EGFR-ADC (Becotatug Vedotin) Combined With PD-1 Inhibitor (Pucotenlimab) in Neoadjuvant Treatment of Advanced Penile Cancer

Penile squamous cell carcinoma (PSCC) is a rare but aggressive malignancy with limited treatment options, particularly for locally advanced disease characterized by penile preservation difficulty or regional lymph node metastasis. Current standard neoadjuvant chemotherapy regimens (e.g., TIP: paclitaxel + ifosfamide + cisplatin) have modest efficacy (surgical resection rate ~60%) and substantial toxicity, leading to unmet clinical needs for more effective and tolerable therapies.

PSCC exhibits unique molecular features that support targeted and immunotherapeutic strategies: 91-100% of PSCC overexpress epidermal growth factor receptor (EGFR), and 50-60% express programmed death-ligand 1 (PD-L1) with significant immune cell infiltration. Antibody-drug conjugates (ADCs) targeting EGFR combine the specificity of monoclonal antibodies with potent cytotoxic payloads, minimizing off-target toxicity compared to conventional chemotherapy. Meanwhile, PD-1 inhibitors can reactivate antitumor immunity, and preclinical/clinical evidence suggests synergistic efficacy when combined with EGFR-targeted agents-likely via enhanced antigen presentation and T-cell infiltration into the tumor microenvironment.

This single-arm, phase II trial evaluates the neoadjuvant use of Becotatug vedotin (an EGFR-ADC consisting of a high-affinity anti-EGFR monoclonal antibody conjugated to monomethyl auristatin E [MMAE] via a valine-citrulline linker) combined with Pucotenlimab (a humanized anti-PD-1 monoclonal antibody) in patients with EGFR-expressing PSCC. The trial employs a Simon two-stage design to efficiently assess the primary endpoint of surgical resection rate, with secondary endpoints focused on efficacy (tumor response, pathological remission, survival) and safety.

Study Rationale Becotatug vedotin has demonstrated promising activity in EGFR-positive solid tumors (e.g., head and neck squamous cell carcinoma, nasopharyngeal carcinoma) in phase I/II trials, with a favorable safety profile (predominantly grade 1-2 skin toxicity and hematological effects). Pucotenlimab, a fully humanized IgG4 antibody, blocks PD-1-PD-L1/PD-L2 binding to activate T-cell function and has shown clinical benefit in multiple solid tumors. Preclinical data indicate that combining EGFR-ADCs with PD-1 inhibitors enhances tumor cell killing and reduces immune suppression, supporting their use in PSCC.

The neoadjuvant setting is chosen to maximize curative potential: successful downsizing of tumors may convert unresectable disease to resectable, improve penile preservation rates, and eliminate micro-metastatic disease. Postoperative adjuvant Pucotenlimab (for 1 year) is administered to consolidate antitumor immunity and reduce recurrence risk.

Study Design Overview Screening Period: ≤28 days, including histopathological confirmation of PSCC, EGFR expression assessment (IHC 1+/2+/3+), baseline imaging (CT/MRI of pelvis/abdomen, chest imaging), laboratory tests, and cardiac function evaluation (echocardiogram).

Neoadjuvant Treatment Period: 4-6 cycles of Becotatug vedotin (2.0 mg/kg IV) + Pucotenlimab (200 mg IV) every 3 weeks. Tumor response is assessed every 6 weeks per RECIST 1.1 via imaging.

Surgical Evaluation: Multidisciplinary team (MDT) review after 4-6 cycles to determine resectability. Patients with resectable disease undergo radical surgery (penile-sparing resection or partial/total penectomy + inguinal/pelvic lymph node dissection as indicated). Postoperative adjuvant Pucotenlimab is administered for 1 year in patients achieving R0 resection.

Follow-Up Period: Patients are monitored every 3 months for 2 years to assess disease recurrence, survival, and long-term safety.

Statistical Considerations The trial targets 55 evaluable patients (60 enrolled, accounting for 10% dropout) to detect an increase in surgical resection rate from 60% (historical control) to 80% (hypothesized experimental rate) with α=0.025 (one-sided) and 80% power. The Simon two-stage design allows early termination if ≤10 of the first 15 patients achieve resection (futility), or continuation to 55 patients if >10 achieve resection.

Safety Monitoring Adverse events (AEs) are graded per CTCAE v5.0 and monitored continuously. Special attention is paid to EGFR-ADC-related toxicities (skin reactions, hematological toxicity) and immune-related AEs (irAEs; e.g., pneumonitis, hepatitis, thyroid dysfunction). Severe AEs (SAEs) and suspected unexpected serious adverse reactions (SUSARs) are reported to the ethics committee and regulatory authorities per GCP requirements.

This trial addresses a critical gap in advanced PSCC treatment by evaluating a novel, mechanism-driven combination of targeted therapy and immunotherapy in the neoadjuvant setting. Success would provide a new standard of care for patients with unresectable or node-positive PSCC, improving surgical outcomes and survival while minimizing treatment-related morbidity.

• Inclusion Criteria （1）Histologically/cytologically confirmed penile squamous cell carcinoma (PSCC); （2）EGFR expression (IHC 1+, 2+, or 3+) confirmed by local pathology department; （3）No prior systemic therapy, or recurrence ≥6 months after adjuvant therapy for radical resection; （4）Male, aged ≥18 years; （5）Cytologically positive or clinically palpable inguinal lymphadenopathy, fixed mass, radiologically diagnosed pelvic lymph node metastasis, or penile preservation difficulty (unable to perform surgery with negative margin and functional penile stump preservation); （6）At least one measurable lesion per RECIST 1.1; （7）Adequate organ function:

• Left ventricular ejection fraction (LVEF) ≥50%;
• Hemoglobin (HGB) ≥90 g/L, white blood cell (WBC) ≥3.0×10⁹/L, absolute neutrophil count (ANC) ≥1.5×10⁹/L, platelet (PLT) ≥80×10⁹/L;
• Total bilirubin (TBIL) ≤1.5×ULN, AST/ALT ≤2.5×ULN (≤5×ULN for liver metastasis), serum creatinine (Cr) ≤1.5×ULN or creatinine clearance (CrCl) ≥50 mL/min; （8）Voluntarily participate, understand the study, and sign informed consent form.
• Exclusion Criteria （1）Prior systemic therapy (except recurrence ≥6 months after adjuvant chemotherapy for radical resection); （2）Severe concurrent diseases or poor physical condition unsuitable for treatment/surgery (e.g., severely ulcerated/infected inguinal lymph nodes with high risk of poor wound healing); （3）Uncontrolled comorbidities: uncontrolled infection, active tuberculosis, uncontrolled diabetes, cardiovascular diseases (NYHA class III/IV heart failure, ≥grade 2 heart block, myocardial infarction within 12 months, unstable arrhythmia/angina, cerebral infarction within 6 months), interstitial lung disease, deep vein thrombosis/pulmonary embolism within 12 months, decompensated cirrhosis; （4）Active autoimmune diseases requiring systemic treatment within 2 years (except physiological replacement therapy); （5）Positive serological tests: HIV positive; HBsAg positive with HBV DNA ≥2000 copies/mL; HCV antibody positive with positive HCV RNA; （6）Major surgery within 4 weeks prior to enrollment, prior allogeneic hematopoietic stem cell transplantation or solid organ transplantation; （7）Vaccination with anti-tumor vaccine within 4 weeks prior to enrollment or planned during the study; （8）Other conditions deemed unsuitable by the investigator.