HERCULES: Pembrolizumab Plus Platinum-Based Chemotherapy for First-line Advanced Penile Cancer

A recent trial provides the first evidence of efficacy from immune checkpoint inhibitors (ICIs) in advanced penile squamous cell carcinoma (PSCC) with a manageable safety profile.

Results of the phase 2 HERCULES trial are being presented at the 2024 American Society of Clinical Oncology Annual Meeting.

Platinum-based chemotherapy has been considered the standard-of-care first-line treatment for advanced PSCC for the past 6 decades. Patients with this disease have poor prognosis and limited treatment options.

HERCULES is a phase 2, single-arm trial evaluating pembrolizumab plus platinum-based chemotherapy as a first-line option for advanced PSCC. Thirty-three patients with metastatic or locally advanced disease were sampled and received 5-FU (1000 mg/m²/day IV D1-D4), cisplatin (70 mg/m²) or carboplatin AUC 5 (IV D1), and pembrolizumab (200 mg IV D1 Q3W for 6 cycles), followed by pembrolizumab (200 mg IV Q3W up to 34 cycles).

The primary end point of the analysis is confirmed overall response rate (ORR) assessed according to Response Evaluation Criteria in Solid Tumors v1.1 criteria.

The median age in the patient sample was 56 years, 64.9% of patients had metastatic disease, 21.6% had recurrent disease, and 13.5% had locally advanced disease.

Researchers reported a confirmed ORR of 39.4% (95% CI, 22.9-57.9), with 1 complete response and 12 partial responses. They also evaluated for ORR according to PD-L1 status (66.7% in combined positivity score [CPS] 0.0% vs 33.3% in CPS ≥1.0%), tumor mutation burden status (75.0% in high vs 36.4% in low), and HPV16 status (HPV16 positive 55.6% vs HPV16 negative 35.0%).

Among the most frequent genomic alterations detected by next-generation sequencing were TP53 (57.1%), CDKN2A (51.4%), and TERT (31.4%).

The rate of treatment-related adverse events (AEs) of any grade was 91.9%, they acknowledged, and 51.4% of patients experienced grade 3/4 AEs.

“HERCULES is the first trial to demonstrate the efficacy of ICIs in advanced PSCC with a manageable safety profile” they concluded, adding that “HPV16 and tumor mutation burden are potential predictive biomarkers for efficacy,” and “ICIs combined with platinum-based chemotherapy is a promising treatment for advanced PSCC” in need of further investigation.