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

Official title

Neoadjuvant Therapy With EGFR-ADC (Becotatug Vedotin) Combined With PD-1 Inhibitor (Pucotenlimab) for Penile Squamous Cell Carcinoma With Penile Preservation Difficulty or Regional Lymph Node Metastasis: A Single-Arm, Phase II Clinical Trial

Overview

This clinical study is a Phase II research trial focused on a new preoperative treatment for men with advanced penile squamous cell carcinoma (a type of penile cancer). The cancer may be hard to treat with penile-sparing surgery, or it may have spread to nearby lymph nodes (like groin lymph nodes). We are testing a combination of two medicines: Becotatug vedotin (a targeted therapy that finds and kills cancer cells with high levels of a protein called EGFR) and Pucotenlimab (an immunotherapy that helps your body's immune system fight cancer). The goal is to see if this combination can shrink the tumor, make surgery more likely to remove all cancer cells, and improve treatment outcomes-while keeping side effects manageable. Who can join? To be eligible, you must: Be a man 18 years or older with confirmed penile squamous cell carcinoma; Have cancer that is hard to treat with penile-sparing surgery or has spread to regional lymph nodes; Have cancer cells that test positive for EGFR (a protein most penile cancers make); Have not received prior systemic cancer treatment (or had recurrence more than 6 months after adjuvant therapy for radical resection); Have adequate organ function (e.g., healthy heart, liver, and kidney function) to tolerate treatment; Understand the study and voluntarily agree to participate by signing an informed consent form. What will happen during the study? Screening (up to 28 days): You will have tests to confirm eligibility, including imaging scans, blood work, and EGFR testing on your tumor sample. Preoperative treatment (4-6 cycles): You will receive intravenous infusions of Becotatug vedotin (2.0 mg/kg) and Pucotenlimab (200 mg) every 3 weeks. Every 6 weeks, you will have imaging scans to check if the tumor is shrinking. Surgery: If the tumor responds to treatment (assessed by a team of doctors), you will undergo radical surgery to remove the cancer. If surgery is successful, you may continue Pucotenlimab as adjuvant therapy for 1 year. Follow-up: After treatment, you will be checked every 3 months for 2 years to monitor for cancer recurrence and long-term side effects. What are the study goals? Primary goal: To find out how many patients can have successful surgery to remove all visible cancer (R0 resection) after the combination treatment. Secondary goals: To measure how much the tumor shrinks (objective response rate), if the cancer stage improves (downstaging rate), if surgery removes all cancer cells (pathological complete response rate), how long patients stay cancer-free (disease-free survival), and how safe the treatment is. What are the potential risks? As with any cancer treatment, this combination may cause side effects. Common expected side effects include skin reactions (e.g., rash), digestive issues, changes in blood cell counts, liver function changes, and immune-related reactions (e.g., thyroid problems, lung inflammation). These side effects will be closely monitored by the study team, and treatments to manage them will be provided. This study is being conducted at West China Hospital, Sichuan University. It is a single-arm trial (all participants receive the same combination treatment) and will enroll about 60 patients. The study is expected to run from April 2026 to April 2028.

Detailed description

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.

Interventions

• Drug Becotatug Vedotin
  Becotatug vedotin is an EGFR-targeted antibody-drug conjugate (ADC) composed of a high-affinity anti-EGFR monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a cleavable valine-citrulline linker. In this phase II neoadjuvant trial, it is administered intravenously at a dose of 2.0 mg/kg once every 3 weeks for 4-6 cycles, in combination with Pucotenlimab, for patients with EGFR-expressing locally advanced penile squamous cell carcinoma.
• Drug Pucotenlimab
  Pucotenlimab is a humanized, high-affinity anti-PD-1 monoclonal antibody that blocks PD-1/PD-L1/PD-L2 binding to reactivate antitumor immunity. In this trial, it is administered intravenously at 200 mg once every 3 weeks: 4-6 cycles as neoadjuvant therapy with Becotatug vedotin, followed by 1 year of adjuvant therapy for patients achieving R0 resection, for EGFR-expressing locally advanced penile squamous cell carcinoma.

Primary outcome measures

• Surgical Resection Rate [Time frame: Up to 6 months after the start of neoadjuvant therapy (after completion of 4-6 cycles of treatment and MDT evaluation).]

Secondary outcome measures (8)

• Objective Response Rate (ORR) [Time frame: Every 6 weeks during neoadjuvant therapy, up to 6 months.]
• Downstaging Rate [Time frame: After completion of neoadjuvant therapy (up to 6 months).]
• Pathological Complete Response (pCR) Rate [Time frame: Within 1 month after surgery.]
• Major Pathological Response (MPR) Rate [Time frame: Within 1 month after surgery.]
• Tumor Regression Grade (TRG) [Time frame: Within 1 month after surgery.]
• Event-Free Survival (EFS) [Time frame: From first dose to 2 years after study completion, assessed every 3 months.]
• Disease-Free Survival (DFS) [Time frame: From surgery to 2 years after study completion, assessed every 3 months.]
• Safety Profile [Time frame: From signing informed consent to 28 days after last dose.]

Eligibility criteria

• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• West China Hospital of Sichuan University — Chengdu

Identifiers

NCT: NCT07518979 · MH-Penile-002

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗