• Participants must have histologically confirmed CRC or HCC that is metastatic or unresectable and have progressive disease or intolerance after standard front-line therapies as defined below:

∙ Participants with CRC (cohort 1): Participants must have had progressive disease or intolerance after at least 2 but no more than 3 prior lines of systemic therapy in advanced or metastatic setting. Prior lines of therapy should include fluoropyrimidine (5-fluorouracil or capecitabine), oxaliplatin, and irinotecan with or without anti EGFR antibody for RAS/RAF wild-type CRC or bevacizumab unless contraindicated. For patients with microsatellite instability high (MSI-H) CRC, previous lines of therapy should include a PD-1/PD-L1 immune checkpoint inhibitor in additional to the chemotherapy agents mentioned above. Adjuvant chemotherapy with radiographic progression greater than 12 months after the last dose is not considered as a line of therapy.

∙ Participants with HCC (cohort 2): Participants must have had progressive disease or intolerance after at least 1 but no more than 2 prior lines of systemic therapy in advanced or metastatic setting. Prior lines of therapy should include a PD-1/PD-L1 immune checkpoint inhibitor or a multikinase inhibitor, which was administered either alone or in combination.

• Participants must have measurable disease according to RECIST v1.1. Lesions in a prior radiation field must have progressed subsequent to radiotherapy to be considered measurable.

• Participants must have had progression or recurrence of CRC or HCC during or following receipt of most recent therapy.

• Legally an adult according to local regulation at the time of signing informed consent, and minimum age of 18 years

• ECOG performance status ≤1

• Participants must have adequate organ and marrow function as defined below:

‣ Absolute neutrophil count (ANC) ≥ 1500/mm3

⁃ Platelet count ≥100 × 109/L

⁃ Hemoglobin ≥9 g/dL

⁃ Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for subjects with Gilbert's disease

⁃ Creatinine clearance (CrCl) ≥30 mL/min as estimated per institutional standards

⁃ Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN or ≤ 5 x ULN for subjects with liver metastases

⁃ Liver function status should be Child-Pugh (CP) Class A.

• Tumor tissue samples must be available for submission prior to study treatment.

• Participants must have an anticipated life expectancy of ≥3 months as assessed by the investigator.

• The effects of enfortumab vedotin on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 4 months after the last dose. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

• Ability to understand and the willingness to sign a written informed consent document.