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.

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.

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