Becotatug Vedotin Plus Pucotenlimab for Metastatic Colorectal Cancer

• Becotatug Vedotin (MRG003) (Drug): Becotatug vedotin is an EGFR-targeted antibody-drug conjugate. It will be administered at 2.0 mg/kg by intravenous infusion on Day 1 of each 21-day cycle, after the pucotenlimab infusion. Treatment will continue for up to 2 years or until a protocol-defined discontinuation criterion is met.
• Pucotenlimab (Drug): Pucotenlimab is a humanized monoclonal antibody targeting PD-1. It will be administered at a fixed dose of 200 mg by intravenous infusion on Day 1 of each 21-day cycle, before the becotatug vedotin infusion. Treatment will continue for up to 2 years or until a protocol-defined discontinuation criterion is met.

Primary outcomes

• Objective Response Rate (ORR) [From the first dose of study treatment through the end of tumor response assessment, up to 24 months.]: Percentage of participants whose best overall response is complete response (CR) or partial response (PR), assessed according to Response Evaluation Criteria in Solid Tumors (RECIST)

Secondary outcomes

• Disease Control Rate (DCR) [From the first dose of study treatment through the end of tumor response assessment, up to 24 months.]: Percentage of participants whose best overall response is confirmed complete response (CR), confirmed partial response (PR), or stable disease (SD), assessed according to RECIST version 1.1.
• Duration of Response (DOR) [From the first dose of study treatment through the end of tumor response assessment, up to 24 months.]: Time from the first documentation of complete response (CR) or partial response (PR) to disease progression according to RECIST version 1.1 or death from any cause, whichever occurs first. DOR will be assessed in participants with a confirmed objective response. Participants without progression or death will be censored at their last tumor assessment.
• Progression-Free Survival (PFS) [From the first dose of study treatment to disease progression or death, assessed up to 24 months.]: Time from the first dose of study treatment to disease progression according to RECIST version 1.1 or death from any cause, whichever occurs first. Participants without progression or death will be censored at their last tumor assessment.
• Overall Survival (OS) [From the first dose of study treatment to death from any cause, assessed up to 24 months.]: Time from the first dose of study treatment to death from any cause. Participants without a reported death at the time of analysis will be censored at the date they were last known to be alive.
• Incidence and Severity of Treatment-Emergent Adverse Events (TEAEs) [From the first dose of study treatment through 30 days after the last dose.]: Percentage of participants experiencing treatment-emergent adverse events. Events will be summarized by type and severity, with severity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0.
• Incidence and Severity of Treatment-Related Adverse Events (TRAEs) [From the first dose of study treatment through 30 days after the last dose.]: Percentage of participants experiencing adverse events considered related to either study drug by the investigator. Events will be graded according to NCI-CTCAE version 5.0. The percentage of participants experiencing Grade 3 or higher treatment-related adverse events will also be reported.
• Incidence of Serious Adverse Events (SAEs) [From the first dose of study treatment through 30 days after the last dose, with subsequent collection of study-treatment-related SAEs as specified in the protocol.]: Percentage of participants experiencing serious adverse events. Events will be summarized by type, severity, and relationship to study treatment. Seriousness and severity will be assessed separately, with severity graded according to NCI-CTCAE version 5.0.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* (1) Age ≥18 years at the time of signing informed consent, regardless of sex;(2) Able and willing to provide written informed consent, understand the study requirements, and comply with all study procedures and follow-up visits;(3) Histologically or cytologically confirmed recurrent or metastatic colorectal cancer, with EGFR-positive tumor expression confirmed by immunohistochemistry;(4) Previously received at least two lines of standard systemic therapy for recurrent or metastatic colorectal cancer;(5) At least one measurable lesion according to RECIST version 1.1, with a longest diameter ≥10 mm;(6) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, assessed within 7 days before the first dose;(7) Estimated life expectancy ≥12 weeks;(8) Adequate hematologic and organ function, without blood transfusion or use of cell growth factors within 14 days before the first dose: absolute neutrophil count ≥1.5 × 10\^9/L; platelet count ≥75 × 10\^9/L; hemoglobin ≥85 g/L; serum creatinine ≤1.5 times the upper limit of normal (ULN); AST and ALT ≤2.5 times ULN, or ≤5 times ULN in participants with liver metastases; total bilirubin ≤1.5 times ULN; and INR and activated partial thromboplastin time ≤1.5 times ULN, except in participants receiving anticoagulant therapy;(9) Women of childbearing potential must have a negative serum pregnancy test within 7 days before treatment. Women of childbearing potential and men with partners of childbearing potential must agree to use highly effective contraception from signing informed consent until 1 year after the last dose.

Exclusion Criteria:

* (1) Grade ≥2 peripheral neuropathy according to NCI-CTCAE version 5.0;(2) Anticipated need for surgery or other systemic or local anticancer treatment during the study;(3) Previous treatment with an antibody-drug conjugate containing a monomethyl auristatin E (MMAE) payload;(4) Receipt of an investigational drug from another clinical trial within 28 days before the first dose;(5) Radiotherapy within 28 days before the first dose, or palliative radiotherapy for bone metastases within 2 weeks before the first dose;(6) Anticancer drug treatment within 3 weeks before the first dose. The required washout period is ≥14 days for oral fluoropyrimidines, folinic acid agents, and weekly dose-dense paclitaxel, and ≥42 days for nitrosoureas or mitomycin;(7) Active central nervous system metastases or carcinomatous meningitis. Participants with previously treated brain metastases may be eligible only if their condition is stable and they meet the protocol-specified neurologic, imaging, and corticosteroid requirements;(8) History of another malignancy, unless potentially curative treatment has been received and there has been no recurrence for 5 years. Exceptions include definitively treated basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix;(9) Uncontrolled pleural effusion, pericardial effusion, or recurrent ascites requiring drainage ≥1 time per month;(10) Tumor involvement of major arteries associated with a high risk of bleeding, a substantial risk of perforation, or an existing fistula;(11) Residual toxicity or clinically significant laboratory abnormalities from prior anticancer therapy exceeding Grade 1 according to NCI-CTCAE version 5.0, except alopecia, fatigue, and Grade 2 hypothyroidism;(12) Severe cardiac dysfunction, stroke, or transient ischemic attack within 6 months before enrollment; a history of ventricular tachycardia or torsades de pointes; or clinically significant abnormalities of cardiac rhythm, conduction, or morphology, including QTc >450 ms in men or >470 ms in women, complete left bundle branch block, or third-degree atrioventricular block;(13) Clinically significant cardiac disease, including acute myocardial infarction, New York Heart Association Class III or IV congestive heart failure, unstable angina, or an arrhythmia requiring treatment within 6 months before the first dose. Participants receiving antiarrhythmic treatment may be eligible if the screening ECG demonstrates a controlled rhythm and heart rate;(14) Pulmonary embolism or deep vein thrombosis within 3 months before the first dose;(15) Uncontrolled or poorly controlled hypertension, such as systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg, or uncontrolled or poorly controlled hyperglycemia;(16) Active acute or chronic inflammatory skin disease, or a history of Stevens-Johnson syndrome or toxic epidermal necrolysis;(17) Known allergy to any component or excipient of becotatug vedotin, or a history of Grade ≥3 allergic reactions to another anti-EGFR agent or monoclonal antibody;(18) Active hepatitis B, defined as HBsAg positivity with HBV DNA ≥500 IU/mL, or active hepatitis C, defined as hepatitis C antibody positivity with HCV RNA above the assay's lower detection limit;(19) Other serious liver disease, including chronic autoimmune liver disease, primary biliary cirrhosis, sclerosing cholangitis, alcoholic liver disease, or nonalcoholic steatohepatitis;(20) Severe uncontrolled infection, known HIV infection or AIDS, uncontrolled autoimmune disease, or a history of allogeneic tissue or organ transplantation, stem cell or bone marrow transplantation, or solid organ transplantation;(21) Active bacterial, viral, fungal, rickettsial, or parasitic infection requiring intravenous anti-infective treatment, unless treated and resolved before the first dose;(22) Moderate to severe dyspnea at rest due to advanced cancer or its complications; severe primary pulmonary disease requiring continuous oxygen with oxygen saturation <93% without supplemental oxygen; or a history of interstitial lung disease or noninfectious pneumonitis;(23) Immunologically based treatment, including chronic systemic corticosteroids exceeding 10 mg/day prednisone equivalent within 7 days before the first dose or during the study. The protocol permits inhaled or topical steroids or systemic corticosteroids at ≤10 mg/day prednisone equivalent, and short-term corticosteroid use above this dose, such as premedication for contrast administration;(24) Chronic autoimmune or inflammatory disease requiring systemic treatment within the past 2 years or currently receiving systemic treatment, including inflammatory bowel disease, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, granulomatosis with polyangiitis, Sjögren syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Exceptions include vitiligo, hypothyroidism treated with stable hormone replacement, controlled asthma, type 1 diabetes, Graves disease, or Hashimoto disease;(25) Positive pregnancy test or breastfeeding;(26) Unwillingness or inability to use adequate contraception during treatment and for 180 days after the last dose;(27) Any other disease, clinically significant laboratory abnormality, serious medical or psychiatric condition, or substance abuse, including alcohol abuse, that the investigator considers likely to compromise participant safety, study integrity, participation, or interpretation of the results.