Penile cancer is a rare malignancy, and treatment options for advanced stages are limited, often yielding unsatisfactory outcomes. This prospective, multicenter, phase 1 clinical study was conducted to evaluate the preliminary safety, tolerability, and antitumor activity of the anti-epidermal growth factor receptor (EGFR) monoclonal antibody CDP1 in combination with chemotherapy, in patients with penile cancer. The trial comprised two parts: a 3 + 3 dose-escalation CDP1 monotherapy study to determine the dose for the combination study, in which 12 patients with advanced solid tumors received CDP1 alone, and a CDP1-chemotherapy combination study, in which 20 patients with recurrent or metastatic penile cancer received CDP1 combined with the paclitaxel-ifosfamide-cisplatin regimen (TIP). CDP1 monotherapy and combination treatment were well tolerated, and the maximum tolerated dose was not reached. The most common treatment-related adverse events for CDP1 monotherapy included rash (83%), dry skin (50%), and hypomagnesemia (50%), while for CDP1 combined with chemotherapy, they were anemia (85%), nausea (80%), and white blood cell decreased (80%). Among penile cancer patients receiving the combination therapy, the objective response rate was 74%, tumor downstaging enabled surgery in seven patients (35%), and the median progression-free survival was 6.9 months. In conclusion, the combination of an anti-EGFR monoclonal antibody and chemotherapy was well tolerated and showed potential efficacy in penile cancer, supporting further investigation.© 2025 UICC.