A phase II trial of pembrolizumab plus platinum-based chemotherapy as first-line systemic therapy in advanced penile cancer: HERCULES (LACOG 0218) trial.

5009 Background: Over the last six decades, platinum-based chemotherapy has been the standard of care first-line treatment for advanced penile squamous cell carcinoma (PSCC). Advanced PSCC has poor prognosis with limited treatment options. Immune checkpoint inhibitors (ICI) have been associated with improved efficacy in different types of malignancies, however the benefit in PSCC is uncertain. Methods: LACOG 0218 ( NCT04224740 ) is a phase II single arm trial evaluating pembrolizumab plus platinum-based chemotherapy as first-line treatment in advanced PSCC. Patients (pts) with metastatic or locally advanced disease (recurrent or TanyN3M0 or T4NanyM0) not amenable to curative-intent therapy received: 5-FU 1000mg/m²/day IV D1-D4; cisplatin 70mg/m² (or carboplatin AUC 5) IV D1; and pembrolizumab 200mg IV D1 every 3 weeks (Q3W) for 6 cycles, followed by pembrolizumab 200mg IV Q3W up to 34 cycles. The primary endpoint is confirmed overall response rate (cORR) assessed by investigator (INV) according to RECIST 1.1. Considering a drop-out rate of 10%, 33 patients were required to reject the null hypothesis that ORR is 20% or less, if the true ORR is 40% (two-sided alpha level of 0.10, power 78.5%). Results: From Aug2020 to Dec2022, 37 pts were enrolled in 11 Brazilian centers and 33 pts were eligible for efficacy analysis. Median age was 56y (range, 30-76), 64.9% of pts had metastatic disease, 21.6% had recurrent disease, and 13.5% had locally advanced disease. Efficacy results are presented in the table. cORR by INV was 39.4% (95% CI 22.9-57.9); with 1 complete response and 12 partial responses. cORR INV according to PD-L1 status (66.7% in CPS 0% vs. 33.3% in CPS≥1%); TMB status (75% in high vs. 36.4% in low); and HPV16 status (HPV16 positive 55.6% vs. 35.0%). The most frequent genomic alterations detected by NGS were: TP53(57.1%), CDKN2A (51.4%), and TERT (31.4%). Treatment-related adverse events (AE) rate of any grade was 91.9% and grade 3-4 was 51.4%. Ten pts experienced Grade 5 AE, none of them related to study treatment. Immune-related AEs of any grade was 21.6% and grade 3-4 was 5.4%. 10.8% discontinued treatment due to AE. Conclusions: HERCULES is the first trial to demonstrate the efficacy of ICI in advanced PSCC with manageable safety profile. HPV16 and TMB are potential predictive biomarkers for efficacy. ICI combined with platinum-based chemotherapy is a promising treatment for advanced PSCC warranting further investigation. Clinical trial information: NCT04224740 . [Table: see text]