent malignancy are eligible provided the malignancy is not expected to interfere with study treatment, safety assessment, or interpretation of study endpoints, in the opinion of the treating investigator
10. Any condition, diagnosis, or physical exam finding that, in the opinion of the investigator, would pose excessive risk or interfere with study participation
11. Known history of autoimmune disease requiring systemic immunosuppression (if applicable to durvalumab safety profile)
12. Has not had ctDNA testing prior to study enrollment
13. Known history of interstitial lung disease or pneumonitis requiring steroids (if applicable)
14. Known active hepatitis B, hepatitis C, or HIV infection with uncontrolled viral load or clinically significant active disease
