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

Plain English Summary

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 is a Phase 3 clinical trial sponsored by National Cancer Institute (NCI) studying 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. This trial tests if adding radiation therapy to standard immunotherapy (with or without chemotherapy) improves outcomes for advanced non-small cell lung cancer. It is for patients with advanced non-small cell lung cancer that tests negative for a marker called PD-L1. Participation involves receiving standard treatment with or without radiation therapy, along with regular medical assessments and tests. Standard treatment options for this type of lung cancer include chemotherapy and immunotherapy. The trial aims to enroll 427 participants.

Official 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.

Who Can Participate

Here is what you need to know about eligibility for this trial. Patients aged 18 or older with advanced non-small cell lung cancer (Stage IIIB, IIIC, or IV) are eligible. Patients must have tumors that are negative for PD-L1 (less than 1%). Patients with specific genetic mutations (EGFR, ALK, ROS1) that can be treated with oral medications are not eligible. Patients with active autoimmune diseases or certain other serious health conditions may not be eligible. This trial is studying 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, so participants generally need a confirmed diagnosis.

What They're Measuring

Progression-free survival means the time patients live without their cancer getting worse, and overall survival means the total time patients live. The specific primary outcome measures are: Progression-free survival (PFS) (Phase II) (From randomization to disease progression or death of all causes, whichever comes first, assessed up to 5 years); Overall survival (OS) (Phase III) (From randomization and death of all causes, assessed up to 5 years). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 3, the final and most rigorous stage before seeking FDA approval. Phase 3 trials involve 300-3,000+ patients across multiple sites and compare the new treatment directly against the current standard of care. These pivotal trials generate the evidence needed for regulatory review. About 58% of Phase 3 drugs receive FDA approval. Successful Phase 3 results typically lead to a New Drug Application submission.

Why This Trial Matters

This trial addresses a critical need for effective treatments for PD-L1 negative advanced non-small cell lung cancer, a group that may not respond as well to current immunotherapy alone. As a Phase 3 trial, positive results could directly lead to FDA approval, making this treatment available to the broader patient population. This research targets 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, where improved treatment options are needed.

Investor Insight

This trial, sponsored by the National Cancer Institute, investigates a novel combination therapy for a significant subset of lung cancer patients, potentially impacting the market for advanced lung ca Phase 3 trials have approximately a 50-60% chance of gaining FDA approval if they reach this stage.

Is This Trial Right for Me?

Ask your doctor if this trial is a good fit for your specific type and stage of lung cancer. Understand that participation involves regular visits for treatment, scans, and blood tests, which may include radiation therapy. Be prepared for potential side effects from immunotherapy, chemotherapy, and radiation. The trial is being conducted at 20 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 427 participants

Interventions

• PROCEDURE: Biopsy Procedure — Undergo tissue biopsy
• PROCEDURE: Biospecimen Collection — Undergo blood sample collection
• PROCEDURE: Computed Tomography — Undergo CT
• PROCEDURE: Echocardiography Test — Undergo ECHO
• BIOLOGICAL: Ipilimumab — Given IV

Primary Outcomes

• Progression-free survival (PFS) (Phase II) (From randomization to disease progression or death of all causes, whichever comes first, assessed up to 5 years)
• Overall survival (OS) (Phase III) (From randomization and death of all causes, assessed up to 5 years)

Secondary Outcomes

• PFS (From randomization to disease progression or death of all causes, whichever comes first, assessed up to 5 years)
• Objective response rate (ORR) (Up to 5 years)
• Quality of life (Up to 5 years)
• Incidence of treatment-related adverse events (Up to 5 years)

Full Eligibility Criteria

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)

Trial Locations

• 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
• University of California Davis Comprehensive Cancer Center, Sacramento, California, United States
• ...and 10 more locations

Frequently Asked Questions

Related Conditions

• Non-Small Cell Lung Cancer
• Lung Adenocarcinoma
• Lung Adenosquamous Carcinoma
• Stage IIIB Lung Cancer
• Stage IIIC Lung Cancer
• Stage IV Lung Cancer
• Metastatic Lung Cancer
• PD-L1 Negative Cancer
• Thoracic Oncology
• Cancer Immunotherapy

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