Neoadjuvant Immunoradiation for Resectable Non-Small Cell Lung Cancer

Inclusion Criteria:

* Written informed consent and any locally-required authorization obtained.
* Histologically-confirmed diagnosis of stage III non-small cell lung cancer (NSCLC)
* Age≥18 years
* Life expectancy \>6 months
* Body weight \>30kg
* Subjects with non-small cell lung cancer deemed surgically resectable by an attending thoracic surgeon with lobectomy
* ECOG Performance Status 0-1
* Normal bone marrow and organ function on routine laboratory tests, as defined in section 4.1
* Evidence of post-menopausal status or negative urinary/serum pregnancy test for female pre-menopausal subjects. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause.
* Ability to understand and willingness of sign consent form
* Willingness to comply with the protocol for the duration of the study

Exclusion Criteria:

* Involvement in the planning and/or conduct of the study (includes AstraZeneca staff and staff at the study site)
* Prior investigational therapy within 28 days/at least 5 half-lives before study drug administration
* Prior chest radiation
* Prior history of interstitial lung disease or pneumonitis requiring corticosteroids, or active non-infectious pneumonitis
* Patients only suitable for surgical management with pneumonectomy, deemed by an attending thoracic surgeon
* Prior therapy with PD-1, PD-L1, CTLA-4 or anti-cancer vaccines, including durvalumab and tremelimumab
* Participation in another clinical study with an investigational product in the last 4 weeks or equivalent of 5 half-lives of the first dose of study treatment, whichever is shorter
* History of another primary malignancy that requires active ongoing treatment or, in the opinion of the investigator, is likely to require treatment within 6 months of trial enrollment
* Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. The following are exceptions to this criterion:

  * Intranasal, inhaled, topical steroids, or local steroid injections (e.g., 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 (e.g., CT scan premedication)
* Any unresolved toxicity (\>CTCAE grade 2) from previous anti-cancer therapy
* Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripherally neuropathy)
* Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable
* Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug.
* Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable
* History of allogenic organ transplantation.
* Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], 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 (vitiligo or alopecia; hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement; any chronic skin condition that does not require systemic therapy; active disease in the last 5 years may be included but only after consultation with the study physician; celiac disease controlled by diet alone.)
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
* Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
* Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab or tremelimumab
* Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control.
* Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study result.
* Known allergy or hypersensitivity to IP or any excipient
* Uncontrolled psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written consent
* Any condition that, in the opinion of the investigator would interfere with evaluation of study treatment or interpretation of patient safety or study results.