Impact of Radiotherapy-Immunotherapy Timing in NSCLC Brain Metastases ((RT-ICI))

Immune Microenvironment-driven Radiotherapy-immunotherapy Combined With Time-series Strategy for NSCLC Brain Metastases: an Exploratory Study Based on a Clinical Cohort.

The goal of this observational study is to learn about the effects of the timing of radiation therapy and immunotherapy in adults with non-small cell lung cancer (NSCLC) that has spread to the brain. The main questions it aims to answer are:

1. Does the timing of the two treatments change how long the brain tumor stays stable and how long participants live?
2. What medical problems do participants have when receiving these treatments at different times?
3. How does the timing of treatments affect the body's immune system?

Researchers will compare participants who receive radiation and immunotherapy 30 days or less apart to those who receive them more than 30 days apart to see if the timing affects the treatment's success and safety.

Participants already receiving radiation and immunotherapy as part of their regular medical care will:

1. Allow researchers to collect information about their treatment, health, and medical imaging during regular checkups.
2. Give a small blood sample during their routine blood draws.
3. Have standard magnetic resonance imaging (MRI) scans of their brain.

Study Overview

• Status: Not yet recruiting
• Conditions: Non Small Cell Lung; Brain Metastasases
• Intervention / Treatment: Radiation: Brain radiotherapy

• Study Type: Observational
• Enrollment (Estimated): 150

Contacts and Locations

• Study Contact: Name: Rongrong Zhou, MD, PHD; Phone Number: +8613875898127; Email: zhourr@csu.edu.cn
• Study Contact Backup: Name: Weihua Liao, MD, PHD; Phone Number: +8613973126486; Email: ouwenliao@163.com

Study Locations

• China
  • Hunan
    • Changsha, Hunan, China
      • Xiangya Hospital of Central South University
      • Contact: Rongrong Zhou, MD, PHD; Phone Number: +8613875898127; Email: zhourr@csu.edu.cn
      • Contact: Weihua Liao, MD, PHD; Phone Number: +8613973126486; Email: ouwenliao@163.com
      • Sub-Investigator: Xianjing Chu, MD

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

The study population comprises adult patients (aged 18 years and older) histologically or cytologically diagnosed with non-small cell lung cancer (NSCLC) accompanied by brain metastases, confirmed via contrast-enhanced head MRI. These patients are seeking treatment at Xiangya Hospital and are scheduled to receive a combination of radiotherapy and PD-1/PD-L1 immune checkpoint inhibitors according to their routine, real-world clinical care plans. The cohort specifically represents a real-world NSCLC population with relatively good performance status (ECOG 0-2), intact local brain anatomy (no prior history of whole-brain radiotherapy, stereotactic radiosurgery, or brain surgery), and who are negative for actionable driver mutations or have experienced disease progression following prior targeted therapies.

Description

Inclusion Criteria:

• Age ≥ 18 years; no gender restriction;
• Histologically or cytologically confirmed NSCLC, with brain metastases confirmed by contrast-enhanced cranial MRI;
• Scheduled to receive radiotherapy combined with a PD-1/PD-L1 inhibitor, in accordance with real-world clinical treatment plans;
• Negative for driver gene mutations, or positive for mutations but with documented failure of prior targeted therapy;
• ECOG Performance Status score of 0-2, with an estimated life expectancy of ≥ 3 months;
• Voluntarily signs the informed consent form and agrees to cooperate with blood/imaging data collection and follow-up procedures.

Exclusion Criteria:

• History of whole-brain radiotherapy, stereotactic radiotherapy for brain metastases, or brain surgery;
• Presence of contraindications to MRI or inability to tolerate gadolinium-based contrast agents (e.g., severe hepatic or renal insufficiency);
• Presence of active autoimmune disease requiring systemic treatment, or requirement for long-term use of high-dose immunosuppressive agents;
• Pregnant or lactating women;
• Other circumstances deemed by the investigator to involve severe complications or render the patient unsuitable for enrollment.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Non-small cell lung cancer brain metastases; This cohort comprises adult patients (aged 18 years and older) with histologically or cytologically confirmed (NSCLC who have brain metastases confirmed by contrast-enhanced head MRI. Participants in this cohort are scheduled to receive standard-of-care radiotherapy combined with PD-1/PD-L1 immune checkpoint inhibitors based on real-world clinical treatment plans. Eligible participants must have an ECOG performance status of 0 to 2, an expected survival of at least 3 months, and be either driver-gene negative or have experienced disease progression following prior targeted therapies. The cohort strictly excludes patients who have a history of WBRT, SRS for brain metastases, or brain surgery. Additionally, individuals with contraindications to MRI (or intolerance to gadolinium contrast agents), active autoimmune diseases requiring systemic treatment or long-term high-dose immunosuppressants, and pregnant or lactating women are excluded.

Radiation: Brain radiotherapy; Participants in this observational study receive standard-of-care radiotherapy for brain metastases combined with PD-1/PD-L1 immune checkpoint inhibitors. The specific radiotherapy parameters (e.g., technique, target volume, and dose) and immunotherapy details (e.g., specific drug type, dosage, and administration schedule) are entirely determined by the treating physicians or multidisciplinary team (MDT) based on current clinical guidelines and real-world practice. This study does not assign, alter, or proactively intervene in any treatment plans. What distinguishes the exposure in this study is the specific tracking and categorization of the real-world timing interval and administration sequence between radiotherapy and immunotherapy (e.g., synchronous vs. asynchronous, radiation-first vs. immunotherapy-first), aiming to evaluate how these naturally occurring temporal variations impact clinical outcomes and immune status.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intracranial Progression-Free Survival (iPFS)	Defined as the time from study enrollment (or completion of baseline assessment) to the first documented intracranial disease progression according to the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria via blinded independent central review, or death from any cause.	Up to approximately 2 years (Assessed every 2-3 months in the first year, and every 3-6 months thereafter until disease progression or death).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intracranial Objective Response Rate (iORR)	The proportion of patients achieving an intracranial Complete Response (CR) or Partial Response (PR) per RANO-BM criteria. Responses must be confirmed by consecutive imaging assessments at least 4 weeks apart.	Up to approximately 2 years.
Overall Survival (OS)	Defined as the time from study enrollment to death from any cause.	Up to approximately 2 years.
Duration of Response (DOR)	For patients achieving confirmed CR or PR, defined as the time from the first documented objective response to the first documented disease progression or death from any cause.	Up to approximately 2 years.
Best Overall Response (BOR)	The best disease response recorded from the start of the study treatment until disease progression or recurrence.	Up to approximately 2 years.
Intracranial Disease Control Rate (iDCR)	The proportion of patients who achieve CR, PR, or Stable Disease (SD) maintained for at least a specified time period (e.g., 24 weeks).	At 24 weeks
Incidence of Grade ≥3 Immune-Related Adverse Events (irAEs)	Evaluated and tracked according to the NCI CTCAE v5.0 and specific irAE management guidelines to assess the safety of different treatment sequences.	From enrollment up to 1 years after the last dose of immunotherapy.
Incidence of Radiation Necrosis and Severe Brain Edema	Dynamic monitoring and evaluation of the occurrence of radiation necrosis and Grade ≥3 radiation-induced brain edema, utilizing RANO-BM and related imaging criteria.	Up to approximately 2 years.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Parasagittal Dura (PSD) Volume	Quantitative measurement of the parasagittal dura (PSD) volume derived from contrast-enhanced 7.0T MRI. PSD volume will be calculated using standardized image segmentation and volumetric analysis procedures and reported in cubic millimeters (mm³).	Baseline and follow-up MRI assessments up to approximately 2 years.
Meningeal Lymphatic Drainage Rate	Quantitative assessment of meningeal lymphatic drainage efficiency measured using contrast-enhanced 7.0T MRI. Drainage rate will be calculated according to predefined imaging analysis protocols and expressed as a percentage or kinetic parameter reflecting lymphatic drainage function.	Baseline and follow-up MRI assessments up to approximately 2 years.
Meningeal Lymphatic Vessel Diameter	Mean diameter of visualized meningeal lymphatic vessels measured on contrast-enhanced 7.0T MRI using standardized image analysis methods and reported in millimeters (mm).	Baseline and follow-up MRI assessments up to approximately 2 years.
Deep Cervical Lymph Node (dCLN) Inflow Rate	Quantitative assessment of contrast agent inflow into deep cervical lymph nodes measured using contrast-enhanced 7.0T MRI. The inflow rate will be used as an indicator of meningeal lymphatic drainage function.	Baseline and follow-up MRI assessments up to approximately 2 years.

Collaborators and Investigators

• Sponsor: Xiangya Hospital of Central South University

Study record dates

Study Major Dates

• Study Start (Estimated): June 5, 2026
• Primary Completion (Estimated): May 31, 2029
• Study Completion (Estimated): June 1, 2030

Study Registration Dates

• First Submitted: June 4, 2026
• First Submitted That Met QC Criteria: June 9, 2026
• First Posted (Actual): June 10, 2026

Study Record Updates

• Last Update Posted (Actual): June 10, 2026
• Last Update Submitted That Met QC Criteria: June 9, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Other Study ID Numbers: 2026051108; ZXQ2026B05 (Other Grant/Funding Number: Central South University)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: IPD will not be made publicly available on open-access platforms to safeguard patient privacy. However, de-identified and aggregated datasets, or specific subsets of IPD underlying the published results, might be shared conditionally. Such data will only be provided upon reasonable request from qualified academic researchers, subject to the approval of the Institutional Review Board (IRB) of Xiangya Hospital and the execution of a formal Data Use Agreement (DUA).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No