Inclusion Criteria:
* Subject or legally authorized representative, is willing and able to provide written informed consent.
* Histologically- or cytologically- confirmed colorectal cancer.
* ≥ 18 years of age on day of signing informed consent.
* Consent for use of archival tissue and blood draws for research purposes.
* Performance status of ECOG 0 or 1.
* Known non-MSI-H/pMMR by IHC, PCR or NGS testing. MSKCC confirmation of non-MSI-H/pMMR status is not mandatory prior to enrollment and treatment on the study. For patients with outside testing, if sufficient tissue is available testing may be repeated at MSKCC and will not impact initial eligibility.
* Consent to undergo MSK IMPACT or NGS, if not previously done
* Disease specific criteria:
1. Cohorts 1a and 2a: Undergone a complete surgical resection (R0) for stage III colon or rectal cancer, followed by adjuvant chemotherapy with FOLFOX or CAPEOX. Post-operative chemotherapy not required if received previous oxaliplatin-based therapy. Total Neoadjuvant Therapy for rectal cancer with complete clinical and radiographic response is allowed.
2. Cohorts 1b and 2b: Undergone a complete surgical resection (R0) for liver metastasis (ablation or stereotactic body radiation therapy \[SBRT\], but not Y-90, is permitted) and completed standard peri-operative chemotherapy. Peri-operative chemotherapy not required if received previous oxaliplatin-based therapy. Prior floxuridine via Hepatic Arterial Infusion Pump is permitted. Completed definitive treatment for the primary tumor including (R0) resection, or Total Neoadjuvant Therapy for rectal cancer with complete clinical and radiographic response.
* Positive ctDNA following completion of appropriate standard of care therapy.
* Patients must sign informed consent within 6 weeks of positive ctDNA result. The 6 weeks is considered from the date that the ctDNA is resulted, and not the date it is drawn.
Adequate organ function, defined as:
1. Absolute Neutrophil Count ≥ 1,500/mm3.
2. Platelet count ≥ 75,000/mm3.
3. Hemoglobin ≥ 9.0 g/dL
4. Creatinine clearance (CrCl) ≥60 mL/min.
5. AST and ALT ≤ 2.5 × ULN
6. Bilirubin ≤ 1.5 × ULN or Direct bilirubin ≤ ULN
* Subjects of childbearing potential (or with partners of childbearing potential) must use effective contraception for the course of the study starting with the screening visit through at least 5 months after the last dose of study treatment. Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives, or double barrier method (diaphragm plus condom).
Exclusion Criteria:
* Presence of metastatic or recurrent disease.
* Known DNA polymerase epsilon (POLE) or DNA polymerase delta (POLD) activating mutation.
* R1 (microscopic residual tumor) or R2 resection (macroscopic residual tumor at resection margin).
* Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
* Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
1. Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., dexamethasone containing antiemetic regimen or steroids as CT scan contrast premedication) may be enrolled.
2. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed.
* Hypersensitivity to botensilimab or balstilimab or any of its excipients.
* Chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent
a. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
* History of, or any evidence of active, non-infectious pneumonitis.
* Active infection requiring systemic therapy.
* Current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
* Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
* Pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 90 days after the last dose of trial treatment.
* Prior therapy with an anti-PD-1, anti-PD-L1, or anti-CTLA-4 agent.
* Active autoimmune disease or history of autoimmune disease that required systemic treatment within 2 years of the start of study treatment (i.e., with use of disease-modifying agents or immunosuppressive drugs). The following are exceptions:
1. Subjects with vitiligo or alopecia
2. Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement or psoriasis not requiring systemic treatment
* Known active TB (Bacillus tuberculosis).
* Uncontrolled infection with human immunodeficiency virus (HIV). Patients on stable highly active antiretroviral therapy with undetectable viral load and normal CD4 counts for at least 6 months prior to study entry are eligible. Serological testing for HIV at screening is not required
* Known to be positive for hepatitis B virus (HBV) surface antigen, or any other positive test for HBV indicating acute or chronic infection. Patients who are receiving or who have received anti-HBV therapy and have undetectable HBV DNA prior to study entry are eligible. Serological testing for HBV at screening is not required.
* Known active hepatitis C virus (HCV) as determined by positive serology and confirmed by polymerase chain reaction (PCR). Patients on or who have received antiretroviral therapy are eligible provided they are virus-free by PCR for at least 6 months prior to study entry. Serological testing for HCV at screening is not required.
* Received a live vaccine within 30 days of planned start of study therapy
