The purpose of the study is to determine the feasibility of genomically guided radiation therapy (RT) with concurrent chemotherapy in the management of stage II and III non-small cell lung cancer (NSCLC).

Inclusion Criteria:

• Diagnosis of AJCC Stage 2 or Stage 3 unresectable NSCLC as determined by a multidisciplinary oncology team
• Confirmation of NSCLC with availability of fresh tumor biopsy by tissue biopsy which can include adenocarcinoma, squamous cell, large cell carcinoma, or NSCLC not otherwise specified
• Life expectancy >12 weeks
• Normal renal (creatinine <1.5 × upper limit of normal [ULN]), liver (bilirubin < 1.5 × ULN, transaminases <3.0 × ULN, except in known hepatic disease, wherein may be <5 × ULN) and blood counts (white blood cells ≥2.5, neutrophils ≥1000, platelets ≥50, 000, hemoglobin ≥8)
• ECOG 0-1
• Age ≥ 18 years
• Participants with surgery within 14 days should have recovered from all effects of the surgery and be cleared by their surgeon
• There is no limit on prior systemic or therapies
• Women of childbearing potential and sexually active males must commit to the use of effective contraception while on study
• Ability to sign an informed consent form, which can be signed by a family member or health care proxy. Informed consent must be given before any study related procedures occur.

Exclusion Criteria:

• Current or prior participation in a study of an investigational agent or investigational device within 2 weeks of the first dose of study treatment
• Major surgery or significant traumatic injury that has not been recovered from 14 days before the initiation of study drug
• Women who are pregnant or breastfeeding
• History of allergy or hypersensitivity to any of the study drugs or study drug components
• Concurrent brain metastases or leptomeningeal disease
• History of prior malignancy within 2 years prior to screening, with the exception of those with a negligible risk of metastasis or death (e.g., 5-year OS of > 90%), such as but not limited to, non-melanoma skin carcinoma, ductal carcinoma in situ, or stage I endometriod uterine cancer, and others at the discretion of the PI
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
• • Patients with vitiligo or alopecia
• • Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement
• • Any chronic skin condition that does not require systemic therapy
• • Patients without active disease in the last 5 years may be included but only after consultation with the Principal Investigator
• • Patients with celiac disease controlled by diet alone
• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:
• • Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular injection)
• • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
• • Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)