Inclusion Criteria:

• Participant must be ≥ 18 years at the time of signing the ICF.
• Histopathologically confirmed colorectal adenocarcinoma.
•  All races, gender and ethnic groups are eligible for this study.
• Presence of measurable disease by RECIST 1.1 criteria.
  • Previously irradiated lesions or lesions located in the previous irradiated area may not be the target lesion unless there has been documented progression in those lesions.
• ECOG performance status of 0 or 1, with no deterioration (that is, ECOG PS > 1) over the previous 4 weeks prior to baseline at screening and prior to randomization.
• Life expectancy ≥ 12 weeks at the time of screening
• Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
• Provision of a signed and dated written ICF prior to any mandatory study-specific procedures, sampling, and analyses.
• Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative  Participants not giving consent for optional genetic research will still be eligible for the main study.
  • Note: For participants ≥ 65 years old, use of geriatric screening tools and/or formal Geriatric Assessment (eg, CGA) should be considered, in line with local or national guidelines, prior to randomization. For participants ≥ 80 years old, formal Geriatric Assessment (eg, CGA), if not required already by local or national guidelines, should be strongly considered prior to randomization.

Exclusion Criteria:

• Brain metastases or spinal cord compression (including asymptomatic and adequately treated disease). Participants with suspected brain metastases at screening should have an MRI (preferred)
• Known history of severe allergy to any monoclonal antibody or study intervention excipients or any of the study intervention of the chemotherapy regimen.
• Clinically meaningful ascites, pleural effusion, pericardial effusion defined as any ascites/effusion requiring non-pharmacologic intervention (eg, paracentesis) to maintain symptomatic control, within 6 months prior to the first scheduled dose. Participants on stable doses of diuretics for ascites for ≥ 2 months are eligible.
• Evidence of the following infections:
  • Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination, and radiographic findings and tuberculosis testing in line with local practice).
  • Uncontrolled HIV infection; the following criteria are required to define well-controlled HIV infection:
    • undetectable viral RNA load for 6 months,
    • CD4+ count of >500 cells/μL, stable for at least 6 months on the same anti-HIV medications, and
    • no history of AIDS (defined by either CD+T cell count <200 cells/μL and/or AIDS-defining opportunistic infection).
  • Co-infection of HBV and HDV. HBV positive infection is indicated by the presence of HBsAg and/or anti-HBcAb with detectable HBV DNA; HDV positive infection is indicated by the presence of anti-HDV antibodies.
  • Active or uncontrolled hepatitis B or hepatitis C; Participants are eligible if they:
    • Have controlled hepatitis C viral load defined as undetectable hepatitis C RNA by PCR either spontaneously or in response to a successful prior course of anti-hepatitis C therapy.
    • Have received HBV vaccination with only anti-HBs positivity and no clinical signs of hepatitis
    • Are HBsAg- and anti-HBc+ (ie, those who have cleared HBV after infection) and 
    • Are HBsAg+ with chronic HBV infection (lasting 6 months or longer) and meet the conditions  below:
      • HBV DNA viral load < 100 IU/mL
      • Have normal transaminase values, or, if liver metastases are present, abnormal transaminases, with a result of AST/ALT < 3 × ULN, which are not attributable to HBV infection
      • Start or maintain antiviral treatment if clinically indicated as per the investigator
  • Known active hepatitis A.
• Any unresolved toxicity NCI CTCAE Grade ≥ 2 from a previous anticancer therapy, with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria of the respective substudy.
  • Participants with irreversible toxicity not reasonably expected to be exacerbated by treatment with study treatment may be included only after consultation with the study physician.
• History of another primary malignancy except for:
  •  Malignancy treated with curative intent with no known active disease ≥ 2 years before the first dose of study intervention and of low potential risk for recurrence.
  •  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
  • Adequately treated carcinoma in situ without evidence of disease.
• As judged by the investigator, any condition that would interfere with evaluation of the investigational product or interpretation of participant safety or study results.
• Known history of immunodeficiency, or other acquired, congenital immunodeficiency disorders, or history of organ transplantation and allogeneic bone marrow transplantation.
• Radiation therapy within 6 months prior to initiation of study treatment, except for palliative radiation therapy for bone metastasis at least 14 days prior to initiation of study treatment; radiation therapy covering more than 30% of the bone marrow area within 28 days prior to the first dose is not allowed.
• Treatment with live attenuated vaccine within 30 days before the randomization.
• Treatment with botanical preparations (eg herbal supplements or traditional Chinese medicines) intended to treat the disease under study within 2 weeks prior to the first dose, except with the approval of the study physician.
• Severe infection (CTCAE Grade > 2) within 4 weeks prior to the first dose of study drug, such as severe pneumonia, bacteremia, and infection complications requiring hospitalization; active pulmonary inflammation accompanied with relevant clinical symptoms or signs based on chest X-ray at baseline; symptoms and signs of infection requiring oral or IV antibiotic therapy within 2 weeks prior to the first dose of study intervention, except prophylactic use of antibiotics.
• Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 4 weeks, prior to first dose of study treatment or concurrent enrollment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study.
• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
• Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
• Previous enrollment in the present study.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 12/31/2024. Questions regarding updates should be directed to the study team contact.