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First-line treatment of metastatic non‑small cell lung cancer with high PD‑L1 expression: ivonescimab versus pembrolizumab

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 study looks at patients with metastatic non-small cell lung cancer whose tumors show high levels of PD‑L1. This type of lung cancer has spread beyond the lungs and does not have certain activating genetic changes. The trial compares two medicines given by IV infusion: the experimental drug ivonescimab and the approved drug pembrolizumab. Both are administered as an injection into a vein.

The purpose of the study is to determine which medicine helps patients live longer and stay free of cancer growth. Participants are randomly assigned to receive one of the two drugs, and neither the participants nor the doctors know which one is being given (double‑blinded). Treatments are given at regular intervals, and patients are monitored with scans that are evaluated using RECIST criteria to decide if the disease is stable, shrinking, or growing. The study follows patients for several years to record how long they survive (overall survival) and how long the cancer does not get worse (progression‑free survival), while also checking safety and any side effects.

The research process

The trial runs in 9 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Enrollment Confirmation

    You receive confirmation that you have been enrolled in the study for the first‑line treatment of metastatic non‑small cell lung cancer with high PD‑L1 expression.

  2. Step 2

    Baseline Assessments

    You undergo a series of initial examinations, including medical history review, blood tests, and imaging scans that measure the size of the tumors. These assessments create a reference point for later comparisons.

    The imaging results are evaluated using the RECIST (Response Evaluation Criteria in Solid Tumors) system, which provides standardized measurements of tumor changes.

  3. Step 3

    Randomization

    The study assigns you, without revealing the assignment to you or the clinical staff, to receive either ivonescimab or pembrolizumab. This process is called randomization and ensures that the comparison between the two treatments is unbiased.

  4. Step 4

    First Intravenous Infusion

    You receive the first dose of the assigned medication by intravenous infusion in a clinic setting.

    If you are assigned to ivonescimab, the dose is 20 mg per kilogram of your body weight, administered as an injection.

    If you are assigned to pembrolizumab, the dose is a fixed 200 mg, delivered as a solution for infusion.

  5. Step 5

    Ongoing Treatment Infusions

    You continue to receive additional infusions of the same medication at regular intervals defined by the study protocol. Each infusion follows the same dosage and method described for the first infusion.

  6. Step 6

    Safety and Laboratory Monitoring

    At each visit, you undergo safety checks that include blood tests and physical examinations to identify any adverse events or abnormal laboratory results.

    The study records the incidence and severity of any side effects you experience.

  7. Step 7

    Tumor Response Evaluations

    Periodically, you undergo imaging scans that are again evaluated using the RECIST criteria. These scans help determine the objective response rate, disease control rate, and the duration of any response.

  8. Step 8

    Pharmacokinetic and Immunogenicity Assessments

    Blood samples are collected at specified times to measure the concentration of ivonescimab in your serum and to check for the presence of anti‑drug antibodies.

  9. Step 9

    End of Treatment and Follow‑Up

    Treatment continues until the study protocol specifies an end point, such as disease progression, unacceptable toxicity, or the completion of the planned treatment period.

    After treatment stops, you remain in the study for follow‑up visits that monitor overall survival and any long‑term effects.

Who can join the trial?

16 criteria

  • Sign a written informed consent form voluntarily.
  • Have adequate organ function, which means:
    • Blood tests show enough white cells (absolute neutrophil count ≥ 1.5 × 10⁹/L), platelets (≥ 100 × 10⁹/L), and hemoglobin (≥ 9.0 g/dL).
    • Kidney tests show good filtering ability (creatinine clearance ≥ 30 mL/min or eGFR ≥ 30 mL/min) and low protein in urine (less than 2+ on a dipstick or less than 1 g in 24 hours).
    • Liver tests show normal bilirubin (≤ 1.5 times the normal limit, or ≤ 3 times if you have liver metastases or Gilbert syndrome) and normal enzymes (AST and ALT ≤ 2.5 times normal, or ≤ 5 times if you have liver metastases).
    • Blood clotting tests are within limits (prothrombin time/INR ≤ 1.5 times normal and aPTT ≤ 1.5 times normal) unless you are already on a stable dose of blood‑thinning medication.
    • Women who could become pregnant must have a negative pregnancy test before randomization and another negative test on the day the first dose is given.
    • Women who could become pregnant and have sex with an unsterilized male partner must agree to use a highly effective method of contraception from the start of screening until 120 days after the last dose.
    • Men who are not sterilized and have a female partner who could become pregnant, or who have a pregnant or breastfeeding partner, must agree to use a male condom for the whole treatment period and until 120 days after the last dose; the female partner must also use at least one highly effective form of contraception.
    • Be at least 18 years old at the time of enrollment.
    • Have an ECOG performance status of 0 or 1, which means you are fully active or able to do light work but are still able to care for yourself.
    • Have an expected life expectancy of at least 3 months.
    • Have metastatic (Stage IV) non‑small cell lung cancer as defined by the American Joint Committee on Cancer (AJCC) 8th edition, meaning the cancer has spread beyond the original lung site.
    • Have a diagnosis confirmed by a tissue test (histology) or cell test (cytology) showing either squamous or non‑squamous non‑small cell lung cancer.
    • Show high PD‑L1 expression (50 % or more of tumor cells) on a laboratory test that uses immunohistochemistry (IHC) with approved kits (22C3 or SP263).
    • Have at least one measurable tumor that is not in the brain, according to RECIST v1.1 criteria, which means the lesion can be measured accurately on imaging scans.
    • Have not received any prior systemic (whole‑body) treatment for metastatic disease. You may have had earlier (adjuvant or neoadjuvant) chemotherapy, chemoradiotherapy, or PD‑1/PD‑L1 inhibitor therapy if it was finished at least 6 months before the cancer spread.

Who cannot join the trial?

30 criteria

  • Having small cell lung carcinoma (a different type of lung cancer) confirmed by tissue testing.
  • Receiving high‑dose chest radiation (>30 Gy) within the past 6 months, or non‑chest radiation >30 Gy within the past 4 weeks, or palliative radiation ≤30 Gy within the past 7 days.
  • Having pre‑existing peripheral neuropathy (nerve damage in the arms or legs) that is moderate or worse (grade 2 or higher) according to standard grading.
  • Receiving a live or live‑attenuated vaccine within 4 weeks before randomization, or planning to receive one during the study (inactivated vaccines are allowed).
  • Having a severe infection within 4 weeks before randomization (such as infection requiring hospitalization, sepsis, or severe pneumonia) or an active infection that needs systemic anti‑infective drugs within 2 weeks (except antiviral treatment for hepatitis B or C).
  • Undergoing a major surgical procedure or serious trauma within 4 weeks before randomization, or planning a major surgery within 4 weeks after the first dose; also minor local procedures (except placing a central line or port) within 3 days before randomization.
  • Having a history of bleeding problems or coagulopathy (trouble clotting) and/or significant bleeding risk within 4 weeks, including coughing up a teaspoon of fresh blood (hemoptysis) or ongoing nosebleeds; unstable use of blood thinners is not allowed unless clotting tests are within therapeutic range.
  • Having poorly controlled high blood pressure (hypertension) with repeated systolic ≥150 mmHg or diastolic ≥100 mmHg despite oral medication.
  • Having uncontrolled fluid buildup that causes symptoms: fluid around the lungs (pleural effusion), around the heart (pericardial effusion), or in the abdomen (ascites) (catheters for drainage are allowed).
  • Having a history of non‑infectious pneumonia that required systemic steroids, or having current interstitial lung disease (a scarring lung condition).
  • Having active or prior inflammatory bowel disease (such as Crohn’s disease, ulcerative colitis, or chronic diarrhea).
  • Having known cancer‑driving gene changes (EGFR, ALK, ROS1, BRAF V600E) for which specific first‑line treatments exist.
  • Having HIV infection that is not controlled (viral load not suppressed).
  • Currently taking systemic corticosteroids higher than 10 mg daily prednisone (or equivalent).
  • Having a history of an allogeneic organ transplant or allogeneic hematopoietic stem‑cell transplant (transplant from another person).
  • Having active hepatitis B without stable or decreasing viral DNA levels on antiviral therapy for at least one month, or any active hepatitis C infection.
  • Being allergic to any component of the study drugs or having a severe allergic reaction to other monoclonal antibodies.
  • Having any medical, surgical, psychiatric condition, or laboratory abnormality that could confuse study results, increase risk, or make participation unsafe, as judged by the investigator.
  • Being currently breastfeeding or planning to breastfeed during the study.
  • Having received any prior systemic therapy for metastatic NSCLC (local radiation to the brain or bone is allowed).
  • Being enrolled in another interventional clinical trial (non‑interventional studies are allowed).
  • Imaging showing tumor invading major blood vessels (such as the central pulmonary artery, aorta, or superior vena cava) or organs (heart, trachea, esophagus, central bronchi), or creating a high risk of serious bleeding, major vessel narrowing, lung cavity, or tumor necrosis.
  • Having symptomatic brain or spinal cord metastases, brain metastases larger than 1.5 cm, bleeding brain metastases, recent brain radiation (within 7 days), need for brain radiation in the first cycle, or leptomeningeal disease; steroid use must be ≤10 mg prednisone daily or physiologic replacement.
  • Having another prior cancer (including earlier NSCLC) unless it was cured with no evidence of recurrence for at least 3 years; exceptions include certain skin cancers, superficial bladder cancer, in‑situ cervical cancer, other in‑situ cancers, low‑risk prostate cancer, or other local tumors considered cured.
  • Having an active autoimmune disease or lung disease that required systemic therapy (such as disease‑modifying drugs, steroids >10 mg, or immunosuppressants) within the past 2 years, except stable hormone replacement or occasional inhaled medications.
  • Having major heart or vascular problems within the past 12 months, such as unstable chest pain (angina), heart attack, moderate‑to‑severe heart failure (NYHA ≥ grade 2), dangerous aneurysm, serious blood‑vessel disease, uncontrolled irregular heart rhythms, or heart muscle oxygen shortage.
  • Having serious stomach or intestinal problems within the past 6 months, such as large esophageal or gastric varices, severe ulcers, non‑healing wounds, abdominal fistula, intra‑abdominal abscess, or acute gastrointestinal bleeding.
  • Having significant clotting events within the past 12 months, such as arterial clot (stroke, transient ischemic attack), serious venous clot, or severe hypertensive crises.
  • Having an acute worsening of chronic obstructive pulmonary disease (COPD) within the past 4 weeks.
  • Having a history of major gastrointestinal perforation, fistula, or bowel obstruction (including need for IV nutrition) or extensive bowel surgery (partial colectomy or major small‑bowel resection) within the past 6 months.
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Investigated drugs

  • ivonescimab

    is an experimental medicine that is given by a drip into a vein (intravenous infusion). In this study it is being tested as a first‑line treatment for people with advanced non‑small cell lung cancer whose tumors show a high level of PD‑L1. The drug is being evaluated to see if it can help patients live longer and keep the cancer from getting worse compared with the standard treatment.

  • pembrolizumab

    (known commercially as KEYTRUDA) is an approved immunotherapy that is also given by an intravenous infusion. In this trial it serves as the standard treatment against which the new drug ivonescimab is compared. Researchers are looking at how well pembrolizumab works to extend overall survival and delay disease progression in the same group of patients.

What is already known about the treatment

  • ivonescimab

    Ivonescimab is given by intravenous infusion as an injection at a dose of 20 mg per kilogram of body weight. It is currently an investigational drug being studied in a phase 3 trial and is not yet approved for any indication. The trial tests it as a first‑line therapy for metastatic non‑small cell lung cancer that shows high PD‑L1 expression. Ivonescimab works by binding to the PD‑L1 protein on tumor cells, blocking its interaction with the PD‑1 receptor on immune cells, which helps the immune system recognize and attack the cancer; it is classified as a PD‑L1‑targeting monoclonal antibody, an immune‑checkpoint inhibitor.

  • pembrolizumab

    Pembrolizumab is administered as a 200 mg intravenous infusion of a solution for infusion. It is an approved medication that is listed in medical literature for the treatment of several cancers, including metastatic non‑small cell lung cancer with high PD‑L1 expression. The drug is used as a first‑line treatment for this type of lung cancer. Pembrolizumab works by attaching to the PD‑1 receptor on immune cells, preventing it from binding to PD‑L1 and thereby restoring the immune system’s ability to fight the tumor; it belongs to the class of PD‑1‑targeting monoclonal antibodies, known as immune‑checkpoint inhibitors.

Investigated diseases

Metastatic non‑small cell lung cancer - Metastatic non‑small cell lung cancer is a type of lung cancer that starts in the larger cells lining the airways. It is called “non‑small cell” to distinguish it from small‑cell lung cancer, which behaves differently. In the metastatic stage, cancer cells have broken away from the original tumor and traveled through the bloodstream or lymph system to form new tumors in other parts of the body. Common sites for these secondary tumors include the brain, bones, liver, and adrenal glands. The disease typically progresses as the new tumors grow, causing worsening of symptoms such as cough, shortness of breath, and pain in affected areas. Over time, the spread can involve multiple organs, leading to a broader burden of disease.
Trial detailsLast updated 6 Nov 2026
Age18+ yearsPhasePhase IIITrial ID2024-518629-14-00Protocol codeSMT112-3007Estimated enrolment709 patientsSponsorSummit Therapeutics Inc.

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