Professor Andrea Necchi presented updates on penile cancer treatment at the 2024 European Society for Medical Oncology (ESMO) Annual Congress, emphasizing neoadjuvant chemotherapy, ongoing clinical trials, and the role of immunotherapy. Penile cancer, while rare, representing only 0.4–0.6% of malignancies in the U.S. and Europe, exhibits significant geographic variation, with higher incidence in South America, Africa, and India.
Surgical and Systemic Treatment Strategies
Surgical indications for inguinal/pelvic lymph node dissection in penile squamous cell carcinoma are based on the disease's predictable clinical course. Data from the National Cancer Database (NCDB) showed an increase in systemic chemotherapy use from 38% to 48% between 2004 and 2014 in node-positive disease. However, only 53% of patients with cN3 disease received chemotherapy, while 67% underwent lymph node dissection. Inguinal lymph node dissection was associated with better overall survival.
The EAU-ASCO guidelines recommend neoadjuvant chemotherapy as an alternative to upfront surgery for selected patients with bulky mobile inguinal nodes or bilateral disease who are candidates for cisplatin and taxane-based chemotherapy.
Neoadjuvant Chemotherapy Regimens
Several chemotherapy regimens are available for locally advanced penile squamous cell carcinoma, with much of the evidence originating from retrospective studies. A phase II trial of neoadjuvant TIP (paclitaxel, ifosfamide, and cisplatin) showed a 50% objective response rate in men with cN2-3M0 penile cancer, with a median overall survival of 17 months. A systematic review of neoadjuvant chemotherapy showed a pooled objective response rate of 53% and a pathologic complete response of 16%.
Ongoing Clinical Trials
The International Penile Advanced Cancer Trial (InPACT) ECOG-EA8134 is evaluating neoadjuvant therapy, including chemotherapy and chemoradiation, in patients with cN1-3 squamous cell carcinoma of the penis. The primary endpoint is overall survival, with a target accrual of 400 patients across international sites. As of 2023, 114 patients have been enrolled, with a target completion date of May 2024.
Systemic Therapy in Metastatic Disease
For metastatic or relapsed penile squamous cell carcinoma, vinflunine and dacomitinib have shown objective response rates of approximately 30% in single-arm phase II trials.
Role of HPV and Tumor Mutational Burden
The incidence of HPV DNA in penile cancer ranges from 42–70%, varying by histologic subtype. HPV+ patients tend to have superior survival outcomes and lower inguinal lymph node metastasis density. However, there is no definitive prospective evidence to support the efficacy of the quadrivalent HPV vaccine for the prevention of penile intraepithelial neoplasia (PeIN) or penile cancer.
Most penile tumors are TMB-low (85%), with about 7% of patients having an underlying germline mutation.
Immunotherapy Approaches
Recent studies have evaluated immunotherapy, both as single agents and in combination regimens. A combination of cabozantinib, nivolumab, and ipilimumab showed a partial response in 4 out of 9 penile cancer patients. The phase II PERICLES study of atezolizumab +/- radiation failed to meet its primary endpoint, but improved progression-free survival was observed in patients with high-risk HPV-positive tumors and high infiltration of intratumoral CD3+CD8+ T cells. The phase II ORPHEUS trial of retifanlimab showed a 17% objective response rate with a median overall survival of 7.2 months.
HERCULES Trial: Pembrolizumab Combination
The HERCULES trial (LACOG 0218) evaluated pembrolizumab + platinum-based chemotherapy as first-line treatment in advanced penile squamous cell carcinoma. The confirmed overall response rate was 39%, with a median progression-free survival of 5.4 months and a median overall survival of 9.6 months. Responses were enriched in TMB-high and HPV+ tumors. Grade 3-4 treatment-related adverse events were observed in 51.4% of patients.
Professor Necchi concluded that neoadjuvant chemotherapy should be considered for unresectable or recurrent lymph node metastases, and chemo-immunotherapy combinations may be an alternative to TIP in biomarker-selected patients. Future trials should focus on penile squamous cell carcinoma as distinct biological entities, with TMB-high/HPV+ tumors warranting next-generation immune checkpoint inhibitor therapy-based trials.
