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Pembrolizumab Plus Platinum-Based Chemotherapy for Patients With Advanced Penile Cancer: The Nonrandomized HERCULES
Fernando Cotait Maluf1,2,3, Karine Trindade1,4, Daniel Preto5
1Latin American Cooperative Oncology Group (LACOG), Porto Alegre, Brazil.
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.
Insights
Adding pembrolizumab to chemotherapy improved outcomes for advanced penile squamous cell carcinoma (PSCC). This combination therapy showed a 39.4% overall response rate and manageable safety, offering a new treatment option for this challenging cancer.
Area of Science:
- Oncology
- Immunotherapy
- Clinical Trials
Background:
- Advanced penile squamous cell carcinoma (PSCC) has a poor prognosis with limited treatment advancements.
- There is a critical need for more effective and tolerable therapeutic strategies for advanced PSCC.
Purpose of the Study:
- To assess the efficacy and safety of combining immune checkpoint inhibitors with chemotherapy in patients with advanced PSCC.
- To evaluate pembrolizumab plus platinum-based chemotherapy as a first-line treatment for advanced PSCC.
Main Methods:
- The HERCULES (LACOG 0218) trial was a phase 2, single-arm, nonrandomized study.
- 33 patients with advanced PSCC received first-line pembrolizumab and platinum-based chemotherapy.
- The primary endpoint was overall response rate (ORR) per RECIST 1.1 criteria.
Main Results:
- The ORR was 39.4% (95% CI, 22.9%-57.9%).
- Median progression-free survival was 5.4 months, and median overall survival was 9.6 months.
- Any-grade treatment-related adverse events occurred in 91.9% of patients, with 51.4% experiencing grade 3-4 events.
Conclusions:
- The HERCULES trial is the first to show efficacy for immune checkpoint inhibitors plus chemotherapy in advanced PSCC.
- This combination demonstrates a manageable safety profile, offering a promising new treatment avenue.
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