Radical RADiotherapy and Immunotherapy for Metastatic CAncer of the Lung (RRADICAL)

Radical-Dose Image Guided Radiation Therapy in Treating Patients With Metastatic Non-small Cell Lung Cancer Undergoing Immunotherapy

This phase II trial studies how well radical-dose image guided radiation therapy works in treating patients with non-small cell lung cancer that has spread to other places in the body who are undergoing immunotherapy. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving radical-dose image guided radiation therapy to patients with non-small cell lung cancer may help to improve response to immunotherapy anti-cancer treatment.

Study Overview

• Status: Completed
• Conditions: Stage IV Non-Small Cell Lung Cancer
• Intervention / Treatment: Radiation: Image-guided Radiation Therapy; Drug: Immunotherapy (physician's choice for standard of care immunotherapy)

Detailed Description

PRIMARY OBJECTIVES:

I. Determine if progression-free survival at 24 weeks with this treatment combination is improved compared to historical controls who received immunotherapy without radiation therapy.

SECONDARY OBJECTIVES:

I. Assess acute (0-6 months) and late (> 6 months) grade 3-5 toxicity. II. Assess overall survival. III. Correlate circulating tumor deoxyribonucleic acid (DNA) (ratio of post-radiation therapy [RT] to pre-RT level) with radiographic response.

IV. Correlate immune markers in peripheral blood with radiographic response.

TERTIARY OBJECTIVES:

I. Analyze progression-free survival with immune-related response criteria. II. Measure time to discontinuation of study immunotherapy agent. III. Assess patterns of progression.

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM I: Patients undergo radical-dose image guided radiation therapy daily for up to 10 days (within 2 weeks) while undergoing standard of care immunotherapy.

Arm II: Patients who decline to undergo radiation therapy receive standard of care immunotherapy.

After completion of study treatment, patients are followed up at 30 days and every 6 months thereafter.

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University, School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Has stage IV non-small cell lung cancer, or initially stage I-III disease with distant metastatic recurrence
2. Age ≥ 18
3. Has been receiving anti-PD-1 or anti-PD-L1 immunotherapy for at least four weeks (refer to section 4.2.1)
4. Has had restaging imaging after initiation of immunotherapy, at least 4 weeks after pre-immunotherapy baseline imaging. CT or PET/CT of at least chest/upper abdomen must be performed within 4 weeks prior to registration. For patients with history of brain metastases, brain MRI or CT is required within 4 weeks of registration; for other patients brain MRI or CT is required within 12 weeks of registration. Diagnostic PET/CT performed as part of radiation simulation can be used as the restaging imaging.
5. Most recent imaging shows measurable disease as defined by RECIST 1.1

6. Evaluation by a Stanford medical oncologist must show:

   1. The patient is expected to continue on immunotherapy for at least three more months
   2. Imaging must show response, stable disease, or modest progression
   3. If there is modest progression, the patient must be clinically stable in terms of performance status and overall disease-related symptoms
7. Has at least one extracranial tumor safely treatable with radical-dose radiation therapy and that has not been previously treated with radiation
8. ECOG performance status 0-2
9. Has the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Untreated brain metastases, if not planned to be treated in this course of radiation therapy
• Pregnancy or women of childbearing potential not willing/able to use contraception during protocol treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Immunotherapy plus Image-guided Radiation Therapy; Patients undergo radical-dose image guided radiation therapy daily for up to 10 days (within 2 weeks) while continuing their prior treatment with the treating physician's choice of regular medical care immunotherapy.	Radiation: Image-guided Radiation Therapy; Ablative treatment as 50 Gy in 5 or 10 fractions. Non-ablative treatment as 27 Gy in 3 fractions, or 40 Gy in 10 fractions.; Other Names: IGRT; Drug: Immunotherapy (physician's choice for standard of care immunotherapy); Continue regular medical care immunotherapy. Other than being an anti-PD-1 or anti-PD-L1 immunotherapy, the agent, dose, and schedule is not specified by protocol.; Other Names: biologic therapy
Active Comparator: Immunotherapy Alone (Regular Medical Care); Patients who decline to undergo radiation therapy will continue their prior treatment with the treating physician's choice of regular medical care immunotherapy.	Drug: Immunotherapy (physician's choice for standard of care immunotherapy); Continue regular medical care immunotherapy. Other than being an anti-PD-1 or anti-PD-L1 immunotherapy, the agent, dose, and schedule is not specified by protocol.; Other Names: biologic therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	Defined as percentage of participants without disease progression or death at 24 weeks from date of study entry, assessed per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete Response (CR): Disappearance of all target lesions Partial Response (PR): ≥30% decrease in the sum of the longest diameter of target lesions Overall Response (OR): CR + PR	24 weeks from study entry

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Circulating Tumor Deoxyribonucleic Acid Levels as Measured Using CAncer Personalized Profiling by Deep Sequencing	Will correlate with radiographic response. Plasma biomarkers (e.g. cell free deoxyribonucleic acid level) will be summarized using medians and interquartile ranges; changes in biomarkers will be assessed using the Wilcoxon signed rank test. Correlation of biomarkers with radiographic response will be evaluated using a Wilcoxon rank sum test on patients with and without the event of interest. If feasible, these analyses will be supplemented by more formal analyses with the Cox model.	Baseline (pre-treatment)
Change in Immune Marker Levels as Measured From Peripheral Blood Using Flow Cytometry Performed by the Human Immune Monitoring Core at Stanford University	Change in immune marker levels was measured using flow cytometry performed by the Human Immune Monitoring Core at Stanford University. These changes will correlate with radiographic response.	Pre-radiation (up to 14 days before RT) and post-radiation (up to 14 days after completion of RT)
Number of Participants With Acute (0-6 Months) and Late (> 6 Months) Grade 3-5 Toxicity	This outcome measured the number of participants who experienced Grade 3-5 acute (0-6 months) and late (>6 months) toxicities, assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 4, through up to 4 years after study entry.	Up to 4 years after study entry
Overall Survival	The electronic medical record was monitored for patient deaths.	Time from study entry to death, assessed up to 4 years after study entry

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Tumor Response (Including Abscopal Responses)	Number of participants who experienced a tumor response, including abscopal responses, following image-guided radiation therapy. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.	Up to 4 years
Progression Free Survival	Evaluated with immune-related Response Criteria. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.	Pre-radiation (up to 14 days before RT) and post-radiation (up to 14 days after completion of RT)
Time to Discontinuation of Study Immunotherapy Agent	Time to discontinuation of study immunotherapy agent was measured.	Up to 4 years

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: Varian Medical Systems
• Investigators: Principal Investigator: Michael Gensheimer, Stanford University

Study record dates

Study Major Dates

• Study Start (Actual): June 28, 2017
• Primary Completion (Actual): November 24, 2021
• Study Completion (Actual): January 31, 2025

Study Registration Dates

• First Submitted: June 1, 2017
• First Submitted That Met QC Criteria: June 1, 2017
• First Posted (Actual): June 5, 2017

Study Record Updates

• Last Update Posted (Estimated): November 5, 2025
• Last Update Submitted That Met QC Criteria: October 13, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung; Therapeutics; Radiotherapy; Immunomodulation; Immunotherapy; Radiotherapy, Image-Guided; Biological Therapy
• Other Study ID Numbers: IRB-40088; NCI-2017-00952 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); LUN0088 (Other Identifier: OnCore)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No