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Ivonescimab with drug combination in patients with asymptomatic brain metastases from non‑small cell lung cancer – randomized phase II trial

Verified siteRegistered drugNo placebo
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What is this trial about?

A plain-language summary of the goals, design and what participants do

The trial involves adults with Non-small cell lung cancer that has spread to the brain (called brain metastases). Participants receive a combination of medicines that include an antibody called ivonescimab together with standard chemotherapy drugs such as pemetrexed, carboplatin and paclitaxel. In one group the brain lesions are first treated with a precise form of radiation known as SRT, after which the drug and chemotherapy are given. In the other group the drug and chemotherapy start right away without the upfront radiation.

The purpose of the study is to find out whether the sequence that begins with radiation can keep the brain disease from growing for a longer time, measured as intracranial progression-free survival. Participants will be randomly assigned to one of the two treatment plans, receive the assigned therapy in cycles that last several weeks, and will be followed with regular scans and health checks to see how the disease and any side effects evolve.

The research process

The trial runs in 8 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Randomization and Assignment to Treatment Arm

    After joining the study, you will be randomly placed into one of two treatment groups. One group receives upfront stereotactic radiosurgery (SRT) to all brain metastases followed by systemic therapy, while the other group starts systemic therapy without prior SRT.

  2. Step 2

    Baseline Medical Evaluations

    Before any treatment begins, you will undergo a series of assessments that may include brain imaging, scans of the chest and abdomen, blood tests, and a review of your medical history. These evaluations establish a reference point for measuring the effect of the study treatments.

  3. Step 3

    Stereotactic Radiosurgery (SRT) to Brain Metastases

    If you are assigned to the SRT arm, you will receive precise, high‑dose radiation (SRT) directed at each brain metastasis. The procedure is performed in a single session and is designed to target tumor tissue while sparing surrounding healthy brain tissue.

  4. Step 4

    Start of Systemic Therapy with Ivonescimab

    You will begin intravenous infusion of ivonescimab at a dose of 20 mg per kilogram of body weight. The infusion is administered through a vein and is given according to the schedule defined by the study protocol.

  5. Step 5

    Administration of Chemotherapy Agents

    Along with ivonescimab, you will receive three chemotherapy drugs:

    Pemetrexed – 500 mg per square meter of body‑surface area, given intravenously as a solution for infusion.

    Carboplatin – 6 mg, given intravenously as a solution for infusion.

    Paclitaxel – either 100 mg per square meter (powder for dispersion) or 200 mg per square meter (solution for infusion), both administered intravenously.

  6. Step 6

    Repeated Treatment Cycles

    The combination of ivonescimab and the three chemotherapy agents will be repeated in multiple cycles. The exact number of cycles, as well as the interval between them, follows the timing set by the study protocol.

  7. Step 7

    Ongoing Monitoring and Safety Checks

    During the treatment period, you will have regular visits for imaging studies, blood work, and clinical examinations. These assessments help the study team evaluate the response of the brain metastases and monitor any side effects.

    All adverse events are recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

  8. Step 8

    End of Treatment and Final Assessments

    After completing the planned treatment cycles, you will undergo a final set of evaluations similar to the baseline assessments. These final tests determine the overall outcome of the study, including intracranial progression‑free survival and overall survival.

Who can join the trial?

10 criteria

  • You must be 18 years old or older.
  • Your overall health must allow daily activities with a score called ECOG performance status less than 2 (this means you are able to take care of yourself and are not bedridden).
  • You must have a confirmed diagnosis of non‑small cell lung cancer (NSCLC) that has spread (metastatic) and does not have a genetic change that can be treated with a special targeted medicine approved in Europe.
  • Your brain tumors must be asymptomatic or only mildly symptomatic, meaning you need no more than 4 mg of the steroid medication dexamethasone per day in the past week to control any nerve‑related symptoms, and you should not need immediate brain surgery or radiation. If you have seizures, they must be well‑controlled.
  • You must have newly diagnosed brain tumors that meet these details:
    • Between 1 and 10 brain tumors that have not been treated before (unless they were surgically removed).
    • At least one tumor must be at least 5 mm by 5 mm in size.
    • The largest tumor must be smaller than 40 mm (about the size of a small grape) in its longest dimension.
    • You need to be a candidate for stereotactic radiosurgery or stereotactic body radiotherapy (SRS/FSRT), which are precise radiation treatments for brain tumors, and you must be able to receive systemic (whole‑body) cancer therapy as discussed by a team of doctors.
    • Your body’s organs (such as liver, kidneys, and blood cells) must be working well enough to handle the treatments.
    • You must give written informed consent, meaning you understand the study and agree to take part, following international and local research rules.

Who cannot join the trial?

11 criteria

  • If you have only a few (called oligometastatic) lung‑cancer spots outside the brain and plan to receive aggressive local treatment (such as surgery or high‑dose radiation) to those spots, you cannot join the study.
  • If you have ever had a hole (perforation) or abnormal connection (fistula) in your stomach or intestines, a blockage that required feeding through a vein (parenteral nutrition), or major bowel surgery (like removal of part of the colon or a large part of the small intestine) within the last 6 months, you cannot join.
  • If cancer has spread to the lining of the brain and spinal cord (known as leptomeningeal disease), you cannot join.
  • If you have an active autoimmune disease (where the immune system attacks your own body) that needed strong medicines such as steroids or immune‑suppressing drugs in the past 2 years, you cannot join.
  • If you received high‑dose radiation to your chest (more than 30 Gy) within the past 6 months, any other radiation above 30 Gy in the past 4 weeks, or even low‑dose palliative radiation (30 Gy or less) in the past 7 days, you cannot join. (Gy is a unit that measures radiation dose.)
  • If you have already had any brain radiation, including whole‑brain radiation or stereotactic radiosurgery (SRS), you cannot join.
  • If you have already been treated with chemotherapy or other drug therapy for metastatic lung cancer, you cannot join, unless that treatment was given as a curative plan before the cancer spread and finished at least 6 months ago. (Terms: adjuvant = treatment after primary surgery; neoadjuvant = treatment before surgery.)
  • If you had major surgery or a serious injury in the past 4 weeks, or you plan to have major surgery in the next 4 weeks, you cannot join. Also, if you had a small local procedure (other than placing a vein line or port) in the past 3 days, you cannot join.
  • If you have a bleeding disorder (coagulopathy) or have experienced significant bleeding problems in the past 4 weeks, you cannot join.
  • If your high blood pressure is not well controlled, with readings of 150 mm Hg (systolic) or higher or 100 mm Hg (diastolic) or higher even while taking medication, you cannot join. (Systolic = pressure when the heart beats; diastolic = pressure between beats.)
  • If you have a known serious other illness (such as severe heart, lung, liver, or kidney disease) that could affect the study, you cannot join.
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Investigated drugs

  • Pemetrexed

    is a chemotherapy medicine that interferes with the way cancer cells make DNA and other building blocks they need to grow. By stopping these processes, it helps slow down or shrink the lung cancer that has spread to the brain.

  • Carboplatin

    is another chemotherapy drug that works by damaging the DNA inside cancer cells. This damage makes it harder for the cells to multiply, helping to control the spread of the disease.

  • ivonescimab

    is an experimental laboratory‑made protein (a monoclonal antibody) that is designed to help the body’s immune system recognize and attack the cancer cells. In this study it is given together with chemotherapy to see if it improves control of brain metastases.

  • Paclitaxel

    is a chemotherapy agent that stops cancer cells from dividing by locking the structures (microtubules) they need to separate during cell division. This helps to reduce the growth of the lung cancer that has spread to the brain.

  • Stereotactic Radiotherapy (SRT)

    is a highly precise form of radiation treatment that targets each brain metastasis individually. It delivers a strong dose of radiation to the tumors while sparing most of the surrounding healthy brain tissue, aiming to control the cancer in the brain before the medicines are given.

What is already known about the treatment

  • Pemetrexed

    This drug is given by intravenous infusion after being mixed into a solution for infusion. It is an approved chemotherapy medication widely used and described in medical literature for treating non‑small cell lung cancer and malignant pleural mesothelioma. It works by blocking enzymes that the cancer cell needs to build DNA, which stops the cells from growing and dividing. Pharmacologically, it belongs to the antifolate class of antineoplastic agents.

  • Carboplatin

    Carboplatin is administered as an intravenous infusion of a sterile solution. It is an established platinum‑based chemotherapy drug that is approved and extensively studied for many cancers, including non‑small cell lung cancer. It creates cross‑links in the DNA of cancer cells, preventing the DNA strands from separating and causing the cells to die. It is classified as a platinum compound, an alkylating‑like antineoplastic agent.

  • Ivonescimab

    Ivonescimab is given by intravenous infusion as an injection, dosed in milligrams per kilogram of body weight. It is an experimental monoclonal antibody currently in clinical trials and has not yet received market approval. It binds to a specific protein on cancer cells or immune cells, helping the immune system to recognize and attack the tumor. This drug is classified as an immune‑checkpoint inhibitor (monoclonal antibody).

  • Paclitaxel

    Paclitaxel is administered by intravenous infusion, either as a powder that is dispersed for infusion or as a ready‑to‑use solution. It is an approved chemotherapy agent widely used for non‑small cell lung cancer and several other solid tumors. It works by stabilizing microtubules inside the cell, which blocks the cells from dividing and leads to cancer cell death. It belongs to the taxane class of antineoplastic agents.

Investigated diseases

Non‑small cell lung cancer - Non‑small cell lung cancer is a group of lung cancers that arise from the larger cells lining the airways. It usually begins as a small tumor inside the lung and can grow slowly or more quickly. Over time the tumor may invade nearby lung tissue and spread to lymph nodes. The disease can also spread through the bloodstream to other parts of the body such as the brain, bones, or liver. When cancer cells reach the brain they form new tumors called brain metastases. The pattern of growth and spread determines how the disease changes over time.
Trial detailsLast updated 21 Oct 2026
Age18+ yearsPhasePhase IITrial ID2025-522985-60-00Protocol codeEORTC-2456-LCG-BTGEstimated enrolment42 patientsSponsorEuropean Organisation For Research And Treatment Of Cancer

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