Summary

This phase III trial studies how well an antibody (durvalumab) with chemotherapy and radiation therapy (chemoradiation) works in treating patients with stage III non-small cell lung cancer that cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This study is being done to see if adding durvalumab to standard chemoradiation followed by additional durvalumab can extend patients life and/or prevent the tumor from coming back compared to the usual approach of chemoradiation alone followed by durvalumab.

Objectives

PRIMARY OBJECTIVE:
I. To evaluate whether there is an improvement in overall survival with concomitant chemotherapy/radiation therapy/MEDI4736 (durvalumab) followed by one year (12 cycles) of MEDI4736 (durvalumab) as compared to concomitant chemotherapy/radiation followed by one year (12 cycles) of MEDI4736 (durvalumab).

SECONDARY OBJECTIVES:
I. To evaluate the difference in response using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria to assess whether or not MEDI4736 (durvalumab) added to concomitant chemo/radiation results in an improvement in response rates.
II. To evaluate any difference in progression free survival (PFS) with concomitant chemotherapy/radiation therapy/MEDI4736 (durvalumab) followed by one year (12 cycles) of MEDI4736 (durvalumab) as compared to concomitant chemotherapy/radiotherapy followed by one year of MEDI4736 (durvalumab).
III. To evaluate whether the incidence of recurrence and recurrence pattern is affected by giving MEDI4736 (durvalumab) during chemo/radiation.
IV. To evaluate any difference in toxicity when MEDI4736 (durvalumab) is added to concomitant chemo/radiation using the Common Terminology Criteria for Adverse Events (CTCAE).

OUTLINE:
STEP 1 (CONCURRENT THERAPY): Patients are randomized to 1 of 2 arms.

ARM A: Patients receive durvalumab intravenously (IV) over 60 minutes on days 1 and 15 of cycle 1 and day 1 of cycle 2. Patients also receive 1 of 3 treatment regimens per investigator choice: 1) etoposide IV over 60 minutes on days 1-5 and cisplatin IV over 60 minutes on days 1 and 8 every 28 days for 2 cycles; 2) pemetrexed disodium IV over 60 minutes and cisplatin IV over 60-120 minutes on day 1 every 21 days for 2 cycles; or 3) paclitaxel IV over 60 minutes and carboplatin IV over 30 minutes on day 1 every 7 days for 6 cycles. Treatment continues in the absence of disease progression or unacceptable toxicity. Beginning on day 1 of chemotherapy, patients receive radiation therapy 5 days a week for 6 weeks.

ARM B: Patients receive 1 of 3 investigator's choice treatment regimens and radiation therapy as in Arm A.

STEP 2 (CONSOLIDATION THERAPY): Within 14 days after the last dose of radiation (from Step 1), all patients then receive durvalumab IV over 60 minutes on day 1. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months if less than 2 years from study entry, every 6 months if 2-5 years from study entry, and then yearly for years 5-10 from study entry.

Eligibility

1. STEP 1 INCLUSION ELIGIBILITY CRITERIA - CONCURRENT THERAPY
2. Patient must be >= 18 years old
3. Patient must have one of the following: * Newly diagnosed stage IIIA/B/C non-small cell lung cancer (NSCLC) (per the American Joint Committee on Cancer [AJCC] 8th edition) that is unresectable and is histologically and/or cytologically confirmed * Nodal recurrence after surgery for early stage NSCLC
4. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
5. Patient must have a body weight > 30 kg
6. Patient must not have unintentional weight loss > 10% within 30 days prior to registration
7. Patient must have a baseline electrocardiography (ECG) obtained within 6 weeks prior to registration
8. Patient must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. Baseline imaging assessments and measurements used to evaluate all measurable or non-measurable sites of disease must be done within 4 weeks prior to registration
9. Absolute neutrophil count (ANC) >= 1500 cells/uL (obtained =< 7 days prior to registration)
10. White blood cells (WBC) counts >= 2500/uL (obtained =< 7 days prior to registration)
11. Platelet count >= 100,000/uL (obtained =< 7 days prior to registration)
12. Hemoglobin >= 9.0 g/dL (obtained =< 7 days prior to registration)
13. Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) with the following exception: patients with known Gilbert disease who have serum bilirubin level < 3 x ULN may be enrolled (obtained =< 7 days prior to registration)
14. Aspartate aminotransferase (AST) and alanine transaminase (ALT) =< 3.0 x institutional ULN (obtained =< 7 days prior to registration)
15. Serum creatinine =< 1.5 x institutional ULN or creatinine clearance >= 45 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation (obtained =< 7 days prior to registration)
16. Patient must have pulmonary function tests (PFTs) with both forced expiratory volume in 1 second (FEV1) and diffusion capacity of the lung for carbon monoxide (DLCO) >= 40% of predicted, obtained within 5 months prior to registration
17. Patient is expected to have lung volume (V)20 of =< 35%, after radiation oncologist views pre-treatment work up
18. Patients with nodal recurrence after surgery for early-stage NSCLC are eligible if the following criteria are met: * No prior chemotherapy or radiation was ever administered for this lung cancer originally or for recurrence prior to entering this protocol * Prior curative-intent surgery was at least 90 days prior to the nodal recurrence * No prior radiation was administered to the region of study cancer that would cause overlap of treatment fields
19. Patients who are human immunodeficiency virus (HIV) positive may participate in the study IF they meet all of the following eligibility requirements: * They must be stable on their anti-retroviral regimen, and they must be healthy from an HIV perspective * They must have a CD4 count of greater than 250 cells/mcL, obtained within 6 months prior to registration * They must not be receiving prophylactic therapy for an opportunistic infection
20. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Patients must not have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to registration
21. Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used.
22. All patients of childbearing potential must have a negative blood test or urine study, with a minimum sensitivity 50 mlU/L or equivalent units of HCG, within 7 days prior to registration to rule out pregnancy. A patient of childbearing potential is anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
23. Patients must not expected to conceive or father children by using accepted and highly effective method(s) of contraception during sexual intercourse for at least one week prior to the start of treatment, during protocol treatment, and continue for 90 days after the last dose of protocol treatment. * Highly effective methods of contraception include Etonogestrel-releasing implants (Implanon or Norplant), Intravaginal: Ethinylestradiol/etonogestrel-releasing intravaginal devices: e.g., NuvaRing, injection: Medroxyprogesterone injection: e.g., Depo-Provera, combined pill: Normal and low dose combined oral contraceptive pill, patch: Norelgestromin/ethinylestradiol-releasing transdermal system: e.g., Ortho Evra, Minipillc: Progesterone based oral contraceptive pill using desogestrel: Cerazette is currently the only highly effective progesterone based pill * Methods that are considered inadequate include male or female condom with or without spermicide; female cap, diaphragm, or sponge with or without spermicide; non-copper containing intrauterine device; progestogen-only oral hormonal contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral contraceptive pills)
24. STEP 2 INCLUSION ELIGIBILITY CRITERIA - CONSOLIDATION
25. Patients with any > grade 2 non-hematologic or > grade 3 hematologic toxicities must recover to grade 2 (or less) within 45 days after the end of Step 1 concurrent chemo/radiation, with the exception of alopecia and vitiligo