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

Phase 2

Recruiting

• Conditions: Lung Adenocarcinoma; Stage IIIC Lung Cancer AJCC v8; Stage IV Lung Cancer AJCC v8; Lung Adenosquamous Carcinoma; Lung Non-Small Cell Carcinoma; Stage IIIB Lung Cancer AJCC v8
• Interventions: Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Echocardiography Test; Biological: Ipilimumab; Procedure: Magnetic Resonance Imaging; Biological: Nivolumab; Procedure: Positron Emission Tomography; Other: Quality-of-Life Assessment; Radiation: Radiation Therapy

• Registration Number: NCT04929041
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

This phase II/III trial compares the addition of radiation therapy to the usual treatment (immunotherapy with or without chemotherapy) 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. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill tumor cells and shrink tumors. Immunotherapy with monoclonal antibodies, such as nivolumab, ipilimumab may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. 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

PRIMARY OBJECTIVE:

I. To assess if radiation 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 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 or patients may receive standard of care systemic immunotherapy. 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.

Arm B: Patients receive nivolumab 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 or patients may receive standard of care systemic immunotherapy. Patients also undergo 3 fractions of radiation therapy 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.

Study Timeline

• Study First Submitted: 2021-06-16
• Study First Submitted QC: 2021-06-16
• Study First Posted: 2021-06-18
• Study Start: 2022-10-07
• Status Verified: 2025-09
• Last Update Submitted: 2025-09-06
• Last Update Posted: 2025-09-09
• Primary Completion: 2027-12-31
• Study Completion: 2027-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 427

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 three 8 gray (Gy) doses of radiation
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• No more than three weeks of treatment with systemic chemotherapy or immunotherapy for advanced NSCLC
• No more than three weeks of treatment with checkpoint inhibitors for metastatic lung cancer
• No treatment with chemotherapy or immunotherapy for non-metastatic disease (e.g., adjuvant therapy) within 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. Steroid premedication per local standard is allowed
• >= 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 and is allowed
• 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)

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A (immunotherapy, +/- chemotherapy)	Biopsy Procedure	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 or patients may receive standard of care systemic immunotherapy. 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 A (immunotherapy, +/- chemotherapy)	Biospecimen Collection	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 or patients may receive standard of care systemic immunotherapy. 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 A (immunotherapy, +/- chemotherapy)	Computed Tomography	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 or patients may receive standard of care systemic immunotherapy. 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 A (immunotherapy, +/- chemotherapy)	Echocardiography Test	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 or patients may receive standard of care systemic immunotherapy. 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 A (immunotherapy, +/- chemotherapy)	Ipilimumab	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 or patients may receive standard of care systemic immunotherapy. 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 A (immunotherapy, +/- chemotherapy)	Magnetic Resonance Imaging	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 or patients may receive standard of care systemic immunotherapy. 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 A (immunotherapy, +/- chemotherapy)	Nivolumab	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 or patients may receive standard of care systemic immunotherapy. 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 A (immunotherapy, +/- chemotherapy)	Positron Emission Tomography	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 or patients may receive standard of care systemic immunotherapy. 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 A (immunotherapy, +/- chemotherapy)	Quality-of-Life Assessment	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 or patients may receive standard of care systemic immunotherapy. 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 (immunotherapy, +/- chemotherapy, radiation therapy)	Biopsy Procedure	Patients receive 1 of 6 treatment options as in Arm A. Patients also undergo 3 fractions of radiation therapy 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.
Arm B (immunotherapy, +/- chemotherapy, radiation therapy)	Biospecimen Collection	Patients receive 1 of 6 treatment options as in Arm A. Patients also undergo 3 fractions of radiation therapy 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.
Arm B (immunotherapy, +/- chemotherapy, radiation therapy)	Computed Tomography	Patients receive 1 of 6 treatment options as in Arm A. Patients also undergo 3 fractions of radiation therapy 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.
Arm B (immunotherapy, +/- chemotherapy, radiation therapy)	Echocardiography Test	Patients receive 1 of 6 treatment options as in Arm A. Patients also undergo 3 fractions of radiation therapy 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.
Arm B (immunotherapy, +/- chemotherapy, radiation therapy)	Ipilimumab	Patients receive 1 of 6 treatment options as in Arm A. Patients also undergo 3 fractions of radiation therapy 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.
Arm B (immunotherapy, +/- chemotherapy, radiation therapy)	Magnetic Resonance Imaging	Patients receive 1 of 6 treatment options as in Arm A. Patients also undergo 3 fractions of radiation therapy 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.
Arm B (immunotherapy, +/- chemotherapy, radiation therapy)	Nivolumab	Patients receive 1 of 6 treatment options as in Arm A. Patients also undergo 3 fractions of radiation therapy 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.
Arm B (immunotherapy, +/- chemotherapy, radiation therapy)	Positron Emission Tomography	Patients receive 1 of 6 treatment options as in Arm A. Patients also undergo 3 fractions of radiation therapy 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.
Arm B (immunotherapy, +/- chemotherapy, radiation therapy)	Quality-of-Life Assessment	Patients receive 1 of 6 treatment options as in Arm A. Patients also undergo 3 fractions of radiation therapy 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.
Arm B (immunotherapy, +/- chemotherapy, radiation therapy)	Radiation Therapy	Patients receive 1 of 6 treatment options as in Arm A. Patients also undergo 3 fractions of radiation therapy 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.

Primary Outcome Measures

Name	Time	Method
Progression-free survival (PFS) (Phase II)	From randomization to disease progression or death of all causes, whichever comes first, assessed up to 5 years	Will be performed on an intent-to-treat (ITT) basis.
Overall survival (OS) (Phase III)	From randomization and death of all causes, assessed up to 5 years	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.

Secondary Outcome Measures

Name	Time	Method
Quality of life	Up to 5 years
Incidence of treatment-related adverse events	Up to 5 years	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.
PFS	From randomization to disease progression or death of all causes, whichever comes first, assessed up to 5 years	Assessed per Response Evaluation Criteria in Solid Tumors (RECIST).
Objective response rate (ORR)	Up to 5 years	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.

Trial Locations

Locations (165)

Providence Saint Mary Regional Cancer Center; 🇺🇸 Walla Walla, Washington, United States

Mayo Clinic Hospital in Arizona; 🇺🇸 Phoenix, Arizona, United States

University of Arkansas for Medical Sciences; 🇺🇸 Little Rock, Arkansas, United States

Alta Bates Summit Medical Center-Herrick Campus; 🇺🇸 Berkeley, California, United States

City of Hope Comprehensive Cancer Center; 🇺🇸 Duarte, California, United States

City of Hope at Irvine Lennar; 🇺🇸 Irvine, California, United States

City of Hope Antelope Valley; 🇺🇸 Lancaster, California, United States

Fremont - Rideout Cancer Center; 🇺🇸 Marysville, California, United States

Memorial Medical Center; 🇺🇸 Modesto, California, United States

Providence Queen of The Valley; 🇺🇸 Napa, California, United States

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