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 anattending thoracic surgeon with lobectomy

• ECOG Performance Status 0-1

• Normal bone marrow and organ function on routine laboratory tests, as defined insection 4.1

• Evidence of post-menopausal status or negative urinary/serum pregnancy test forfemale pre-menopausal subjects. Women will be considered post-menopausal if theyhave 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 staffand staff at the study site)

• Prior investigational therapy within 28 days/at least 5 half-lives before study drugadministration

• 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 anattending thoracic surgeon

• Prior therapy with PD-1, PD-L1, CTLA-4 or anti-cancer vaccines, including durvalumaband 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, inthe opinion of the investigator, is likely to require treatment within 6 months oftrial enrollment

• Current or prior use of immunosuppressive medication within 14 days before the firstdose of durvalumab or tremelimumab. The following are exceptions to this criterion:

• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intraarticular injection)

• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day ofprednisone or its equivalent

• Steroids as premedication for hypersensitivity reactions (e.g., CT scanpremedication)

• Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy

• Subjects with irreversible toxicity that is not reasonably expected to beexacerbated 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., hormonereplacement therapy) is acceptable

• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field ofradiation within 4 weeks of the first dose of study drug.

• Major surgical procedure (as defined by the Investigator) within 28 days prior tothe first dose of IP. Note: Local surgery of isolated lesions for palliative intentis acceptable

• History of allogenic organ transplantation.

• Active or prior documented autoimmune or inflammatory disorders (includinginflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [withthe exception of diverticulosis], systemic lupus erythematosus, Sarcoidosissyndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease,rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions tothis criterion (vitiligo or alopecia; hypothyroidism (eg, following Hashimotosyndrome) stable on hormone replacement; any chronic skin condition that does notrequire systemic therapy; active disease in the last 5 years may be included butonly after consultation with the study physician; celiac disease controlled by dietalone.)

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis,active bleeding diatheses including any subject known to have evidence of acute orchronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), orpsychiatric illness/social situations that would limit compliance with studyrequirements or compromise the ability of the subject to give written informedconsent

• Active infection including tuberculosis (clinical evaluation that includes clinicalhistory, physical examination and radiographic findings, and TB testing in line withlocal practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Subjectswith a past or resolved HBV infection (defined as the presence of hepatitis B coreantibody [anti-HBc] and absence of HBsAg) are eligible. Subjects positive forhepatitis C (HCV) antibody are eligible only if polymerase chain reaction isnegative 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 ofreproductive potential who are not employing an effective method of birth control.

• Any condition that, in the opinion of the investigator, would interfere withevaluation 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 withstudy requirements or compromise the ability of the subject to give written consent

• Any condition that, in the opinion of the investigator would interfere withevaluation of study treatment or interpretation of patient safety or study results.