Testing the Addition of Radiation Therapy to the Usual Treatment (Immunotherapy With or Without Chemotherapy) for Stage IV Non-Small Cell Lung Cancer Patients Who Are PD-L1 Negative

Study Overview
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Brief Summary
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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.

Detailed Description
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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), computed tomography (CT), or positron emission tomography (PET) throughout the trial. Patients may undergo blood sample collection and tissue biopsy on study as well as echocardiography (ECHO) during screening. 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, CT, or PET throughout the trial. Patients may undergo blood sample collection and tissue biopsy on study as well as ECHO during screening. 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, CT, or PET throughout the trial. Patients may undergo blood sample collection and tissue biopsy on study as well as ECHO during screening. 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, CT, or PET throughout the trial. Patients may undergo blood sample collection and tissue biopsy on study as well as ECHO during screening. 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, CT, or PET throughout the trial. Patients may undergo blood sample collection and tissue biopsy on study as well as ECHO during screening. 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, CT, or PET throughout the trial. Patients may undergo blood sample collection and tissue biopsy on study as well as ECHO during screening. 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, CT, or PET throughout the trial. Patients may undergo blood sample collection and tissue biopsy on study as well as ECHO during screening. 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.

Official Title
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A Randomized Phase II/III Trial of Modern Immunotherapy Based Systemic Therapy With or Without SBRT for PD-L1-Negative, Advanced Non-Small Cell Lung Cancer

Conditions
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Lung Adenocarcinoma, Lung Adenosquamous Carcinoma, Lung Non-Small Cell Carcinoma, Stage IIIB Lung Cancer AJCC v8, Stage IIIC Lung Cancer AJCC v8, Stage IV Lung Cancer AJCC v8

Intervention / Treatment
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* Procedure: Biopsy
* Procedure: Biospecimen Collection
* Drug: Carboplatin
* Procedure: Computed Tomography
* Procedure: Echocardiography
* Biological: Ipilimumab
* Procedure: Magnetic Resonance Imaging
* Drug: Nab-paclitaxel
* Biological: Nivolumab
* Drug: Paclitaxel
* Biological: Pembrolizumab
* Drug: Pemetrexed
* Procedure: Positron Emission Tomography
* Other: Quality-of-Life Assessment
* Radiation: Stereotactic Body Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic or cytologic diagnosis of stage IV NSCLC using version American Joint Committee on Cancer (AJCC) 8th edition (includes M1a, M1b, and M1c stage disease). Patients with stage IIIB and IIIC disease are eligible if they are not a candidate for combined chemotherapy and radiation PD-L1 expression tumor proportion score (TPS) < 1% in tumor cells. If PD-L1 expression TPS is unevaluable or the testing could not be completed patients are not eligible. The assay must have been performed locally by a Clinical Laboratory Improvement Act (CLIA) (or equivalent) certified laboratory. The type of assay will be recorded For non-squamous patients only (adenocarcinoma or adenosquamous): EGFR, ALK and ROS1 testing must be done locally. No patients with known actionable EGFR mutations (except exon 20 insertion), ALK or ROS1 mutations that can be treated with oral tyrosine inhibitors Measurable disease based on RECIST 1.1, including at least two cancerous deposits. At least one deposit must be RECIST measurable (and not to be irradiated) while at least one OTHER deposit (measurable or non-measurable) must meet criteria for SBRT Age >= 18 years Eastern Cooperative Oncology Group (ECOG) performance status 0-2 No prior systemic chemotherapy or immunotherapy for advanced NSCLC No prior treatment with checkpoint inhibitors for metastatic lung cancer Chemotherapy for non-metastatic disease (e.g., adjuvant therapy) or immunotherapy for locally advanced stage III disease is allowed if terminated at least 6 months prior to registration No systemic immunostimulatory or immunosuppressive drugs, including > 10 mg prednisone equivalent per day, within 2 weeks or 5 half-live of the drug, whichever is shorter >= 1 week prior to registration since palliative (including central nervous system [CNS]) radiotherapy to any tumor site No prior allogeneic tissue/solid organ transplant No uncontrolled intercurrent illness including, but not limited to, serious ongoing or active infection, symptomatic congestive heart failure, uncontrolled cardiac arrhythmia, unstable angina pectoris, that would limit compliance with study requirements No current pneumonitis or history of non-infectious pneumonitis that required steroids Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration No active auto-immune disease that requires systemic therapy within 2 years prior to registration. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid release therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment No known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known hepatitis C virus (defined as HCV ribonucleic acid [RNA] [qualitative] is detected) infection No patients with symptomatic central nervous system metastases and/or carcinomatous meningitis. Patients with small asymptomatic brain metastases are eligible as are patients with treated brain metastases that require no steroids Not pregnant and not nursing, because this study involves radiation as well as potentially chemotherapy which have known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative urine or serum pregnancy test done =< 7 days prior to registration is required No patients with a currently active second malignancy that is progressing or has required active treatment within the last 2 years. Participants with non-melanoma skin cancers or carcinoma in-situ (e.g., breast carcinoma, urothelial carcinoma or cervical cancer in situ) or localized prostate cancer (T1-3, N0, M0) that have undergone potentially curative therapy are eligible No hypersensitivity (>= grade 3) to immunotherapy and/or any of its excipients No live vaccine within 30 days prior to registration. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g.,FluMist [registered trademark]) are live attenuated vaccines and are not allowed. COVID-19 vaccine is allowed Absolute neutrophil count (ANC) >= 1,500/mm^3 Platelet count >= 100,000/mm^3 Calculated (Calc.) creatinine clearance >= 45 mL/min Total bilirubin =< 1.5 x upper limit of normal (ULN) Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (immunotherapy, +/- chemotherapy)<br>See Detailed Description | Procedure: Biopsy<br>* Undergo tissue biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Biological: Ipilimumab<br>* Given IV<br>* Other names: Yervoy;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Drug: Nab-paclitaxel<br>* Given IV<br>* Other names: Protein-bound Paclitaxel;Biological: Nivolumab<br>* Given IV<br>* Other names: Opdivo;Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Biological: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;Drug: Pemetrexed<br>* Given IV<br>* Other names: Pemfexy;Procedure: Positron Emission Tomography<br>* Undergo PET<br>* Other names: PT;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Arm B (immunotherapy, +/- chemotherapy, SBRT)<br>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, CT, or PET throughout the trial. Patients may undergo blood sample collection and tissue biopsy on study as well as ECHO during screening. | Procedure: Biopsy<br>* Undergo tissue biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Biological: Ipilimumab<br>* Given IV<br>* Other names: Yervoy;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Drug: Nab-paclitaxel<br>* Given IV<br>* Other names: Protein-bound Paclitaxel;Biological: Nivolumab<br>* Given IV<br>* Other names: Opdivo;Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Biological: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;Drug: Pemetrexed<br>* Given IV<br>* Other names: Pemfexy;Procedure: Positron Emission Tomography<br>* Undergo PET<br>* Other names: PT;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Radiation: Stereotactic Body Radiation Therapy<br>* Undergo SBRT<br>* Other names: Stereotactic Ablative Body Radiation Therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) (Phase II) | Will be performed on an intent-to-treat (ITT) basis. | From randomization to disease progression or death of all causes, whichever comes first, assessed up to 5 years | 
| Overall survival (OS) (Phase III) | Will be performed on an ITT basis. The comparison of the distributions of OS between treatment arms will be done with a one-sided stratified log-rank test). The rates at various time points (e.g., every 6 months after randomization) and medians of OS for each arm will be estimated using the Kaplan-Meier estimator. The associated 95% confidence interval (CI) will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Hazard ratios will be estimated using a stratified Cox regression model. The final phase III analysis of OS will be considered as positive if the stratified log-rank test statistics Z-value greater than the critical value adjusted for type 1 error using group sequential methods. Multivariable Cox models will be used to evaluate the treatment effect on survival time and its interaction with baseline covariates, including stage, systemic therapy, histology and performance status. | From randomization and death of all causes, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS | Assessed per Response Evaluation Criteria in Solid Tumors (RECIST). | From randomization to disease progression or death of all causes, whichever comes first, assessed up to 5 years | 
| Objective response rate (ORR) | Assessed per RECIST for both irradiated and un-irradiated areas. The ORRs between treatments will be compared with Fisher's exact test. The difference of ORR between treatments will be estimated by the Miettinen-Nurminen method and its 95% CI will be given. Multivariable logistic regression will be used to evaluate the treatment effect on ORR while adjusting for significant baseline covariates. | Up to 5 years | 
| Quality of life |  | Up to 5 years | 
| Incidence of treatment-related adverse events | Treatment-related toxicity will be summarized by grade, type, and system organ class. Comparisons of the percentages of patients experiencing an adverse event between Arm A and Arm B will be performed using Fisher's exact test. | Up to 5 years |