Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.
Patients are eligible to be included in the study only if all of the following inclusion criteria and none of the exclusion criteria apply.
1. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol
2. Provision of signed and dated written ICF prior to any mandatory study specific procedures, sampling, and analyses
3. Genetics research study (optional) For inclusion in the optional (DNA) genetics research study, patients must fulfil the following criteria:
− Provide informed consent for the optional genetic sampling and analyses. If a patient declines to participate in the optional genetics research, there will be no penalty or loss of benefit to the patient. A patient who declines optional genetics research participation will not be excluded from any other aspect of the main study.
Note: The optional genetic research study is not conducted in China.
4. Age ≥18 years at the time of screening. For patients aged <20 years and enrolled in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative.
Type of patient and disease characteristics
5. Histologically or cytologically documented Stage I to II NSCLC (American Joint Committee on Cancer Stage [AJCC Cancer Staging Manual, Eighth Edition], with clinical Stage I/II lymph node-negative (T1 to T3N0M0) disease and planned to receive definitive treatment with SBRT. In order to be eligible for this trial, patients
Medically inoperable as determined by physician or
Medically operable with patient refusal of surgery
Patients with medically operable disease who choose to have SBRT are also eligible.
6. Planned SoC SBRT as definitive treatment (see Appendix H) using one of the following doses:
For peripheral tumors: 54 Gy total dose delivered in 3 fractions, 42 or 48 Gy total dose delivered in 4 fractions, or 50 or 55 Gy total dose delivered in 5 fractions.
For central tumors: 50 or 55 Gy total dose delivered in 5 fractions, or 50 or 60 Gy total dose delivered in 8 fractions.
7. World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) PS of 0, 1, or 2 at enrollment and randomization
8. Tumor sample requirements:
- Provision of archived tumor tissue block or slides (6 newly cut unstained slides is strongly encouraged) ≤6 months old.
If an archival sample is not available, provision of a recent (≤3 months) tumor biopsy is encouraged, provided that a biopsy procedure is technically feasible, and the procedure is not associated with unacceptable clinical risk.
If archival tumor tissue block, slides are unavailable, cell blocks or slides from fine needle aspirate (FNA) samples ≤6 months old will be accepted.
In situation when tissue from initial biopsy is exhausted, rebiopsy is encouraged but not mandatory for enrolling onto study if biopsy is associated with unacceptable clinical risk
- For China: Only tumor slides (sectioned from biopsy or FNA cell blocks) should be provided.
9. Patients with central or peripheral lesions are eligible. Central lesions are defined as tumor within or touching the zone of the proximal bronchial tree, defined as a volume of 2 cm in all directions around the proximal bronchial tree (carina, right and left main bronchi, right and left upper lobe bronchi, intermedius bronchus, right middle lobe bronchus, lingular bronchus right, and left lower lobe bronchi). Patients with Ultra-central tumors are NOT eligible. Ultra-central tumors are defined as tumors abutting the trachea, mainstem bronchus, or esophagus.
10. Patients with a history of metachronus stage I/II (T1-T3N0M0) NSCLC treated definitively with surgery only or SBRT only >1 year prior to enrollment are eligible. Patients with a previous history of SBRT to the lung are eligible provided additional radiation is deemed safe by the treating radiation oncologist and after consultation with the Study Physician/International Coordinating Investigator. Patients with synchronous NSCLC tumors are allowed when there is maximum of 2 intrathoracic lesions. Each lesion will be staged separately according to TNM system and identified in CRF. Please see section 5.3. Lesions must be treated with the same dose/fraction to each lesion and meet the Organ at Risk constraints identified in the study protocol.
11. Adequate organ and marrow function as defined below prior to randomization:
Hemoglobin ≥9.0 g/dL
Absolute neutrophil count ≥1.0 × 109/L
Platelet count ≥75 × 109/L
Serum bilirubin ≤1.5 × the upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome, who will be allowed in consultation with their physician.
ALT and AST ≤2.5 × ULN within 2 weeks prior to randomization
Measured creatinine clearance (CL) >30 mL/min or calculated CL >30 mL/min as determined by Cockcroft-Gault (using actual body weight)
Creatinine CL (mL/min) = Weight (kg) × (140 - Age) / 72 × serum creatinine (mg/dL)
Creatinine CL (mL/min) = Weight (kg) × (140 - Age) / 72 × serum creatinine (mg/dL) x0.85
12. Must have a life expectancy of at least 12 weeks
13. The following staging studies must be done within 10 weeks before randomization:
Positron emission tomography (PET)/CT scan from at least the base of the skull to mid-thigh is required for staging purposes. If PET scan not previously performed, may be performed during screening to ensure adequate clinical staging.
Patients with hilar or mediastinal lymph nodes ≤1 cm and no abnormal hilar or mediastinal uptake on PET will be considered N0. Mediastinal lymph node sampling by any technique is allowed but not required. Patients with >1 cm hilar or mediastinal lymph nodes on CT or abnormal PET (including suspicious but nondiagnostic uptake) may still be eligible if directed tissue biopsies of all abnormally identified areas are negative for cancer.
14. Body weight >30 kg
15. Male and/or female
16. Pulmonary Function Testing within 12 weeks of randomization
1. Mixed small cell and non-small cell cancer
2. History of allogeneic organ transplantation
3. 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 Study Physician
Patients with celiac disease controlled by diet alone
4. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure (NYHA Class III or IV), uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs, or compromise the ability of the patient to give written informed consent. Patients with controlled chronic obstructive pulmonary disease (COPD) are allowed.
5. History of another primary malignancy except for
Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
Adequately treated carcinoma in situ without evidence of disease
6. History of active primary immunodeficiency
7. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B (known positive hepatitis B surface antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus (positive human immunodeficiency virus [HIV] 1/2 antibodies). Patients with a past or resolved hepatitis B (HBV) infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
8. History of non-infectious pneumonitis requiring steroids, or patients with Grade ≥2 pneumonitis
9. (Exclusion Criterion #1 is no longer applicable as of Protocol Version 3.0.)
10. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
11. Prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 antibodies, excluding therapeutic anticancer vaccines
12. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable. If patient has been on adjuvant hormonal treatment for early stage breast cancer for more than 5 years, and there is no evidence of recurrence, then patient is eligible with study physician discussion.
13. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine while receiving IP and up to 90 days after the last dose of IP.
14. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP.
15. Current or prior use of immunosuppressive medication within 14 days before the first dose of IP. 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) Prior/concurrent clinical study experience
16. Participation in another clinical study with an IP administered in the last 4 weeks
17. Previous IP assignment in the present study
18. Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
19. Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment group assignment
20. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
21. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab.
22. Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.
Genetics research study (optional):
23. Exclusion criteria for participation in the optional (DNA) genetics research component of the study include:
-Previous allogeneic bone marrow transplant
-Non-leukocyte-depleted whole blood transfusion in 120 days of genetic sample collection