Treating Early-stage Non-Small Cell Lung Cancer With Durvalumab and Radiation Therapy

Inclusion Criteria:

• Capable of giving signed informed consent which includes compliance with therequirements and restrictions listed in the informed consent form (ICF) and in thisprotocol. Written informed consent and any locally required authorization obtainedfrom the patient/legal representative prior to performing any protocol- relatedprocedures.

• Patient age ≥ 18 at time of consent

• Early stage NSCLC (Stage I to IIIA; T1-4 excluding patients with satellite nodulesin the same or ipsilateral lobes, N0; AJCC 8th edition)

• Ineligible for or unwilling to undergo surgical resection. Reasons for surgicalineligibility include: medically inoperable or surgically unresectable (due to tumorsize, location etc.), as assessed by MSKCC thoracic surgeon or multi-disciplinarytumor board consensus. Reasons for ineligibility or patient's unwillingness toundergo surgical resection must be clearly documented.

• Histological and/or cytological confirmation of NSCLC as per standard of carebiopsy; no additional research protocol-specific biopsy is needed.

• ECOG/WHO PS 0-1 (KPS 70-100)

• Candidates for definitive SBRT

° If, after candidates have been planned for RT, they are unable to be treated withthe institutional dose constraints as listed in the appendix, they will be labeledineligible and removed from the study. Ineligible patients will be replaced.

• A predicted 2-year PFS of <80% (≥20% risk for disease progression) based on anMSKCC-developed radiomics risk prediction model (see section 9.0).

• Body weight > 30kg

• Adequate normal organ and marrow function as defined below:

• Hemoglobin ≥9.0 g/dL

• Absolute neutrophil count (ANC) 1.5 x (> 1500 per mm^3)

• Platelet count ≥75 x 10^9/L (>75,000 per mm^3)

• Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will notapply to patients with confirmed Gilbert's syndrome (persistent or recurrenthyperbilirubinemia that is predominantly unconjugated in the absence ofhemolysis or hepatic pathology), who will be allowed only in consultation withtheir physician.

• AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal

• Evidence of post-menopausal status or negative urinary or serum pregnancy test forfemale pre-menopausal patients. Women will be considered postmenopausal if they havebeen amenorrheic for 12 months without an alternative medical cause. The followingage- specific requirements apply:

• Women <50 years of age would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of exogenous hormonaltreatments and if they have luteinizing hormone and follicle-stimulatinghormone levels in the postmenopausal range for the institution or underwentsurgical sterilization (bilateral oophorectomy or hysterectomy).

• Women ≥50 years of age would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of all exogenous hormonaltreatments, had radiation-induced menopause with last menses >1 year ago, hadchemotherapy-induced menopause with last menses >1 year ago, or underwentsurgical sterilization (bilateral oophorectomy, bilateral salpingectomy orhysterectomy).

• Must have a life expectancy of at least 12 weeks

Exclusion Criteria:

• Participation in another clinical study with an investigational product during thelast 4 weeks.

• Previous thoracic radiation precluding definitive SBRT to the current tumor.

• 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:

1. Patients with vitiligo or alopecia

2. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable onhormone replacement

3. Any chronic skin condition that does not require systemic therapy

4. Patients without active disease in the last 5 years may be included but onlyafter consultation with the PI

5. Patients with celiac disease controlled by diet alone

• Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with theexception of alopecia, vitiligo, and the laboratory values defined in the inclusioncriteria

1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basisafter consultation with the PI.

2. Patients with irreversible toxicity not reasonably expected to be exacerbatedby treatment with durvalumab may be included only after consultation with thePI.

• Prior/Current Therapies:

1. Treatment with a monoclonal antibody within 4 weeks prior to study Day 1 or hasnot recovered (i.e., ≥ Grade 1 at baseline) from adverse events due to agentsadministered > 4 weeks earlier (intraocular bevacizumab is acceptable).

2. Prior chemotherapy or targeted small molecule therapy, within 3 weeks prior tostudy Day 1 or has not recovered (i.e., ≥ Grade 1 at baseline) from adverseevents due to a previously administered agent).

3. Prior therapy with an anti-PD-1, anti-PD-L1, including durvalumab, anti-PDL2,anti-CD137, anti-Cytotoxic T- lymphocyte-associated antigen-4 (CTLA-4)antibody, or any other antibody or drug specifically targeting T-cellco-stimulation or checkpoint pathways.

4. Current or prior use of immunosuppressive medication within 14 days before thefirst dose of durvalumab. The following are exceptions to this criterion: i. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intraarticular injection) ii. Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent iii. Steroids as premedication forhypersensitivity reactions (e.g., CT scan premedication) e. Any concurrentchemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent useof hormonal therapy for non-cancer-related conditions (e.g., hormone replacementtherapy) is acceptable. f. Prior chemotherapy for this diagnosis of lung cancer

• 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.

• Severe concurrent illness:

1. Known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.

2. Known additional malignancy that is progressing or requires active treatment.Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma ofthe skin, or in situ cervical cancer that has undergone potentially curativetherapy.

3. Active infection including tuberculosis (clinical evaluation that includesclinical history, physical examination and radiographic findings, and TBtesting in line with local practice), hepatitis B (known positive HBV surfaceantigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positiveHIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined asthe presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) areeligible. Patients positive for hepatitis C (HCV) antibody are eligible only ifpolymerase chain reaction is negative for HCV RNA.

4. Active infection requiring systemic therapy.

5. Evidence of interstitial lung disease or active, non-infectious pneumonitis.

6. Clinically significant (i.e., active) cardiovascular disease: symptomaticcerebral vascular accident/stroke (< 6 months prior to enrollment), myocardialinfarction (< 6 months prior to enrollment), unstable angina, congestive heartfailure (≥ New York Heart Association Classification Class II), or seriouscardiac arrhythmia requiring medication.

• Female patients who are pregnant or breastfeeding or male or female patients ofreproductive potential who are not willing to employ a highly effective birthcontrol from screening to 90 days after the last dose of durvalumab monotherapy. a. Highly effective methods of contraception, defined as one that results in a lowfailure rate (ie, less than 1% per year) when used consistently and correctly aredescribed in Appendix B. Note that some contraception methods are not consideredhighly effective (e.g. male or female condom with or without spermicide; female cap,diaphragm, or sponge with or without spermicide; non-copper containing intrauterinedevice; progestogen-only oral hormonal contraceptive pills where inhibition ofovulation is not the primary mode of action [excluding Cerazette/desogestrel whichis considered highly effective]; and triphasic combined oral contraceptive pills).

• Live vaccination within 4 weeks prior to the first dose of durvalumab and while ontrial is prohibited except for administration of inactivated vaccines.

• Connective tissue disorders or idiopathic pulmonary fibrosis involving the lungsand/or esophagus

• Known actionable EGFR or ALK mutation

• Known contraindications to radiotherapy

• History of leptomeningeal carcinomatosis

• History of active primary immunodeficiency

• Known allergy or hypersensitivity to any of the study drugs or any of the study drugexcipients.

• Prior randomization or treatment in a previous durvalumab clinical study regardlessof treatment arm assignment.

• Participants must not donate blood while on durvalumab therapy.