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Adding radiation therapy to immunotherapy for advanced non-small cell lung cancer patients who are PD-L1 negative

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

Phase2; Phase3 Interventional National Cancer Institute (NCI) · NCT04929041

This study is testing whether adding radiation therapy to standard immunotherapy for patients with advanced non-small cell lung cancer who have low PD-L1 levels can help them live longer and feel better.

Quick facts

PhasePhase2; Phase3
Study typeInterventional
Enrollment427 (estimated)
Ages18 Years and up
SexAll
SponsorNational Cancer Institute (NCI) NIH
Drugs / interventionschemotherapy, immunotherapy, radiation, prednisone, nivolumab, ipilimumab
Locations162 sites (Phoenix, Arizona and 161 other locations)
Trial IDNCT04929041 on ClinicalTrials.gov

What this trial studies

This trial evaluates the effectiveness of adding radiation therapy to the standard treatment of immunotherapy, with or without chemotherapy, for patients with advanced non-small cell lung cancer (NSCLC) who have a PD-L1 tumor proportion score of less than 1%. The study aims to determine if this combination improves progression-free survival and overall survival compared to standard treatment alone. Patients will be randomized into two groups, one receiving the additional radiation therapy and the other receiving standard treatment. The trial also assesses the safety and quality of life of participants, as well as changes in the immune microenvironment.

Who should consider this trial

Good fit: Ideal candidates include patients with stage IIIB or IIIC non-small cell lung cancer who are not candidates for combined chemotherapy and radiation and have a PD-L1 tumor proportion score of less than 1%.

Not a fit: Patients with actionable EGFR mutations, ALK or ROS1 mutations that can be treated with oral tyrosine inhibitors will not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could significantly improve survival rates for patients with advanced non-small cell lung cancer who are PD-L1 negative.

How similar studies have performed: Other studies have shown promising results with similar approaches, but this specific combination of treatments is being tested for the first time in this patient population.

Eligibility criteria

Show full inclusion / exclusion 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)

Where this trial is running

Phoenix, Arizona and 161 other locations

+112 more sites — see ClinicalTrials.gov for the full list.

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Lung AdenocarcinomaLung Adenosquamous CarcinomaLung Non-Small Cell CarcinomaStage IIIB Lung Cancer AJCC v8Stage IIIC Lung Cancer AJCC v8Stage IV Lung Cancer AJCC v8
Last reviewed 2026-06-15 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.