Penile cancer is a rare malignant tumor of the male genitourinary system, with 95% being squamous cell carcinoma. Due to social factors, delayed diagnosis is common, leading to a high rate of lymph node metastasis (17%-45% at diagnosis), which significantly impairs quality of life and prognosis. The 5-year survival rate is 27% for patients with lymph node metastasis and 0%-17% for those with pelvic lymph node metastasis (N3).

Current standard treatments recommended by guidelines include surgery and chemotherapy. However, the neoadjuvant TIP regimen (paclitaxel + ifosfamide + cisplatin) in locally advanced disease yields an objective response rate (ORR) of 50%, pathological complete response (pCR) rate of 10%, median progression-free survival (PFS) of 8.1 months, and median overall survival (OS) of 17.1 months. For advanced patients, no standard effective treatments exist after platinum-based chemotherapy resistance, highlighting an urgent need for more effective combination therapies.

High expression of PD-L1 (30%-70%) and EGFR (40%-80%) is common in penile squamous cell carcinoma, especially in poorly differentiated, late-stage disease with lymph node metastasis. A prospective phase II study showed that toripalimab (immunotherapy) combined with nimotuzumab (anti-EGFR antibody) and paclitaxel-based chemotherapy, followed by consolidation surgery, achieved an ORR of 82.8%, pCR rate of 48.3%, 2-year OS rate of 72.4%, and 2-year PFS rate of 65.5%; 41.4% of patients had grade 3-4 treatment-related adverse events, with no treatment-related deaths.

Although immune checkpoint inhibitors and anti-EGFR targeted therapy demonstrate preliminary antitumor activity in advanced penile cancer, their clinical efficacy remains suboptimal with substantial toxicities, thus warranting the development of more effective combinatorial therapeutic strategies.

This trial will evaluate the efficacy and safety of Becotatug Vedotin (recombinant humanized anti-EGFR mAb-MMAE conjugate) combined with Pucotenlimab (recombinant humanized anti-PD-1 mAb) as first-line therapy in the treatment of EGFR-Positive advanced penile cancer in patients who are intolerant to chemotherapy or have failed chemotherapy. Becotatug Vedotin (2.3 mg/kg, IV, Q3W) and Pucotenlimab (200 mg, IV, Q3W) will be administrated on enrolled patients. Treatment continues until disease progression, intolerable toxicity, withdrawal, death, or sponsor termination. After treatment completion, all patients will undergo survival follow-up every 3 months until death, loss to follow-up, consent withdrawal, or study termination by the sponsor.

Inclusion Criteria:

1. Age ≥ 18 years.
2. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0-1.
3. Histologically confirmed penile squamous cell carcinoma with evidence of metastasis, and EGFR expression confirmed positive by immunohistochemistry (IHC).
4. At least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST): non-lymph node lesions with a longest diameter ≥ 10 mm on computed tomography (CT) scan, or lymph node lesions with a short axis diameter ≥ 15 mm on CT scan; or evaluable cutaneous lesions per World Health Organization (WHO) criteria.
5. Have received at least one prior line of chemotherapy, or be deemed chemotherapy-intolerant by the investigator.
6. Adequate organ and bone marrow function, as defined by the following laboratory criteria within the screening period:

1)Hemoglobin > 8.5 g/dL, without blood transfusion or erythropoietin administration within the preceding 14 days; 2)Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L, without granulocyte colony-stimulating factor administration within the preceding 14 days; 3)Platelet count (PLT) ≥ 90 × 10⁹/L, without blood transfusion within the preceding 14 days; 4)Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN) (for patients with Gilbert's syndrome, ≤ 3 × ULN is permitted); 5)Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (if liver metastasis is present, ALT and AST ≤ 5 × ULN is permitted); 6)Serum creatinine (Cr) ≤ 1.5 × ULN, or creatinine clearance ≥ 50 mL/min (calculated by the Cockcroft-Gault formula); 7)Adequate coagulation function, defined as international normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN; 8)Normal thyroid function, defined as thyroid-stimulating hormone (TSH) within the normal range; subjects with an abnormal baseline TSH but normal total T3 (or FT3) and FT4 levels are also eligible.

7.Expected survival of more than 3 months.

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Exclusion Criteria:

1. Diagnosis of another malignancy within 5 years prior to the first dose (excluding radically treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and/or radically resected carcinoma in situ).

2. Prior treatment with an ADC drug containing monomethyl auristatin E (MMAE) as the cytotoxic moiety, or prior treatment with a PD-(L)1 inhibitor.

3. Currently participating in an interventional clinical study, or having received other investigational agents or investigational device therapy within 4 weeks prior to the first dose.

4. History of active autoimmune disease requiring systemic therapy (e.g., disease-modifying agents, corticosteroids, or immunosuppressants) within 2 years prior to the first dose. Replacement therapies (e.g., thyroid hormone, insulin, or physiological glucocorticoids for adrenal or pituitary insufficiency) are not considered systemic therapy.

5. Major surgical procedure (excluding biopsy-only procedures) within 4 weeks prior to the first dose of study drug, or anticipated major surgery during the study period.

6. Hereditary bleeding tendency, coagulation disorder, or history of thrombosis.

7. History of allogeneic organ transplantation (except corneal transplantation) or allogeneic hematopoietic stem cell transplantation.

8. Known hypersensitivity to the active ingredients or excipients of the study drugs vibecotamab and putelimab.

9. Inadequate recovery from toxicity and/or complications caused by any prior intervention (i.e., ≤ Grade 1 or baseline levels, excluding fatigue or alopecia) before starting treatment.

10. Known history of human immunodeficiency virus (HIV) infection (i.e., positive HIV 1/2 antibody).

11. Untreated active hepatitis B (defined as positive HBsAg plus HBV-DNA copy number above the upper limit of normal of the local laboratory).

    *Note: Subjects with hepatitis B meeting the following criteria are eligible: HBV viral load < 1000 copies/mL (200 IU/mL) before the first dose; subjects must receive anti-HBV therapy throughout the study treatment period to prevent viral reactivation.

    For subjects who are anti-HBc(+), HBsAg(-), anti-HBs(-), and HBV viral load(-), prophylactic anti-HBV therapy is not required, but close monitoring for viral reactivation is necessary.

    Subjects with active HCV infection (positive HCV antibody and HCV-RNA level above the lower limit of detection).*

12. Administration of a live vaccine within 30 days prior to the first dose (Cycle 1, Day 1).

    Note: Administration of inactivated seasonal influenza vaccine via injection within 30 days prior to the first dose is permitted; however, intranasal live attenuated influenza vaccine is not allowed.

13. Presence of any severe or uncontrolled systemic disease, such as:

1)Clinically significant and symptomatic uncontrolled abnormalities in cardiac rhythm, conduction, or morphology on resting electrocardiogram (ECG), e.g., complete left bundle branch block, second-degree or higher atrioventricular block, ventricular arrhythmia, or atrial fibrillation; 2)Unstable angina pectoris, congestive heart failure, chronic heart failure of New York Heart Association (NYHA) class ≥ 2; 3)Uncontrolled hypertension (systolic blood pressure > 160 mmHg, diastolic blood pressure > 100 mmHg); 4)Active pulmonary tuberculosis; 6)Active or uncontrolled infection requiring systemic therapy; 7)Clinically active diverticulitis, abdominal abscess, or gastrointestinal obstruction; 8)Liver disease such as cirrhosis, decompensated liver disease, acute or chronic active hepatitis; 9)Uncontrolled diabetes mellitus (fasting blood glucose (FBG) > 10 mmol/L); 10)Urine routine test showing urine protein ≥ ++, confirmed 24-hour urinary protein quantification > 1.0 g; 14.Psychiatric disorders that prevent compliance with study treatment; Any other medical history, evidence of disease, treatment, or abnormal laboratory value that could interfere with study results, prevent the subject from completing the study, or for which the investigator considers the subject to be otherwise ineligible or at potential risk for participation.