Advanced penile squamous cell carcinoma (PSCC) is associated with poor survival, and no new treatment strategies have changed clinical outcomes in past decades. This highlights the unmet need to understand the biology and develop more effective and tolerable treatment options.
To evaluate the efficacy and safety of adding an immune checkpoint inhibitor to chemotherapy for advanced PSCC.
HERCULES (LACOG 0218) was a phase 2 single-arm nonrandomized clinical trial evaluating pembrolizumab plus platinum-based chemotherapy as first-line treatment in patients with advanced PSCC from August 2020 to December 2022. Patients were followed up for 24 months. Patients with metastatic, recurrent, or locally advanced disease not amenable to curative-intent therapy were included. Statistical analyses were performed between November 21, 2023, and January 25, 2024.
Fluorouracil, 1000 mg/m2 per day, intravenously for days 1 to 4; cisplatin, 70 mg/m2 (or carboplatin, area under the curve, 5) intravenously on day 1; and pembrolizumab, 200 mg, intravenously on day 1 every 3 weeks for 6 cycles, followed by pembrolizumab, 200 mg, intravenously every 3 weeks for up to 34 cycles.
The primary end point was the overall response rate (ORR) assessed using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
Overall, 37 patients were enrolled in 11 Brazilian centers and 33 patients were eligible for efficacy analysis. The median (range) age was 56 (30-76) years, 24 patients (64.9%) had metastatic disease, 8 (21.6%) had recurrent disease, and 5 (13.5%) had locally advanced disease. ORR was 39.4% (95% CI, 22.9%-57.9%). At median follow-up of 24.0 months (cut-off date January 24, 2024), median progression-free survival was 5.4 (95% CI, 2.7-7.2) months and median overall survival was 9.6 (95% CI, 6.4-13.2) months. Treatment-related adverse events (AE) rates of any grade and grades 3 to 4 were 91.9% and 51.4%. Immune-related AE rates of any grade were 21.6% and grade 3 to 4 were 5.4%. There were no treatment-related deaths.
The HERCULES clinical trial is the first trial to demonstrate the efficacy of immune checkpoint inhibitors combined with chemotherapy in patients with advanced PSCC with a manageable safety profile.
ClinicalTrials.gov Identifier: NCT04224740.
JAMA oncology. 2025 Sep 18 [Epub ahead of print]
Fernando Cotait Maluf, Karine Trindade, Daniel Preto, Murilo de Almeida Luz, Patrícia Medeiros Milhomem Beato, Diogo Assed Bastos, João Paulo Holanda Soares, Victor Marcondes Lopes, Luis Eduardo Werneck de Carvalho, David Queiroz Borges Muniz, Douglas Jorge Racy, Rafaela Gomes de Jesus, Taiane Francieli Rebelatto, Gustavo Werutsky, Susan Halabi, Fernando Sabino Marques Monteiro, André Poisl Fay
Latin American Cooperative Oncology Group (LACOG), Porto Alegre, Brazil., Barretos Cancer Hospital (Hospital de Amor), Barretos, Brazil., Hospital Erasto Gaertner, Curitiba, Brazil., Fundação Amaral Carvalho, Jaú, Brazil., Hospital Haroldo Juaçaba-Instituto do Câncer do Ceará (ICC), Fortaleza, Brazil., Instituto Nacional do Câncer (INCA), Rio de Janeiro, Brazil., Instituto do Câncer do Estado de São Paulo (ICESP), São Paulo, Brazil., Hospital Beneficência Portuguesa de São Paulo, São Paulo, Brazil., Duke University School of Medicine, Durham, North Carolina.