Non-Small Cell Lung Cancer (NSCLC) Clinical Trials

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

• 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

• PD-L1 tumor proportion score available

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

• Age ≥ 18 years

• Expected life expectancy greater than 3 months

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

• Participant willing to comply with all requirements of study participation

• 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.

⁃ 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)

⁃ 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

⁃ 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.

⁃ 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