Summary

This phase II/III trial compares the addition of radiation therapy to the usual treatment (immunotherapy with or without chemotherapy [carboplatin, pemetrexed, paclitaxel, nab-paclitaxel]) versus (vs.) usual treatment alone in treating patients with non-small cell lung cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) or that has spread from where it first started (primary site) to other places in the body (metastatic) whose tumor is also negative for a molecular marker called PD-L1. Stereotactic body radiation therapy (SBRT) is a type of radiation therapy that uses high energy x-rays to kill tumor cells and shrink tumors. This method uses special equipment to position a patient and precisely deliver radiation to tumors with fewer doses over a shorter period and may cause less damage to normal tissue than conventional radiation therapy. Immunotherapy with monoclonal antibodies, such as nivolumab, ipilimumab and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of cancer cells. Pemetrexed is in a class of medications called antifolate antineoplastic agents. It works by stopping cells from using folic acid to make DNA and may kill cancer cells. Paclitaxel is in a class of medications called antimicrotubule agents. It stops cancer cells from growing and dividing and may kill them. Paclitaxel is in a class of medications called antimicrotubule agents. It stops cancer cells from growing and dividing and may kill them. Nab-paclitaxel is an albumin-stabilized nanoparticle formulation of paclitaxel which may have fewer side effects and work better than other forms of paclitaxel. The addition of radiation therapy to usual treatment may stop the cancer from growing and increase the life of patients with advanced non-small cell lung cancer who are PD-L1 negative.

Objectives

PRIMARY OBJECTIVE:
I. To assess if stereotactic body radiation therapy (SBRT) improves the progression free survival (PFS, phase II portion) and overall survival (OS, phase III portion) of advanced stage non-small cell lung cancer (NSCLC) patients with PD-L1 tumor proportion score (TPS) < 1% who receive immunotherapy with or without chemotherapy.

SECONDARY OBJECTIVES:
I. To estimate and compare the rates of >= grade 3-4 and all grade adverse events by Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 between the arms.
II. To summarize and compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) between the arms.
III. To determine and compare the objective response rate (ORR) per RECIST between the arms (including at both irradiated and un-irradiated sites).

QUALITY OF LIFE (QOL) OBJECTIVE:
I. To assess the health-related QOL in both treatment arms.

CORRELATIVE SCIENCE OBJECTIVE:
I. To evaluate changes in the peripheral immune microenvironment between the arms.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive 1 of 6 treatment options.

Some patients receive immunotherapy alone whether they have squamous or non-squamous histology.

OPTION 1: Patients receive nivolumab intravenously (IV) over 30 minutes on days 1 and 22 and ipilimumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 6 weeks for 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo magnetic resonance imaging (MRI) or computed tomography (CT) on study. Patients may undergo blood sample collection and tissue biopsy on study.

Patients with non-squamous histology receive 1 of 2 options.

OPTION 2: Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle, carboplatin IV on days 1 and 22 of cycles 1 and 2, and pemetrexed IV over 10 minutes on days 1 and 22 of each cycle. Cycles repeat every 6 weeks for 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI or CT on study. Patients may undergo blood sample collection and tissue biopsy on study.

OPTION 3: Patients receive nivolumab IV over 30 minutes on days 1 and 22 and ipilimumab IV over 30 minutes on day 1 of each cycle. Patients also receive carboplatin IV on days 1 and 22 of cycle 1 and pemetrexed IV over 10 minutes on days 1 and 22 of cycle 1. Cycles repeat every 6 weeks for 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI or CT on study. Patients may undergo blood sample collection and tissue biopsy on study.

Patients with squamous histology receive 1 of 3 options.

OPTION 4: Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Patients also receive carboplatin IV and paclitaxel IV over 1-96 hours on days 1 and 22 of cycles 1 and 2. Cycles repeat every 6 weeks for 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI or CT on study. Patients may undergo blood sample collection and tissue biopsy on study.

OPTION 5: Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Patients also receive carboplatin IV on days 1 and 22 of cycles 1 and 2, and nab-paclitaxel IV over 30 minutes on days 1, 8, 15, 22, 29 and 36 of cycles 1 and 2. Cycles repeat every 6 weeks for 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI or CT on study. Patients may undergo blood sample collection and tissue biopsy on study.

OPTION 6: Patients receive nivolumab IV over 30 minutes on days 1 and 22 and ipilimumab IV over 30 minutes on days 1 of each cycle. Patients also receive carboplatin IV and paclitaxel IV over 1-96 hours on days 1 and 22 of cycle 1. Cycles repeat every 6 weeks for 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI or CT on study. Patients may undergo blood sample collection and tissue biopsy on study.

Arm B: Patients receive 1 of 6 treatment options as in Arm A. Patients also undergo 3 fractions of SBRT every other day. Patients also undergo MRI or CT on study. Patients may undergo blood sample collection and tissue biopsy on study.

After completion of study treatment, patients are followed up every 3 months for 3 years and then every 6 months for years 4-5 following randomization until disease progression. Following disease progression patients are followed for survival every 6 months for up to 5 years following randomization.