A Study of Trastuzumab Deruxtecan (T-DXd) and Cetuximab in People With Colorectal Cancer

Inclusion Criteria: * Have histologically confirmed adenocarcinoma of the colon or rectum that is metastatic and/or unresectable. * Unless otherwise contraindicated, participants must have received regimens containing the following agents: fluoropyrimidine (e.g., 5-fluorouracil or capecitabine), oxaliplatin, irinotecan, and if the tumor is MSI-H/MMRd, a PD-(L)1 directed antibody. There is no maximum number of prior lines of therapy. * Prior anti-HER2 therapies other than T-DXd are allowed, with a washout period of at least 4 weeks. * Prior anti-EGFR therapies, including cetuximab, are allowed, with a washout period of at least 4 weeks. * Have progression of unresectable or metastatic CRC after last systemic therapy (as confirmed by Investigator) or be intolerant of last systemic therapy. * Participants with KRAS/NRAS or BRAF-mutant colorectal tumors are eligible. * Willing and able to undergo baseline tumor biopsy, preferably of a lesion that has progressed since the last treatment, if feasible. * Have confirmed HER2-low mCRC, defined in this study by having tumor tissue tested at a CLIA-certified laboratory as HER2 IHC 1+ or 2+, as determined by Ventana's PATHWAY anti-HER2 (clone 4B5), an FDA-approved assay following the package insert's interpretational manual for gastric cancer, regardless of amplification by FISH. Archival tissue may be used for determination of HER2 status as long as tissue was obtained after last dose of most recent HER2-targeted therapy, if applicable. * Have radiographically measurable disease according to RECIST v1.1, with at least one site of disease that is measurable and that has not been previously irradiated. If the participant has had previous radiation to the target lesion(s), there must be evidence of progression since radiation. * Age ≥18 years on the day of signing informed consent. * Have an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. * Have parameters demonstrating adequate organ function, as defined below, obtained ≤14 days prior to the first study treatment, unless otherwise noted: System / Laboratory value Hematologic: Absolute neutrophil count (ANC) / ≥1500/mm3 (G-CSF administration is not allowed within 14 days prior to screening assessment of bone marrow function, or at any time after this day and prior to initiation of treatment with study drug) Hemoglobin / ≥9.0 g/dL (Red blood cell transfusion is not allowed within 14 days prior to screening assessment of bone marrow function, or at any time after this day and prior to initiation of treatment with study drug) Platelet count / ≥100,000/mm3 (Platelet transfusion is not allowed within 14 days prior to screening assessment of bone marrow function, or at any time after this day and prior to initiation of treatment with study drug) Renal: Serum creatinine or creatinine clearance (as calculated using the Cockcroft-Gault equation) / ≤1.5 x ULN or ≥50 mL/min Hepatic: Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) / ≤2.5 x ULN if no liver metastases or ≤5x ULN if liver metastases are present Total bilirubin / ≤1.5 x ULN if no liver metastases or \<3x ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline Serum albumin / ≥2.5 g/dL Coagulation Left ventricular ejection fraction (LVEF) as assessed by echocardiogram documented ≤28 days prior to study treatment / ≥50% * Have adequate treatment washout before enrollment (study treatment) as defined below: Treatment / Washout Period Major surgery / ≥4 weeks Radiation therapy / ≥4 weeks (if palliative stereotactic radiation therapy without abdominal involvement, ≥2 weeks) Chemotherapy (including antibody drug therapy, retinoid therapy) / ≥3 weeks for chemotherapeutics, ≥4 weeks for antibody drug therapy (e.g. bevacizumab, ramucirumab, cetuximab, trastuzumab) Immunotherapy / ≥4 weeks Cytochrome P450 (CYP)3A4 strong inhibitor, OATP inhibitor / ≥3 elimination half-lives of the inhibitor * Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential (Section 6.3) who are sexually active with a non-sterilized male partner. For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at the screening visit. * Male and female participants of reproductive/childbearing potential (Section 6.3) must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and for at least 7 months for females and 4 months for males after the last dose of study drug. Oral contraception alone is not acceptable; additional barrier methods in conjunction with spermicide must be used. Methods considered as highly effective methods of contraception include: 1. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, or transdermal. 2. Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, or implantable. 3. Intrauterine device. 4. Intrauterine hormone-releasing system. 5. Bilateral tubal occlusion. 6. Vasectomized partner. 7. Complete and true sexual abstinence defined as abstinence when it is in line with the preferred lifestyle of the participant. Participants in this study should refrain from heterosexual intercourse during and upon completion of the study and for at least 7 months for females and 4 months for males after the last dose of study drug. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence of the duration of exposure to study drug, and withdrawal are not acceptable methods of contraception. 8. Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy, or post-menopausal defined as 12 months of spontaneous amenorrhea (in questionable cases, a blood sample with simultaneous follicle-stimulating hormone \>40 mIU/mL and estradiol \<40 pg/mL \[\<147 pmol/L\] is confirmatory). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for women of childbearing potential if they wish to continue HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2 to 4 weeks will elapse between cessation of therapy and the blood draw. This interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without the use of contraceptive method. 9. Male participants must be surgically sterile or using an acceptable method of contraception (defined as barrier methods in conjunction with spermicides) for the duration of the study (from the time they sign consent) and for 4 months after the last dose of study drug to prevent pregnancy in a partner. * Male participants must not freeze or donate sperm starting at Screening and throughout the study period, and at least 4 months after the final study drug administration. Preservation of sperm should be considered prior to enrollment in this study. * Female participants must not donate, or retrieve for their own use, ova from the time of Screening and throughout the study treatment period, and for at least 7 months after the final study drug administration. * Participants who are blood donors should not donate blood during the study and for 4 months following the last dose of study drug. * Patient or legally authorized representative (LAR) willing and able to sign informed consent document that has been approved by an IRB prior to initiation of any study-related tests or procedures that are not part of standard of care for the participant's disease. * Willing and able to comply with protocol visits and procedures. Exclusion Criteria: * Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site). * Previous enrollment in the present study. * Currently participating in another interventional clinical trial. * Clinically significant cardiopulmonary disease, such as: 1. History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE v5.0 ≥ Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication are permitted. 2. Congenital long QT syndrome. 3. Corrected QT interval (QTcF) prolongation to \>470 msec (females) or \>450 msec (males) based on average of the screening triplicate 12-lead ECG. 4. History of QT prolongation associated with other medications that required discontinuation of that medication. 5. History of symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV), left ventricular systolic dysfunction, or decrease in ejection fraction. 6. History of myocardial infarction, unstable angina, vascular stenting, angioplasty, or other cardiac surgery within 6 months prior to first dose of study treatment. 7. Uncontrolled or poorly controlled hypertension (\>180 mmHg systolic or \>130 mmHg diastolic) despite medical treatment. 8. History of non-infectious ILD/pneumonitis that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening. 9. Severe dyspnea at rest (CTCAE v5.0 ≥ Grade 3) due to complications of advanced malignancy or hypoxia requiring supplemental oxygen therapy. 10. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g. pulmonary emboli within three months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease \[COPD\], restrictive lung disease pleural effusion, etc.). 11. Any autoimmune, connective tissue, or inflammatory disorders (including Rheumatoid arthritis, Sjogren's, and sarcoidosis) where there is documented, or a suspicion of pulmonary involvement at the time of screening. Full details of the disorder should be recorded in the eCRF for participants who are included in the study. 12. Prior pneumonectomy (complete). * Any concomitant medications that are known to be associated with Torsades de Pointes or potent inducers of cytochrome P450 3A4 (CYP3A4). * Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals. * A pleural effusion, ascites, or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART). * History of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product(s). * History of severe hypersensitivity reactions to other monoclonal antibodies. * History of tick bite(s). * History of allergy to red meat. * Any toxicity related to prior anticancer therapies that has not resolved to ≤ Grade 1, with the following exceptions: 1. Alopecia and neuropathy, which must have resolved to ≤ Grade 2. 2. CHF, which must have been ≤ Grade1 in severity at the time of occurrence and must have * Clinically significant corneal disease in the opinion of the Investigator. * Spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Participants with clinically inactive brain metastases may be included in the study. Participants with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of definitive treatment (4 weeks if surgery) and study enrollment. * History of another malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (e.g. 5-year OS ≥90%), such as adequately treated carcinoma in-situ of the cervix, adequately resected non-melanoma skin cancer, localized prostate cancer, ductal carcinoma in-situ of the breast, or stage I uterine cancer). Cases should be reviewed by the study Principal Investigator. * Substance abuse or any other medical conditions that would increase the safety risk to the participant or interfere with participation of the participant or evaluation of the clinical study in the opinion of the Investigator. * Anticipated need for major surgical procedure during the course of the study. * Positive hepatitis B surface antigen or core antibody at screening. * Known to have active hepatitis C infection (positive by polymerase chain reaction or on antiviral therapy for hepatitis C within the last 6 months). Participants who have been treated for hepatitis C infection are eligible if they have documented sustained virologic response of 12 weeks. * Known to be positive for human immunodeficiency virus (HIV). Participants should be tested for HIV prior to enrollment if required by local regulations or IRB/Ethics Committee (EC). * Prior treatment with an ADC which consists of an exatecan derivative that is a topoisomerase I inhibitor. * Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of T-DXd. Note: Participants, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of Investigational Product. * Pregnant (confirmed with positive pregnancy test), breastfeeding, or planning a pregnancy. * Social, familial, or geographical factors that would interfere with study participation or follow-up Definitions A person of childbearing potential is: * Anyone born female who has experienced menarche and who has not undergone surgical sterilization (e.g. hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or has not completed menopause. Menopause is defined clinically as 12 months of amenorrhea in a person born female over age 45 in the absence of other biological, physiological, or pharmacological causes. * Anyone born male who has testes and who has not undergone surgical sterilization (e.g. vasectomy followed by a clinical test proving that the procedure was effective).