Inclusion Criteria
Patients must meet all of the following inclusion criteria to be enrolled in this study:
1. Voluntarily signed written informed consent.
2. Age ≥18 at the time of enrollment, both male and female.
3. An Eastern Cooperative Oncology Organization Group (ECOG) performance status
score of 0 or 1.
4. Expected life expectancy ≥ 6 months.
5. Patients with histologically or cytologically confirmed metastatic CRC, not amenable to
curative resection.
6. At the time of enrollment, the patient has remaining archival formalin-fixed paraffin
embedded (FFPE) tumor tissue from his/her CRC diagnostic sample or tumor biopsy.
7. Known BRAF, KRAS and NRAS (extended RAS) mutation status from existing
reports, or determined by testing tumor tissue utilizing a clinical assay.
8. No prior systemic therapy for metastatic CRC.
a. If patients have received systemic therapy or radiotherapy for early-stage disease,
>12 months must have elapsed since completion of neoadjuvant therapy and/or
adjuvant therapy (including adjuvant oxaliplatin or radiotherapy) and prior to
diagnosis of recurrent or metastatic disease.
9. At least one measurable tumor lesion according to RECIST v1.1 that is amenable to
repeated accurate measurements.
Note: Brain metastases cannot be selected as target lesions and lesions that have
received radiotherapy in the past cannot be selected as target lesions unless they have
progressed following radiation.
10. Demonstrate adequate organ function as determined by the following requirements:
a. Hematology (no use of any blood components and cell growth factor supportive
therapy within 7 days prior to initiation of study treatment):
i. Absolute neutrophil count (ANC) ≥ 1,500/mm3 (ANC ≥ 1000/mm3 for
African American patients)
ii. Platelet count ≥ 100 × 109/L (100,000/mm3)
iii. Hemoglobin ≥ 10.0 g/dL.
b. Kidney:
i. Creatinine clearance* (CrCL) ≥ 50 mL/min using the Cockcroft-Gault
formula or estimated glomerular filtration rate (eGFR) value ≥50 mL/min
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using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
equation (adjustment by BSA is not required for eGFR).
*CrCL or eGFR can be determined using the calculator from the National
Kidney Foundation website (www.kidney.org).
ii. Urine protein c. 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 x ULN
ii. Aspartate transaminase (AST) and alanine aminotransferase
(ALT) ≤ 2.5× ULN; for patients with liver metastases, AST and
ALT ≤ 5×ULN.
d. Coagulation: prothrombin time or international normalized ratio (INR) ≤ 1.5 × ULN,
and partial thromboplastin 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.
11. Female patients of childbearing age must have negative serum pregnancy test results
before randomization or per region-specific guidance documented in the informed
consent and a negative urine pregnancy test within 3 days before the first dose.
12. Female patients of childbearing potential having sex with an unsterilized male partner
must agree to use a highly effective method of contraception for the duration of
treatment period until 6 months after last dose of ivonescimab/bevacizumab or until
9 months after last dose of chemotherapy (whichever is longer).
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 6 months after last dose of
ivonescimab/bevacizumab or chemotherapy. 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 treatment period until 6 months after
last dose of ivonescimab/bevacizumab or until 9 months after last dose of chemotherapy
(whichever is longer).
14. Patient is willing and able to comply with the visits, treatment regimens, laboratory
tests, and other requirements of the study as specified in the schedule.
 

Exclusion Criteria
Patients who meet any of the following exclusion criteria will not be enrolled in the study:
1. Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) disease as
determined by a health authority approved assay (FDA-approved assay for United
States, CE-IVD marked assay for Europe, MHLW-approved assay for Japan, or
NMPA--cleared assay for China), eg, Ventana MMR RxDx Panel (approved for North
America, Europe, Japan and China), FoundationOne CDx (approved for North America,
Europe, and Japan), Promega OncoMate MSI Dx and Tempus xT CDx (approved for
North America and Europe) conducted at a local clinical laboratory or at the central
laboratory.
2. Known BRAF V600E mutant status; known DPD deficiency (refer to local fluorouracil
label or local clinical guidance for DPD status recommendation prior to starting
treatment).
3. Resectable oligometastastic only disease, with multidisciplinary plan for complete
resection of all disease.
4. Current presence of significant radiographic or clinical manifestations of gastrointestinal
(GI) obstruction.
5. Ascites requiring paracentesis within last 30 days.
6. Symptomatic central nervous system (CNS) metastases with hemorrhagic features, CNS
metastasis ≥ 1.5 cm, CNS radiation within 7 days prior to randomization, potential need
for CNS radiation within the first cycle, or leptomeningeal disease.
Note: Patients who have stopped corticosteroids or are on stable corticosteroid therapy
(prednisone ≤ 10 mg daily or equivalent) are allowed.
7. Presence of brainstem, meningeal metastases, spinal cord metastases, or compression.
8. Other prior malignancy unless the patient has undergone curative therapy with no
evidence of disease recurrence within 3 years prior to randomization.
The following malignancies will be allowed without the 3-year interval after adequate
treatment: basal cell or squamous cell carcinoma of skin, superficial bladder cancer, in
situ cervical cancer, other in situ cancers, prostate cancer with a Gleason score ≤6 that
does not need therapy or other local tumors that are considered cured.
9. Concurrent enrollment in another clinical study, unless it is an observational,
non-interventional clinical study or a follow-up period for an interventional study.
10. Palliative local therapy for non-target lesions and non-specific immunomodulatory
therapy (such as interleukin, interferon, thymus peptide, tumor necrosis factor, etc.)
within 2 weeks before the first dose.
11. Patients who have received prior immunotherapy or anti-angiogenic therapy for
colorectal cancer, including immune checkpoint inhibitors (such as other anti-
programmed cell death-1 or programmed cell death ligand-1 [PD-(L)1]/vascular
endothelial growth factor [VEGF] antibodies, anti-CTLA-4 antibodies, anti-TIGIT
antibodies, anti-LAG3 antibodies, etc.), immune checkpoint agonists (such as ICOS,
CD40, CD137, GITR, OX40 antibodies, etc.), immune cell therapy and any other
therapy based on the mechanism of action of tumor immunity or angiogenesis.
12. Any prior clinically significant or active autoimmune disease requiring systemic therapy
(eg, with disease- modifying drugs, prednisone >10 mg daily or equivalent,
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immunosuppressant therapy or immunomodulatory agents [eg, infliximab or IVIG])
within 2 years prior to randomization; however, the following will be allowed:
x Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency) is permitted.
13. History of major diseases before randomization, specifically:
a. Unstable angina, myocardial infarction, congestive heart failure (New York Heart
Association [NYHA] classification ≥Grade 2) or unstable vascular disease
(eg, 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 (eg, poorly
controlled arrhythmias, myocardial ischemia)
b. History of esophageal gastric varices, severe ulcers, wounds that do not heal, fistula,
intra-abdominal abscesses, or ≥ Grade 3 acute gastrointestinal bleeding within
6 months before randomization
c. History of any grade arterial thromboembolic event (ATE), Grade 3 and above
venous thromboembolic event (VTE), 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 randomization
d. History of perforation of the gastrointestinal tract and/or fistula unless the
perforation was related to the primary colorectal tumor and the patient had resection
or diverting ostomy proximal to the tumor, history of gastrointestinal obstruction
(including incomplete intestinal obstruction requiring parenteral nutrition), extensive
bowel resection within 6 months prior to randomization
14. Has pre-existing peripheral neuropathy that is ≥ Grade 2 by CTCAE version 5.
15. Live vaccine or live attenuated vaccine within 4 weeks prior to planned randomization,
or if scheduled to receive a live vaccine or live attenuated vaccine during the study
period. Inactivated vaccines are permitted.
16. Severe infection within 4 weeks prior to randomization, 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 randomization (excluding antiviral therapy for hepatitis B).
17. 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 within 3 days prior to randomization
(excluding central venous catheterization and port implantation).
18. History of bleeding tendencies or coagulopathy and/or clinically significant bleeding
symptoms or risk within 4 weeks prior to randomization, including but not limited to:
a. Clinically significant GI bleeding such as hematochezia or any episodes of melena
or documented acute hemoglobin drop of more than 1 gm in 2 weeks prior to
randomization