MRG003 Plus HX008 as First-Line Treatment for EGFR-Positive Locally Advanced or Metastatic Penile Squamous Cell Carcinoma

Summary

Penile squamous cell carcinoma (PSCC) is a rare malignancy, with stage IV patients exhibiting a 2-year overall survival (OS) rate of 21% and a 5-year survival rate of 0%. Both the National Comprehensive Cancer Network (NCCN) and European Association of Urology (EAU) guidelines recommend chemotherapy as the first-line treatment. However, the efficacy of chemotherapeutic agents in PSCC remains suboptimal, and options after chemotherapy failure are extremely limited. In recent years, targeted therapy and immunotherapy have demonstrated potential in treating this disease. Combination therapies based on chemotherapy, particularly chemoimmunotherapy combined with targeted therapy, have shown promising antitumor effects. Nevertheless, these regimens are associated with significant adverse effects and impose high physical demands on patients. Therefore, this study aims to explore a "highly effective and low-toxicity" first-line treatment regimen for advanced PSCC patients. The objective is to evaluate the combined therapeutic efficacy of an epidermal growth factor receptor (EGFR)-targeted antibody-drug conjugate (MRG003) and an immune checkpoint inhibitor (HX008) through a single-arm, phase I, prospective clinical trial.

Eligibility

Inclusion Criteria:

1. Histologically and/or cytologically confirmed unresectable, locally advanced, or metastatic penile squamous cell carcinoma.
2. EGFR expression (defined as IHC 1+, 2+, or 3+) confirmed by the institutional pathology department using primary or metastatic tumor tissue samples.
3. No prior systemic therapy for advanced disease.
4. Male, aged ≥18 years.
5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with a life expectancy ≥3 months.
6. At least one measurable lesion per RECIST 1.1 criteria.
7. Adequate organ function (based on institutional laboratory reference ranges):

   Left ventricular ejection fraction (LVEF) ≥50%.

   Hematology:

   Hemoglobin (HGB) ≥90 g/L, White blood cell count (WBC) ≥3.0×10⁹/L, Absolute neutrophil count (ANC) ≥1.5×10⁹/L, Platelet count (PLT) ≥80×10⁹/L.

   Biochemistry:

   Total bilirubin (TBIL) ≤1.5× upper limit of normal (ULN), AST/ALT ≤2.5×ULN (≤5×ULN if liver metastases present), Serum creatinine (Cr) ≤1.5×ULN or creatinine clearance (CrCl) ≥50 mL/min.
8. Willing to provide written informed consent, with full understanding of the study requirements and commitment to comply with trial procedures and follow-up visits.

Exclusion Criteria:

1. Patients who have received prior systemic therapy before enrollment.
2. History of other malignancies, except for cured carcinoma in situ of the cervix, basal cell carcinoma of the skin, or other malignancies that have been disease-free for at least 5 years.
3. Presence of central nervous system metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may be eligible if they have been stable for at least 6 months, show no disease progression on imaging within 4 weeks before treatment, have no neurological symptoms, demonstrate no evidence of new or enlarging brain metastases, and have discontinued radiation, surgery, or steroid therapy for brain metastases at least 28 days prior to the first dose. Carcinomatous meningitis is excluded regardless of clinical stability.
4. Severe or uncontrolled concurrent diseases, including uncontrolled infections, active tuberculosis, uncontrolled diabetes, cardiovascular diseases (such as NYHA Class III or IV heart failure, second-degree or higher heart block, myocardial infarction within the past 12 months, unstable arrhythmia or angina, or cerebral infarction within the past 6 months), pulmonary diseases (such as interstitial lung disease, chronic obstructive pulmonary disease, or a history of symptomatic bronchospasm), deep vein thrombosis or pulmonary embolism within the past 12 months, or decompensated cirrhosis.
5. Active autoimmune disease requiring systemic treatment (e.g., disease-modifying drugs, corticosteroids, or immunosuppressants) within the past 2 years. Replacement therapies (e.g., thyroxine, insulin, or physiologic corticosteroid replacement for adrenal or pituitary insufficiency) are permitted.
6. Positive serological virology test results, including HIV positivity, HBsAg positivity with detectable HBV DNA (≥2000 copies/mL), or HCV antibody positivity (eligible only if HCV RNA PCR-negative).
7. Major surgery within 4 weeks before enrollment, or prior allogeneic hematopoietic stem cell transplantation or solid organ transplantation.
8. Administration of or plans to receive anti-cancer vaccines within 4 weeks before enrollment or during the study.
9. Clinically significant pleural effusion or ascites, as determined by the investigator to be unsuitable for enrollment.
10. Any other condition considered by the investigator to make the patient ineligible for the clinical study.

Conditions2

Interventions2

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