The researchers are doing this study to test the safety of ivonescimab given in combination with standard chemotherapy and stereotactic radiosurgery (SRS) in people with non-small cell lung cancer (NSCLC) that has spread to the brain (brain metastases). The researchers will test different doses of the study drug to find the best dose that causes few or mild side effects in participants. Once the dose is found, the researchers will test it in a new group of participants to see if it is effective in treating their NSCLC brain metastases.

Inclusion Criteria:

1. Histologically or cytologically confirmed non-small cell lung cancer, including squamous and non-squamous histologies.

2. At least one brain metastasis measuring ≥ 1.0 cm and ≤ 3.5 cm in diameter, deemed safe for treatment with SRS by an attending radiation oncologist

3. PD-L1 tumor proportion score available

4. ECOG performance status 0-1 (See Appendix II for performance status criteria)

5. Age ≥ 18 years

6. Expected life expectancy greater than 3 months

7. Participant or Legally Authorized Representative (LAR) able to provide written informed consent

8. Participant willing to comply with all requirements of study participation

9. Adequate Organ Function:

   a. Hematology (no blood transfusions or growth factor therapy used within 7 days of the screening CBC): i. Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L ii. Platelet count ≥ 100 × 10^9/L iii. Hemoglobin ≥ 9.0 g/dL b. Kidneys: i. Creatinine clearance (CrCl) ≥ 50 mL/min using the Cockcroft-Gault formula or estimated glomerular filtration rate (eGFR) value ≥30 mL/min using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation ii. Urine protein < 2+ or 24-hour urine protein quantification < 1.0 g

   Liver:

   i. Serum total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); For patients with liver metastases or confirmed/suspected Gilbert syndrome, TBIL ≤3 × ULN, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN; For patients with liver metastases, AST and ALT ≤ 5 × ULN d. Coagulation: prothrombin time (PT) or international normalized ratio (INR) ≤ 1.5 x ULN,and partial prothrombin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN (unless abnormalities are unrelated to coagulopathy) This applies only to patients who are not on therapeutic anti-coagulation. Patients receiving therapeutic anti-coagulation should be on a stable dose.

10. Resolution of all toxicities of prior therapy or surgical procedures to baseline or Grade 1 (except for neuropathy, hypothyroidism requiring medication and alopecia can be resolved to Grade ≤2)

11. Steroid treatment (dexamethasone) is allowed and patients will be eligible if patients have been tapered to a dose equivalent of ≤ 4mg dexamethasone once a day for at least one week prior to enrollment. For example, a patient who received a 10mg bolus of dexamethasone in the emergency department after an MRI demonstrated brain metastases, as long as they have been tapered to a dose of 4mg or less for at least one week prior to enrollment

12. Female patient of childbearing potential having sex with an unsterilized male partner must agree to use a highly effective method of contraception* from the beginning of screening until 90 days after the last dose of the ivonescimab, which overlaps with the period during which patients are treated with SRS.

13. Unsterilized male patients having sex with a female partner of childbearing potential, or a pregnant or breastfeeding partner must agree to use barrier contraception (male condom) for the duration of the treatment period until 90 days after the last dose of ivonescimab.

Male patients with female partners of childbearing potential must have the female partner agree to use at least 1 form of highly effective contraception* for the duration of the treatment period until 90 days after the last dose of ivonescimab, which overlaps with the period during which patients are treated with SRS.

*See Appendix III - Contraceptive Guidelines

Exclusion Criteria:

1. Histologically confirmed small cell lung cancer.

2. Previous brain-directed radiotherapy will be permitted; however, direct re-treatment with SRS of a brain metastasis that had previously received SRS is not permitted; sites will be reviewed by the P.I. (L.R.G.P.).

3. Unable to undergo contrast-enhanced brain MRI.

4. Brain metastasis in a brainstem location ≥ 1.0 cm in diameter.

5. Leptomeningeal disease.

6. Previous treatment with immunotherapy. Note: for subjects who have received adjuvant/neoadjuvant immunotherapy for non-metastatic diseases for the purpose of cure, if the disease progression is reported ≥ 12 months after the end of last immunotherapy, the subjects can be enrolled in this study.

7. Subjects who have received previous treatment with standard-of-care targeted therapies against EGFR, ALK, and ROS1 can be enrolled in this study, at the discretion of the PI.

8. Previous history of malignant tumor other than NSCLC within 3 years before enrollment.

   Note: for subjects with malignant tumors that have been cured by local treatment (e.g.,basal or cutaneous squamous cell carcinoma, superficial bladder cancer, cervical or breast cancer in situ) or are not on any active systemic anti-tumor therapy, the subjects can be enrolled in this study in discussion with the PI.

9. Major surgical procedures or serious trauma within 4 weeks of enrollment 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 of enrollment.

10. History of bleeding tendencies or coagulopathy and/or clinically significant bleeding symptoms or risk within 4 weeks prior to enrollment, including but not limited to

    1. Hemoptysis (defined as coughing up ≥ 0.5 teaspoon of fresh blood or small blood clots Note: transient hemoptysis associated with diagnostic bronchoscopy is allowed.
    2. Nasal bleeding /epistaxis (bloody nasal discharge is allowed)
    3. Current use of prophylactic or full-dose anticoagulants or anti-platelet agents for therapeutic purposes that is not stable prior to enrollment 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.

11. Poorly controlled hypertension with repeated systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg after oral antihypertensive therapy . Blood pressure will be measured using triple blood pressure assessment to determine the average.

12. Active autoimmune or lung disease requiring systemic therapy (e.g., with disease modifying drugs, dexamethasone >4 mg daily or equivalent, immunosuppressant therapy) within 2 years prior to enrollment, however the following will be allowed:

    1. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is permitted.
    2. Intermittent use of bronchodilators, inhaled corticosteroids, or local corticosteroid injections is permitted

13. History of major diseases before enrollment, specifically:

    1. Unstable angina, myocardial infarction, congestive heart failure (New York Heart Association [NYHA] classification ≥ grade 2 - see Appendix IV - NYHA Classification) or unstable vascular disease (e.g., aortic aneurysm at risk of rupture, Moyamoya disease) that required hospitalization within 12 months prior to enrollment, or other cardiac impairment that may affect the safety evaluation of the study drug (e.g., poorly controlled arrhythmias, myocardial ischemia)
    2. History of esophageal gastric varices, severe ulcers, wounds that do not heal, abdominal fistula, intra-abdominal abscesses, or acute gastrointestinal bleeding within 6 months before enrollment.
    3. History of any grade arterial thromboembolic event, Grade 3 and above venous thromboembolic event, as specified in National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 5.0, transient ischemic attack, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy within 12 months prior to enrollment.
    4. Acute exacerbation of chronic obstructive pulmonary disease within 4 weeks before enrollment
    5. 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 enrollment.

14. Imaging during the screening period shows that the patient has:

    1. Radiologically documented evidence of major blood vessel invasion (central pulmonary artery, central pulmonary veins, aorta, brachiocephalic artery, common carotid artery, subclavian artery, superior vena cava) or tumor invading organs (heart, trachea, esophagus, central bronchi [not including segmental bronchi]) or if there is a risk of esophagotracheal or esophagopleural fistula in the opinion of the investigator.
    2. Radiographic evidence of major blood vessel encasement with narrowing of the vessel or intratumor lung cavitation or necrosis that the investigator determines will pose a significantly increased risk of bleeding.

15. Previous history of intracranial hemorrhage; if one of the visible brain metastases is deemed to have a component of intratumoral hemorrhage, then they will be evaluated by the principal investigator with Neuroradiology to determine if the patient may be enrolled in this study.

16. Live vaccine or live attenuated vaccine within 4 weeks prior to planned enrollment, or if scheduled to receive a live vaccine or live attenuated vaccine during the study period. Inactivated vaccines are permitted.

17. Severe infection within 4 weeks prior to enrollment, including but not limited to comorbidities requiring hospitalization, sepsis, or severe pneumonia; active infection (as determined by the investigator) requiring systemic anti-infective therapy within 2 weeks prior to enrollment (excluding antiviral therapy for hepatitis B or C).

18. Has pre-existing peripheral neuropathy that is ≥ Grade 2 by CTCAE version 5.

19. Uncontrolled pleural effusions, pericardial effusions, or ascites that is clinically symptomatic.

    Note: Patients managed with indwelling catheters (e.g., PleurX) are allowed.

20. History of non-infectious pneumonia requiring systemic corticosteroids (>dexamethasone 4 mg equivalent daily), or current interstitial lung disease.

21. Active or prior history of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, or chronic diarrhea).

22. Known history of human immunodeficiency virus (HIV) whose viral load is not controlled.

    HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

23. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.

24. Patients with active hepatitis B are required to have stable or declining levels of hepatitis B DNA by polymerase chain reaction (PCR) on appropriate anti-viral therapy with acceptable tolerability for one month prior to enrollment.

25. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

26. Known allergy to any component of any study drug; known history of severe hypersensitivity to other monoclonal antibodies.

27. History or current evidence of any condition (medical [including adverse events from prior anticancer therapy, disorders secondary to tumor], surgical or psychiatric [including substance abuse]), or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, might lead to higher medical risk and/or is not in the best interest of the patient to participate, in the opinion of the treating investigator.

28. Patient is breastfeeding or plans to breastfeed during the study.

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made following one year after publication and for up to 36 months later. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.