Neoadjuvant Pucotenlimab and Becotatug Vedotin for Locally Advanced Penile Cancer

Background:

Penile squamous cell carcinoma is a rare genitourinary malignancy with poor outcomes once regional lymph node spread occurs. Up to 45% of patients present with nodal metastasis at initial diagnosis. Patients with pelvic lymph node involvement (N3) have a 0-17% 5-year survival rate, and 86% of locally advanced patients experience recurrence within 2 years after standard surgery alone. The guidelines recommended neoadjuvant chemotherapy regimen (paclitaxel, ifosfamide, cisplatin, TIP) yields only a 10% pathological complete response rate, with limited long-term disease control and short survival after disease progression.

Over 90% of penile squamous cell carcinomas overexpress EGFR, and 40%-60% of patients show PD-L1 positivity, supporting dual targeting of EGFR and PD-1 as a promising therapeutic strategy. Preclinical and early clinical data confirm synergistic anti-tumor activity between EGFR ADCs and PD-1 inhibitors: the ADC payload promotes dendritic cell maturation and antigen presentation, while PD-1 blockade restores anti-tumor T cell function. Previous prospective trials demonstrate that this combination produces meaningful tumor regression and survival outcomes in other squamous cell carcinomas, with manageable toxicities.

This trial adopts a Simon two-stage single-arm design to efficiently test the study regimen's anti-tumor activity without a separate control group. If the first 10 enrolled patients show minimal pathological response, the trial will stop early for futility; otherwise, enrollment will continue to a total of 29 subjects to generate robust efficacy and safety data for this chemotherapy-free neoadjuvant platform.

Safety Oversight:

All adverse events are monitored from enrollment through 28 days after the last study drug dose, graded per CTCAE v5.0. All serious adverse events (SAEs) must be reported to the institutional review board and study sponsor within 24 hours. Standard supportive care, including growth factors for cytopenias, antihistamines and corticosteroids for infusion reactions, and symptom-directed management for immune-related toxicities and peripheral neuropathy, is permitted throughout treatment. Dose modification rules are pre-specified: pucotenlimab cannot be dose-reduced and may only be held or permanently discontinued, while becotatug vedotin allows one dose level reduction for persistent tolerability issues before permanent discontinuation.

A clinical trial liability insurance policy covers study participants for injuries causally related to investigational treatment, in accordance with Chinese clinical research regulations. A dedicated ethics committee hotline is available for participants to raise concerns regarding study participation, rights, or adverse events.

Biospecimen Research:

Collected blood and tumor tissue specimens are anonymized with unique study identifiers to protect participant privacy. No identifiable personal health information will be included in sequencing or laboratory testing. Biomarker analyses include HPV subtyping, PD-L1/EGFR immunohistochemistry, immune cell subset profiling, and multi-omic sequencing (single-cell transcriptomics, spatial transcriptomics, whole-exome and bulk RNA sequencing). Patient-derived xenograft (PDX) models will be established from residual tumor tissue to explore molecular mechanisms of treatment resistance. All biospecimens will be destroyed upon completion of planned exploratory analyses, with no long-term indefinite storage. Biomarker sub-study results will only be published in aggregate, without individual participant data disclosure.

Follow-Up:

After completing neoadjuvant and adjuvant therapy, participants enter a multi-year surveillance phase. Imaging assessments occur every 3-6 months for the first two years post-treatment completion, then annually from year three through year five. Remote telephone follow-up is allowed between scheduled hospital visits to track disease status, subsequent anti-cancer therapies, and overall survival. All participants who discontinue study treatment early-whether due to withdrawal, disease progression, or toxicity-remain in long-term survival follow-up to avoid missing survival endpoint data.

Inclusion criteria

• Aged 18-75 years, biologically male.
• Histologically confirmed penile squamous cell carcinoma, stage T4 any N M0 or any T N2-N3 M0 without distant metastasis.
• Treatment-naive; or relapsed patients with ≥12 months interval from last prior systemic therapy.
• At least one measurable target lesion per RECIST 1.1.
• ECOG performance status 0-2.
• Adequate bone marrow, liver and renal function as predefined lab thresholds.
• Expected survival ≥12 months.
• No severe uncontrolled organ dysfunction.
• Able to understand and voluntarily sign written informed consent.

Exclusion criteria

• Pre-existing grade ≥2 peripheral neuropathy interfering daily activities.
• Prior neoadjuvant therapy for penile cancer; previous use of PD-1/PD-L1 inhibitors or EGFR ADCs including becotatug vedotin.
• Known hypersensitivity to pucotenlimab, becotatug vedotin or excipients.
• Active malignancy within 5 years (excluding cured basal cell skin carcinoma and low-risk prostate cancer).
• Uncontrolled severe cardiovascular disease, active hepatitis B/C, active infection requiring antibiotics within 2 weeks before enrollment.
• Live vaccine administered within 30 days before first dosing.
• HIV infection, autoimmune disease requiring systemic therapy within 2 years, long-term systemic immunosuppressants.
• Other conditions judged by investigators to interfere with study treatment or assessment.