Retifanlimab in Advanced Penile Squamous Cell Carcinoma: The Phase 2 ORPHEUS Study

Background and objective Patients with advanced penile squamous cell carcinoma (PSCC) have poor outcomes and very limited therapeutic options are available. Most PSCC cases have high PD-L1 expression, which is associated with worse prognosis. Immunotherapy targeting PD-L1 could benefit patients with PSCC. Our aim was to evaluate the efficacy and safety of the anti-PD-1 antibody retifanlimab in patients with advanced/metastatic PSCC. Methods ORPHEUS was a single-arm, multicenter, phase 2 trial in 18 patients with advanced/metastatic PSCC, previously untreated with anti-PD-1/anti-PD-L1 agents. Patients received retifanlimab 500 mg intravenously every 4 wk for up to 2 yr. The primary endpoint was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included the clinical benefit rate (CBR), disease control rate, duration of response (DoR), time to response, progression-free survival (PFS), overall survival (OS), maximum tumor shrinkage, and safety. The Wilson method was used for the primary endpoint, and the Clopper-Pearson and Kaplan-Meier methods for secondary endpoints. Key findings and limitations Median follow-up was 7.2 mo. The ORR was 16.7% (95% confidence interval [CI] 5.8–39.2); three patients had a partial response. Median DoR was 3.3 mo (range 1.8–8.5). The CBR was 22.2% (95% CI 6.4–47.6%). Median PFS was 2.0 mo (95% CI 1.6–3.3) and median OS was 7.2 mo (95% CI 3.0–9.8). One patient (5.6%) experienced grade 3 treatment-related adverse events (AEs). There were no grade >= 4 treatment-related AEs. The small sample size is the main limitation. Conclusions and clinical implications Single-agent retifanlimab exhibited signals of clinical activity in advanced/metastatic PSCC, with no new safety signals. Further investigation of retifanlimab in this setting is warranted. Patient summary Advanced penile cancer of the squamous cell type is a rare tumor with poor prognosis. The aggressiveness of this cancer is usually associated with high levels of a protein called PD-L1. We investigated whether retifanlimab, an immunotherapy drug against PD-1, has activity against this type of penile cancer. Tumor regression or stabilization occurred in one-third of the patients and the side effects were manageable.