Neoadjuvant Pucotenlimab and Becotatug Vedotin for Locally Advanced Penile Cancer

Overview

This is an open-label, multicenter, single-arm Phase 2 clinical trial evaluating neoadjuvant pucotenlimab (anti-PD-1 immunotherapy) combined with becotatug vedotin (EGFR-targeted antibody-drug conjugate, ADC) for adults with locally advanced penile squamous cell carcinoma. Eligible patients have high-risk disease defined as T4 primary tumor with any nodal status or any T stage with N2-N3 lymph node metastasis and no distant metastasis. All participants receive up to 4 cycles of combination neoadjuvant therapy every 3 weeks. After treatment completion, a multidisciplinary team will assess if consolidative surgery can be performed. Patients who undergo surgery will continue single-agent pucotenlimab adjuvant treatment for 17 additional cycles (approximately 1 year). The primary goal is to measure the pathological complete response (pCR) rate. Secondary goals include objective response rate (ORR), progression-free survival (PFS),overall survival (OS) and safty profiles. Blood and tumor tissue samples will be collected to explore biomarkers that may predict treatment response and drug resistance. A total of 29 male patients will be enrolled.

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.