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

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