• Written informed consent and HIPAA authorization for release of personal health information

• As determined by the enrolling physician or protocol designee, ability of the participant to understand and comply with study procedures for the entire length of the study

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2

• Have a diagnosis of histologically confirmed metastatic colorectal cancer with primary tumor located beyond the splenic flexure. Histologic confirmation of a colorectal primary tumor is acceptable if accompanied by radiographic evidence of metastatic disease.

‣ For Cohort A: Participants must enroll for study treatment in the first or second-line metastatic setting. Participants may receive 1 month of standard chemotherapy in the metastatic setting and still be eligible to initiate protocol therapy in the first-line setting. Adjuvant or neoadjuvant therapy does not count as a line of therapy even if given in the setting of metastatic disease (oligometastatic), unless disease recurrence was noted within 6 months of completing the last dose of the adjuvant or neoadjuvant therapy.

⁃ For Cohort B: Participants must have had at least stable disease (per treating physician) on a prior EGFR inhibitor containing regimen and it must be at least 4 months since the prior anti-EGFR inhibitor treatment was completed. Participants previously enrolled in Cohort A can later enroll in Cohort B should the eligibility criteria be met.

⁃ For Cohort C: Subjects with no prior use of irinotecan or anti-EGFRi. If patients were treated on cohort A (of this study) they can cross-over to cohort C if other eligibility criteria are met at the time of cross-over.

• Evaluable disease according to RECIST v1.1. Participants do not have to have measureable disease.

• Participants with prior brain metastasis may be considered if they have completed their treatment for brain metastasis at least 4 weeks prior to study registration, have been off of corticosteroids for ≥ 2 weeks, and are asymptomatic.

• Demonstrate adequate organ function; all screening labs to be obtained within 7 days prior to registration. Note minimum platelet requirement differs between Cohort A and B.

‣ Absolute Neutrophil Count (ANC) ≥ 1,000 / mcL

⁃ Platelets ≥ 50,000 / mcL (Cohort A); ≥ 50,000 mcL (Cohort B receiving only EGFRi); ≥75,000 / mcL (cohort B receiving irinotecan and EGFRi; and cohort C)

⁃ Serum creatinine OR measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤ 2.0 X upper limit of normal (ULN) OR ≥ 60 mL/min for subject with creatinine levels \> 2.0 X institutional ULN

⁃ Bilirubin ≤ 1.5 × ULN OR direct bilirubin ≤ ULN for subjects with bilirubin levels \>1.5 x ULN

⁃ Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 5 × ULN

⁃ Albumin ≥ 2.5 mg/dL

• Females of childbearing potential must have a negative serum pregnancy test within 7 days of registration and not be breastfeeding. Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.

• Females of childbearing potential and males must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 120 days after treatment discontinuation. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method.

• Tumor must be mismatch repair (MMR) proficient as determined by microsatellite instability or immunohistochemistry for MMR proteins

‣ Microsatellite instability (MSI) testing must be MSI-stable or MSI-low.

⁃ Or IHC for MMR proteins must demonstrate intact MMR proteins.

• Baseline (prior to any anti-EGFR treatment) tumor molecular profiling with no pathologic variants in KRAS or NRAS or BRAF V600 mutations. If additional molecular profiling is completed (tissue or blood based testing) after receiving treatment for colon cancer and variants in KRAS or NRAS are found, those patients will be considered eligible for this study. Patients with BRAF V600 mutations are not eligible.

• Participants must not have known additional malignancy that is requiring systemic treatment. Participants taking hormonal treatments for breast or prostate cancer are still eligible.

• No major surgery within prior 2 weeks of treatment initiation (4 weeks if will be receiving bevacizumab).

• Urine protein less than 100 mg/dL if planning to receive bevacizumab.

• Blood pressure \<160/90 if planning to receive bevacizumab.

• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to panitumumab or cetuximab, including known severe hypersensitivity reactions to monoclonal antibodies. No history of allergic reactions to 5-Fluorouracil, irinotecan, leucovorin or bevacizumab if the participant will be receiving that agent in this study.

• Participants must have no metastatic cancer lesions greater than 3.5cm in diameter. Any number of metastatic lesions will be allowed.