Phase II Study of Upfront SRT Plus Ivonescimab/Chemotherapy vs Ivonescimab/Chemotherapy in NSCLC Brain Mets

A Randomized Phase II Study Evaluating Upfront SRT to All Brain Metastases Followed by Ivonescimab Plus Chemotherapy Versus Upfront Ivonescimab Plus Chemotherapy in Patients With Asymptomatic Active Brain Metastases From NSCLC

This is a randomized, two-arm, comparative Phase II clinical trial designed to evaluate the difference in intracranial progression-free survival (iPFS) between two treatment strategies, assessed locally.

Approximately 158 patients will be randomized in a 1:1 ratio. Will be included patients with pathology proven metastatic NSCLC without an actionable genomic alteration for which there is first line targeted treatment available and active asymptomatic brain metastasis (newly diagnosed or progressive).

The primary objective is to compare iPFS between the two arms.

Study Overview

• Status: Not yet recruiting
• Conditions: Non Small Cell Lung Cancer
• Intervention / Treatment: Drug: Ivonescimab; Drug: Carboplatin; Drug: Pemetrexed; Drug: Paclitaxel; Drug: Paclitaxel-albumin; Radiation: Stereotactic Radiosurgery (SRS) or Fractionated Stereotactic Radiotherapy (FSRT)

Detailed Description

Main inclusion criteria

• Age 18 years or older
• ECOG PS < 2
• Patients with pathology proven metastatic NSCLC without an actionable genomic alteration for which there is first line targeted treatment approved by EMA and recommended by the ESMO guidelines.
• Asymptomatic or minimally symptomatic brain metastases defined as requiring a dose of steroids of maximum 4 mg equivalent dexamethasone per day for the last 7 days to control neurological symptoms. With the clinically oligosymptomatic further defined as having no indication for immediate localized brain therapy, including neurosurgery or radiotherapy. Patients with controlled seizures can be enrolled.
• Newly diagnosed brain metastasis with the following characteristics:
• 1-10 newly diagnosed and untreated (except resected) brain metastases. Note: if the neuronavigation MRI in the upfront SRS/FSRT arms shows > 10 metastases and if the total volume is deemed safe to be treated, but the MRI used for enrolment showed 1-10 metastases the patient will be still considered eligible.
• At least one metastasis should be at least 5x5 mm. In case of doubt on the diagnosis of brain metastasis, the lesion should not be irradiated but followed up.
• The largest metastasis must be estimated <10 mL in volume and <30 mm in longest diameter (resected lesions would not count).
• The maximum cumulative volume of brain metastases must be estimated <30 mL (resected lesions would not count).
• Candidate for stereotactic radiosurgery/therapy (SRS/FSRT) of BM and systemic treatment (preferably discussed in an MDT)
• Adequate organs function
• Before patient 's enrolment, written informed consent must be given according to ICH/GCP, and national/local regulations.

Main exclusion criteria

• Patients with oligometastatic NSCLC who are scheduled to receive radical local treatment to extra-cranial sites.
• Active auto-immune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. EORTC-2456-LCG-BTG IVO-BRAIN Version 1.0 14 31 October 2025
• Patients with >30 Gy of chest radiation therapy within 6 months prior to randomization; non-thoracic radiation therapy > 30 Gy within 4 weeks prior to randomization, or palliative radiation therapy of ≤ 30 Gy within 7 days prior to randomization.
• Prior brain irradiation (including whole brain radiotherapy and SRS).
• Prior systemic treatment for metastatic NSCLC. Patients receiving adjuvant or neoadjuvant chemotherapy or curative-intent chemoradiotherapy with or without PD-1/L1 inhibitors are eligible if the adjuvant/neoadjuvant therapy was completed at least 6 months prior to the development of metastatic disease.
• Major surgical procedures or serious trauma within 4 weeks prior to randomization or plans for major surgical procedures within 4 weeks after the first dose (as determined by the investigator). Minor local procedures (excluding central venous catheterization and port implantation) within 3 days prior to randomization.
• History of coagulopathy and/or clinically significant bleeding symptoms or risk within 4 weeks prior to randomization, including but not limited to:
• Hemoptysis (defined as coughing up ≥ 0.5 teaspoon of fresh blood or small blood clots) Note: transient hemoptysis associated with diagnostic bronchoscopy is allowed.
• Nasal bleeding /epistaxis (bloody nasal discharge is allowed)
• Current use of prophylactic or full-dose anticoagulants or anti platelet agents for therapeutic purposes that is not stable prior to randomization is not allowed. The use of full-dose anticoagulants is permitted as long as the international normalized ratio (INR) or activated partial thromboplastin time (aPTT) is within therapeutic limits according to the medical standard of the enrolling institution.
• Poorly controlled hypertension with repeated systolic blood pressure ≥ 150 mm Hg or diastolic blood pressure ≥ 100 mm Hg measured in optimal conditions after oral antihypertensive therapy
• Known history of major diseases before randomization, specifically:

• Unstable angina, myocardial infarction, congestive heart failure (New York Heart Association [NYHA] classification

  ≥ grade 2) or unstable vascular disease (e.g., aortic aneurysm at risk of rupture, Moyamoya disease) that required hospitalization within 12 months prior to randomization, or other cardiac impairment that may affect the safety evaluation of the study drug (e.g., poorly controlled arrhythmias, myocardial ischemia)

• History of esophageal gastric varices, severe ulcers, wounds that do not heal, abdominal fistula, intra-abdominal abscesses, EORTC-2456-LCG-BTG IVO-BRAIN Version 1.0 15 31 October 2025 or acute gastrointestinal bleeding within 6 months before randomization
• History of any grade arterial thromboembolic event, Grade 3 and above venous thromboembolic event, as specified in CTCAE 5.0, transient ischemic attack, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy within 12 months prior to randomization
• Acute exacerbation of chronic obstructive pulmonary disease within 4 weeks before randomization
• Known history of perforation of the gastrointestinal tract and/or fistula, history of gastrointestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition), extensive bowel resection (partial colectomy or extensive small bowel resection) within 6 months prior to randomization
• Probable or confirmed leptomeningeal disease per EANO ESMO criteria.

• Study Type: Interventional
• Enrollment (Estimated): 158
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: EORTC HQ; Phone Number: +32 2 774611; Email: eortc@eortc.org

Study Locations

• Austria
  • Linz, Austria, 4021
    • Kepler University Hospital
  • Vienna, Austria, 1090
    • Medical University of Vienna
• France
  • Clermont-Ferrand, France, 63000
    • CLCC-Jean Perrin
  • Lyon, France, 69373
    • Centre Léon Bérard
  • Nice, France, 06189
    • Centre Antoine Lacassagne
  • Reims, France, 51056
    • Institut Godinot
  • Villejuif, France, t 94805
    • Gustave Roussy
• Germany
  • Frankfurt am Main, Germany, 60590
    • University Hospital Frankfurt -Senckenberg Institute of Neurooncology
  • Jena, Germany, 07447
    • Universitaetsklinikum Jena
  • Rostock, Germany, 18058
    • Univ. Rostock-Zentrum für Radiologie mit Klinik und Poliklinik für Strahlentherapi
• Greece
  • Athens, Greece
    • Metropolitan Hospital
  • Athens, Greece, 11528
    • General hospital of Athens 'Alexandra'
  • Athens, Greece, 151 23
    • Diagnostic & Therapeutic Center of Athens Hygeia Hospital S.A.
• Italy
  • Brescia, Italy
    • Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia
  • Milan, Italy
    • RCCS Ospedale San Raffaele
  • Roma, Italy, 00128
    • Policlinico Universitario Campus Bio-Medico- Oncology Center
  • Roma, Italy, 00186
    • Ospedale Fatebenefratelli Isola Tiberina Gemelli Isola
  • Udine, Italy, 33100
    • Azienda Sanitaria Universitaria Friuli Centrale (Ospedaliero Universitario "Santa Maria della Misericordia" )
• Netherlands
  • Maastricht, Netherlands
    • Academisch Ziekenhuis Maastricht
  • Rotterdam, Netherlands
    • Erasmuc Mc
  • Utrecht, Netherlands
    • UMC-Academisch Ziekenhuis Utrecht
• Slovenia
  • Golnik, Slovenia, 4204
    • University Clinic Golnik
  • Ljubljana, Slovenia, 1000
    • The Institute Of Oncology
• Spain
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28006
    • Hospital Universitario de La Princesa
  • Palma de Mallorca, Spain, 07120
    • Hospital Universitari Son Espases

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age 18 years or older
• ECOG PS <= 2
• Patients with pathology proven metastatic NSCLC without an actionable genomic alteration for which there is first line targeted treatment approved by EMA and recommended by the ESMO guidelines.
• Asymptomatic or clinically symptomatic brain metastases defined as requiring a dose of steroids of maximum 4 mg equivalent dexamethasone per day for the last 7 days to control neurological symptoms. With the clinically oligosymptomatic further defined as having no indication for immediate localized brain therapy, including neurosurgery or radiotherapy. Patients with controlled seizures can be enrolled.

• Newly diagnosed brain metastasis with the following characteristics:

  • 1-10 newly diagnosed and untreated (except resected) brain metastases Note: if the neuronavigation MRI in the upfront SRS/FSRT arms shows > 10 metastases, but the MRI used for enrolment showed 1-10 metastases, the patient will be still considered eligible.
  • At least one metastasis should be at least 5x5 mm. In case of doubt on the diagnosis of brain metastasis, the lesion should not be irradiated but followed up.
  • The largest metastasis must be <10 mL in volume and <30 mm in longest diameter (resected lesions would not count).
  • The maximum cumulative volume of brain metastases must be <30 mL (resected lesions would not count)
• Adequate Organ Function

Exclusion Criteria:

• Patients with oligometastatic NSCLC who are scheduled to receive radical local treatment to extra-cranial sites.
• Patients with contra-indications to brain MRI with gadolinium-based contrast agent.
• Active auto-immune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
• Patients with >30 Gy of chest radiation therapy within 6 months prior to randomization; non-thoracic radiation therapy >30Gy within 4 weeks prior to randomization, or palliative radiation therapy of ≤30 Gy within 7 days prior to randomization.
• Prior brain irradiation (including whole brain radiotherapy and SRS).
• Prior systemic treatment for metastatic NSCLC. Patients having received adjuvant or neoadjuvant chemotherapy or curative-intent chemoradiotherapy with or without PD-1/L1 inhibitors can be enrolled if the adjuvant/neoadjuvant therapy was completed at least 6 months prior to the development of metastatic disease.
• Major surgical procedures or serious trauma within 4 weeks prior to randomization or plans for major surgical procedures within 4 weeks after the first dose (as determined by the investigator). Minor local procedures (excluding central venous catheterization and port implantation) within 3 days prior to randomization.
• History of coagulopathy and/or clinically significant bleeding symptoms or risk within 4 weeks prior to randomization
• Poorly controlled hypertension with repeated systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg after oral antihypertensive therapy
• History of serious cardiovascular, gastronintestinal, thromboembolic, neurological, or pulmonary conditions before randomization.
• History of perforation of the gastrointestinal tract and/or fistula, history of gastrointestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition), extensive bowel resection (partial colectomy or extensive small bowel resection) within 6 months prior to randomization

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: Sequencing arm; Patients will receive SRS/FSRT for all BM within ≤14 days from randomization, followed by 4 cycles of platinum-based chemotherapy combined with ivonescimab at 20 mg/kg every 3 weeks (Q3W). The systemic therapy will be followed by maintenance therapy with ivonescimab at 20 mg/kg plus pemetrexed (for patients with non-squamous NSCLC only) Q3W, for up to 2 years.	Drug: Ivonescimab; ivonescimab iv at 20 mg/kg every 3 weeks; Drug: Carboplatin; For adenocarcinoma : Carboplatin area under the curve of 5 mg/mL/min (AUC 5) IV with pemetrexed 500 mg/m2 IV on day 1 every 21 days (Q3W) for 4 cycles; Drug: Pemetrexed; For adenocarcinoma : Carboplatin area under the curve of 5 mg/mL/min (AUC 5) IV with pemetrexed 500 mg/m2 IV on day 1 every 21 days (Q3W) for 4 cycles; Drug: Paclitaxel; For squamous cell carcinoma: Carboplatin AUC 6 mg/mL/min IV/ paclitaxel IV 200 mg/m2 on day 1 every 21 days (Q3W) for 4 cycles (or 175 mg/m2 on D1 for Asian participant) Q3W for 4 cycles; Drug: Paclitaxel-albumin; For squamous cell carcinoma: Carboplatin AUC 6 mg/mL/min IV/ albumin-bound paclitaxel 100 mg/m2 on D1, 8 and 15 Q3W for 4 cycles; Radiation: Stereotactic Radiosurgery (SRS) or Fractionated Stereotactic Radiotherapy (FSRT); Patients will receive SRS/FSRT for all BM within ≤14 days from randomization, followed by 4 cycles of platinum-based chemotherapy combined with ivonescimab at 20 mg/kg every 3 weeks (Q3W). The systemic therapy should be initiated within 7 to 10 days after the end of SRS/FSRT but no earlier than 3 days after its completion. This will be followed by maintenance therapy with ivonescimab at 20 mg/kg plus pemetrexed (for patients with non-squamous NSCLC only) Q3W, for up to 2 years.
Experimental: Systemic treatment alone arm; Patients will receive 4 cycles of platinum-based chemotherapy combined with ivonescimab 20 mg/kg Q3W, followed by maintenance ivonescimab 20 mg/kg with pemetrexed (pemetrexed non-squamous only) Q3W for a maximum of 2 years.	Drug: Ivonescimab; ivonescimab iv at 20 mg/kg every 3 weeks; Drug: Carboplatin; For adenocarcinoma : Carboplatin area under the curve of 5 mg/mL/min (AUC 5) IV with pemetrexed 500 mg/m2 IV on day 1 every 21 days (Q3W) for 4 cycles; Drug: Pemetrexed; For adenocarcinoma : Carboplatin area under the curve of 5 mg/mL/min (AUC 5) IV with pemetrexed 500 mg/m2 IV on day 1 every 21 days (Q3W) for 4 cycles; Drug: Paclitaxel; For squamous cell carcinoma: Carboplatin AUC 6 mg/mL/min IV/ paclitaxel IV 200 mg/m2 on day 1 every 21 days (Q3W) for 4 cycles (or 175 mg/m2 on D1 for Asian participant) Q3W for 4 cycles; Drug: Paclitaxel-albumin; For squamous cell carcinoma: Carboplatin AUC 6 mg/mL/min IV/ albumin-bound paclitaxel 100 mg/m2 on D1, 8 and 15 Q3W for 4 cycles

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intracranial progression-free survival based on local assessment using RANO-BM criteria	Time interval between the date of randomization and the date of intracranial progression or neurological related death, whichever occurs first	First at week 6 and week 12 (±1 week) post-randomization. Then every 12 weeks (±2 weeks) until intracranial progression or study discontinuation.

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall survival	Overall survival is defined as the time interval between the date of randomization and the date of death from any cause, assessed up to 4 years
Intracranial PFS as per central review	Intracranial PFS based on central assessment is defined as the time interval between the date of randomization and the date of intracranial progression or neurological related death, whichever occurs first, assessed up to 2 years
Intracranial overall response rate (icORR), based on RANO-BM criteria as per local assessment	The overall icORR is defined as the time interval between the date of randomization and the date of intracranial response, assessed up to 2 years

Collaborators and Investigators

• Sponsor: European Organisation for Research and Treatment of Cancer - EORTC
• Collaborators: Summit Therapeutics
• Investigators: Principal Investigator: Lizza Hendriks, MD, PhD, Maastricht UMC

Study record dates

Study Major Dates

• Study Start (Estimated): November 1, 2026
• Primary Completion (Estimated): January 1, 2032
• Study Completion (Estimated): April 1, 2032

Study Registration Dates

• First Submitted: September 15, 2025
• First Submitted That Met QC Criteria: November 14, 2025
• First Posted (Actual): November 19, 2025

Study Record Updates

• Last Update Posted (Actual): June 4, 2026
• Last Update Submitted That Met QC Criteria: June 2, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Phase II study; Ivonescimab
• 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; Amino Acids, Peptides, and Proteins; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Investigative Techniques; Therapeutics; Surgical Procedures, Operative; Hydrocarbons; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Enzymes; Enzymes and Coenzymes; Coordination Complexes; Guanine; Hypoxanthines; Purinones; Purines; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Dicarboxylic; Taxoids; Cyclodecanes; Diterpenes; Radiotherapy; Stereotaxic Techniques; Neurosurgical Procedures; Transferases; Alkyl and Aryl Transferases; Pemetrexed; Carboplatin; Paclitaxel; Radiosurgery; Spermine Synthase
• Other Study ID Numbers: EORTC 2456-LCG-BTG

Drug and device information, study documents

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