A Study of Botensilimab and Balstilimab for the Treatment of Colorectal Cancer

Inclusion Criteria:

1. Histologically confirmed diagnosis of unresectable and metastatic CRCadenocarcinoma.

2. The tumor must have been assessed for microsatellite instability high (MSI-H) ordeficient mismatch repair (dMMR) status per a standard local testing method.

3. Voluntarily agree to participate by giving signed, dated, and written informedconsent prior to any study-specific procedures.

4. Must have received at least 1 prior chemotherapy regimen for metastatic or recurrentCRC as follows where approved and locally available in the country of randomization:

5. Standard chemotherapy/therapy including all of the following agents (ifeligible and no contraindication): a fluoropyrimidine, irinotecan, oxaliplatin,bevacizumab or biosimilars, an anti-epidermal growth factor receptor antibody (cetuximab or panitumumab), and v-raf murine sarcoma viral oncogene homolog B1inhibitor/BRAF (encorafenib), if applicable.

6. Participants must have progressed while receiving or within 3 months of thelast administration of their last line of standard therapy or be unable totolerate any of these standard treatments.

7. Participants who received adjuvant chemotherapy and had recurrence during orwithin 6 months of completion of the adjuvant chemotherapy can count this as aline of therapy.

8. Measurable disease on baseline imaging per RECIST 1.1.

9. Life expectancy ≥ 12 weeks.

10. Eastern Cooperative Oncology Group performance status of 0 or 1.

11. Adequate organ function.

12. Women of childbearing potential must have a negative serum pregnancy test atscreening and prior to study drug administration.

13. Male participants with a female partner(s) of childbearing potential must agree touse highly effective contraceptive measures throughout the study, starting with theScreening visit through 2-6 months, depending upon assigned study treatment. Maleswith pregnant partners must agree to use a condom; no additional method ofcontraception is required for the pregnant partner.

14. No growth factor support, transfusions, or albumin administration within 14 days ofrandomization of study treatment.

Exclusion Criteria:

1. Tumor is MSI-H/dMMR per a standard local testing method.

2. Received programmed cell death protein 1, PD-(L)1, or CTLA-4 therapies including anyimmune checkpoint inhibitor or experimental immunologic agents.

3. Received regorafenib or trifluridine/tipiracil as prior therapy(ies).

4. Partial or complete bowel obstruction within the last 3 months, signs/symptoms ofbowel obstruction, or known radiologic evidence of impending obstruction.

5. Refractory ascites.

6. Liver metastases by computed tomography or magnetic resonance imaging. Note:Participants with definitively treated liver metastases (this includes surgicalresection, including microwave or radiofrequency ablation, or stereotactic bodyradiation therapy, but not yttrium-90 or chemotherapy alone) may be eligible if theywere treated at least 6 months prior to enrollment with no evidence of metastaticdisease in the liver on subsequent imaging.

7. Clinically significant (that is, active) cardiovascular disease.

8. Active brain metastases or leptomeningeal metastases with certain exceptions.

9. Concurrent malignancy (present during screening) requiring treatment or history ofprior malignancy active within 2 years prior to the first dose of study treatment.Participants with history of prior early-stage basal/squamous cell skin cancer,low-risk prostate cancer eligible for active surveillance, or noninvasive or in situcancers who have undergone definitive treatment at any time are also eligible.

10. Treatment with one of the following classes of drugs within the delineated timewindow prior to Cycle 1 Day 1 (C1D1):

11. Cytotoxic, targeted therapy or other investigational therapy within 3 weeks.

12. Monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, orsimilar therapy, within 4 weeks, or 5 half-lives, whichever is shorter.

13. Small molecule/tyrosine kinase inhibitors within 2 weeks or less than 5circulating half-lives of investigational drug.

14. Known allergy or hypersensitivity to any of the study drugs or any of the study drugexcipients.

15. Any evidence of current interstitial lung disease (ILD) or pneumonitis, or priorhistory of ILD or non-infectious pneumonitis requiring glucocorticoids.

16. History of allogeneic organ transplant, stem cell transplant, or bone marrowtransplant.

17. Psychiatric or substance abuse disorders that would interfere with cooperation withthe requirements of the study.

18. Participants with a condition requiring systemic treatment with eithercorticosteroids (> 10 milligrams [mg] daily prednisone equivalent) within 14 days oranother immunosuppressive medication within 30 days of the first dose of studytreatment. Inhaled or topical steroids, and adrenal replacement steroid doses (≤ 10mg daily prednisone equivalent) are permitted in the absence of active autoimmunedisease.

19. Active autoimmune disease or history of autoimmune disease that required systemictreatment within 2 years of the start of study treatment (that is, with use ofdisease-modifying agents or immunosuppressive drugs).

20. History or current evidence of any condition, co-morbidity, therapy, any activeinfections, or laboratory abnormality that might confound the results of the study,interfere with the participant's participation for the full duration of the study,or is not in the best interest of the participant to participate, in the opinion ofthe treating Investigator.

21. Previous SARS-CoV-2 infection within 10 days for mild or asymptomatic infections or 20 days for severe/critical illness prior to C1D1.

22. Uncontrolled infection with human immunodeficiency virus.

23. Known to be positive for hepatitis B virus (HBV) surface antigen, or any otherpositive test for HBV indicating acute or chronic infection.

24. Known active hepatitis C virus as determined by positive serology and confirmed bypolymerase chain reaction.

25. Has urine protein ≥ 1 gram/24 hour.

26. Uncontrolled hypertension: systolic pressure ≥ 150 millimeters of mercury (mmHg) ordiastolic pressure ≥ 90 mmHg on repeated measurements that cannot be managed bystandard antihypertension medications ≤ 28 days before the first dose of studydrug(s).

27. Participants who require treatment with strong cytochrome P450 3A4 inducers orinhibitors.

28. Has presence of gastrointestinal condition, for example, malabsorption, that mightaffect the absorption of study drug(s).

29. Non-healing wound(s).

30. Symptomatic active bleeding.