A Study Evaluating The Combination of Immunotherapy With Radiotherapy in Non-Small Cell Lung Cancer (REVIVE)

A Randomized Phase II Study of Radiotherapy Plus Immune Checkpoint Inhibitor Therapy Versus Standard of Care Chemotherapy in Patients With Metastatic or Relapsed Non-Small Cell Lung Cancer Previously Treated With Immunotherapy

Current clinical trials testing the combination of immunotherapy with radiotherapy.

Study Overview

• Status: Not yet recruiting
• Conditions: Non-Small Cell Lung Cancer; Metastatic Lung Cancer
• Intervention / Treatment: Drug: Investigator Choice Immunotherapy (for example: pembrolizumab, cemiplimab, durvalumab, ipilimumab plus nivolumab); Radiation: Ablative Hypofractionated Radiotherapy; Drug: Investigator Choice Chemotherapy (for example docetaxel with or without ramucirumab, gemcitabine, or other National Comprehensive Cancer Network (NCCN)-recommended treatments)

• Study Type: Interventional
• Enrollment (Estimated): 39
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60637
      • o University of Chicago Medicine Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Disease-Related Criteria

  • Patients must have histologically or cytologically confirmed metastatic or recurrent non-small cell lung cancer (NSCLC) with progression on prior immunotherapy
  • The patient's disease is eligible for SOC treatment with immunotherapy or chemotherapy.
  • Patients must have measurable disease per RECIST v1.1, defined as at least one lesion that can be accurately measured in at least one dimension with longest diameter ≥10 mm (or ≥15 mm short axis for lymph nodes) by CT or MRI
  • Patients must have at least one lesion that meets criteria for hypofractionated ablative RT treatment:
  • Tumor volume 0.25 cc to 65 cc (approximately ≤5 cm maximal dimension)
  • Located in sites amenable to ablative RT (see radiotherapy section for specific anatomic criteria)
  • Note: Tumors >65 cc may be partially treated to 65 cc volume
  • Prior/Concurrent Therapy Criteria
  • Patients must have received exactly ONE prior line of anti-PD-1 or anti-PD-L1 therapy for non-small cell lung cancer. This therapy may have been given as:
  • Monotherapy
  • In combination with chemotherapy
  • In combination with another immunotherapy such as CTLA-4 inhibition
  • In combination with a targeted therapy, such as adagrasib
  • Special Cases for Neoadjuvant/Adjuvant Immunotherapy:
  • If patient received neoadjuvant, adjuvant, or consolidation anti-PD-1/PD-L1 therapy for Stage I-III disease and progressed ≤365 days from initiation (Cycle 1 Day 1), this counts as the single allowed therapy for advanced disease
  • If patient progressed >365 days from neoadjuvant/adjuvant therapy initiation, this does NOT count as therapy for advanced disease, and patient must have received subsequent anti-PD-1/PD-L1 therapy for Stage IV or recurrent disease
  • Patients with the following sensitizing mutations are ineligible, given known poor response to immunotherapy: EGFR, ALK, ROS1, RET, NTRK, HER2.
  • Patients with the following sensitizing mutations must have previously received at least one of the appropriate targeted therapies, in addition to prior immunotherapy: BRAF, KRAS, MET. Prior targeted therapy for participants with targetable alterations is allowed if all other eligibility criteria is also met.

• Clinical/Laboratory Criteria

  • Age ≥18 years
  • ECOG Performance Status 0-2 (see Appendix A)
  • Participants must be able to safely receive the investigational drug combination and the investigator's choice of standard of care regimens described in Section 5.1 (Agent Administration), per the current FDA-approved package inserts, treating investigator's discretion, and institutional guidelines.
  • Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy.
  • Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
  • Because radiation and chemotherapy are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Both men and women treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after completion of immunotherapy, radiation, and/or chemotherapy administration.
  • Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Patients with history of (non-infectious) pneumonitis requiring corticosteroids.
• Patients with evidence of interstitial lung disease.
• Patients with uncontrolled intercurrent illness.
• Pregnant women are excluded from this study. Radiation is considered Class X and chemotherapy such as docetaxel are considered Class D agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with radiation, immunotherapy, and chemotherapy breastfeeding should be discontinued if the mother is participating in the study.

Radiation-Specific Exclusions

• Patients who have received prior radiation to any of the planned treatment sites (>10% dose overlap)
• Patients with lesions in locations not amenable to safe ablative RT delivery, including:
• Esophagus or stomach directly involved by tumor (unless dose constraints can be met)
• Small bowel or colon directly involved by tumor (unless dose constraints can be met)
• Spinal cord lesions with <3 mm clearance between epidural disease and spinal cord

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Radiotherapy (RT) + Immunotherapy; Participants will receive standard immunotherapy of investigator's choice in combination with radiation treatment.	Drug: Investigator Choice Immunotherapy (for example: pembrolizumab, cemiplimab, durvalumab, ipilimumab plus nivolumab); Participant will receive an FDA approved immunotherapy according to usual routine practice.; Radiation: Ablative Hypofractionated Radiotherapy; Participant will receive radiotherapy according to usual routine practice.
Active Comparator: Standard Chemotherapy (Investigator's Choice"); Participants will receive standard chemotherapy of investigator's choice.	Drug: Investigator Choice Chemotherapy (for example docetaxel with or without ramucirumab, gemcitabine, or other National Comprehensive Cancer Network (NCCN)-recommended treatments); Description something along the lines of Participant will receive an FDA approved chemotherapy according to usual routine practice.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	To compare progression-free survival (PFS) in patients with metastatic or relapsed non-small cell lung cancer (mNSCLC) who have progressed after immunotherapy-based treatment, randomized to investigators choice standard of care immunotherapy plus hypofractionated ablative radiotherapy versus investigators' choice of standard of care chemotherapy.	48 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	To compare overall survival (OS) between treatment arms	48 months
Objective response rates (ORR)	To compare objective response rates (ORR) between treatment arms.	48 months
Correlation between amount of L1RE1 (LINE1 retrotransposable element 1) and clinical response to treatment	Dose amount of L1RE1 in blood correlate to clinical response (for example are higher levels of the protein in the blood a sign of response to treatment)?	24 months
Pharmacodynamic Properties	Establishing the pharmacodynamic properties of L1RE1 clearance during treatment. L1RE1 serum levels will be measured descriptively using NPX (normalized protein expression) .	24 months
Safety of Giving Ablative Radiation and Immunotherapy Together	Number of Common Terminology Criteria for Adverse Events (CTCAE) version 5 Grade 3 adverse events	3 months

Collaborators and Investigators

• Sponsor: University of Chicago

Study record dates

Study Major Dates

• Study Start (Estimated): December 12, 2026
• Primary Completion (Estimated): June 25, 2030
• Study Completion (Estimated): June 25, 2030

Study Registration Dates

• First Submitted: March 9, 2026
• First Submitted That Met QC Criteria: May 21, 2026
• First Posted (Actual): May 22, 2026

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 21, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Immunotherapy; Radiotherapy; Chemotherapy
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Amino Acids, Peptides, and Proteins; Proteins; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nivolumab; Ipilimumab; Gemcitabine; Ramucirumab; durvalumab; cemiplimab
• Other Study ID Numbers: IRB25-1914

Drug and device information, study documents

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