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

• 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

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
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

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): April 1, 2026
• Primary Completion (Estimated): January 1, 2031
• Study Completion (Estimated): October 1, 2031

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): November 19, 2025
• Last Update Submitted That Met QC Criteria: November 14, 2025
• Last Verified: November 1, 2025

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
• 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