Genomically Guided Radiation Dose Personalization in Locally Advanced 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)