Pembrolizumab Plus Platinum-Based Chemotherapy for Patients With Advanced Penile Cancer: The Nonrandomized HERCULES (LACOG 0218) Clinical Trial.

Importance 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. Objective To evaluate the efficacy and safety of adding an immune checkpoint inhibitor to chemotherapy for advanced PSCC. Design, Setting, and Participants 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. Intervention 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. Main outcome The primary end point was the overall response rate (ORR) assessed using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Results 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. Conclusion and Relevance 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. Trial Registration ClinicalTrials.gov Identifier: NCT04224740.