A Study of Ivonescimab, Chemotherapy, and Stereotactic Radiosurgery for People With Non-Small Cell Lung Cancer

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 hyperte