Penile squamous cell carcinoma (PSCC) is a rare disease, which leads to difficulty in performing prospective, randomized clinical trials. Outcomes are very poor in patients with advanced disease and in those who do not respond to first-line multimodal therapy.2 Therefore, expanding systemic treatment options is crucial for patients with advanced penile cancer.
ORPHEUS was a single-arm, multicenter, open-label phase 2 trial that evaluated the efficacy and safety of retifanlimab in patients with advanced/metastatic PSCC. This trial enrolled adult males with unresectable, locally advanced/metastatic stage IV PSCC (T4 or N3 or M1). Participants had measurable disease according to RECIST v1.1, ECOG PS 0 or 1, and no prior treatment with anti-PD-1 or anti-PD- L1/2 agents. The primary endpoint was the objective response rate (ORR), according to the local investigator’s assessment using RECIST v.1.1. The study also evaluated additional efficacy parameters (Clinical Benefit Rate [CBR], Disease Control Rate [DCR], Duration of Response [DoR], Time to Response [TTR] and progression-free survival [PFS], amongst others) and explored the correlation between biomarkers (PD-L1 and p-16 expression) and response.
A total of 18 patients were included and received at least one dose of retifanlimab. The median age was 66.5 yr (range 42–81). Nine patients (50.0%) had visceral disease, and seven (38.9%) had ECOG PS 0. Overall, ten patients (55.6%) had previously received chemotherapy, including platinum- and taxane-based regimens. Four patients (22.2%) had received previous radiotherapy.
With a median follow-up of 7.2 mo (range 1.0–18.9), the ORR was 16.7% (95% CI 5.8–39.2%), and 3/18 patients achieved partial response (PR). For these patients, median TTR was 1.9 mo (range 1.7–2.4) and median DoR was 3.3 mo (range 1.8– 8.5). Three patients (16.7%) experienced stable disease (SD <24 wk, n = 2; SD 24 wk, n = 1). Four patients (22.2%; 95% CI 6.4–47.6%) experienced a clinical benefit (PR, n = 3; SD 24 wk, n = 1). Disease control was achieved in six patients (33.3%; 95% CI 13.3–59.0%; PR, n = 3; SD, n = 3). Twelve patients (66.6%) had progressed during the first 3 mo. Median PFS was 2.0 mo (95% CI 1.6–3.3) and the 6-mo PFS rate was 11.1% (95% CI 1.9–29.8%. Median OS was 7.2 mo (95% CI, 0.3–9.8), with 6-mo and 12-mo OS rates of 55.6% (95% CI 30.5–74.8%) and 16.7% (95% CI 4.1–36.5%), respectively.
There were 15 tumor samples available at baseline and the exploratory analyses showed that four patients had PD-L1-positive tumors (defined as PD-L1 expression higher than 10%). Amongst these four patients, one had a stable disease for more than 24 weeks, one had a stable disease of less than 24 weeks, and two experienced progressive disease. A numerically better PFS (HR 0.433, 95% CI 0.12–1.59; p = 0.178) and OS (HR 0.378, 95% CI 0.10–1.41; p = 0.121) was reached for PD-L1-positive patients than for PD-L1-negative patients. Considering the limited sample size and the absence of statistical gain, these results need to be interpreted with caution.
Eight patients (53.3%) were p16-negative, and no significant association was observed between p16 status and clinical parameters.
Adverse events (AEs) of any grade occurred in 14 patients (77.8%). The most common AEs were anemia (n = 2; 11.1%) and fatigue (n = 5; 27.8%). Grade 3–4 AEs occurred in eight patients (44.4%), including fatigue (n = 1; 5.6%) and hyporexia (n = 1; 5.6%). Serious AEs occurred in five patients (27.8%), all of which were considered unrelated to retifanlimab.
The most common treatment-related AE was fatigue (n = 4; 22.2%). One patient (5.6%) experienced grade 3 treatment-related AEs (fatigue and hyporexia). No grade 4 nor 5 treatment-related AEs were reported. At the data cutoff, 17 patients had discontinued treatment, mainly because of PD (n = 16; 88.8%).
The findings of the ORPHEUS study are consistent with the results of other trials that evaluated the benefit and the safety of immunotherapy in PSCC. In the PERICLES trial, a nonrandomized phase 2 trial assessing the activity of atezolizumab in 32 patients with PSCC with or without radiotherapy, the primary endpoint of 1-year PFS was not met. However, it showed that patients treated with atezolizumab had an overall response rate of 16.7% and median overall survival of 11.3 mo (95% CI 5.5–18.7).3
There is an increasing interest in the determination of biomarkers that could predict better outcomes. PD-L1 might have a predictive value. Other biomarkers such as HPV16-positive patients and TMB-High have also been studied.4 The predictive capabilities of these biomarkers remain unclear and must be better evaluated in trials with larger sample size.
In conclusion, the take-home messages of the ORPHEUS clinical trial are:
- Retifanlimab monotherapy has clinical activity in patients with advanced or metastatic PSCC
- The safety profile was consistent with previous data, with no treatment-related serious AEs or deaths.
- The present results can stimulate new strategies of combination therapy or studies with larger sample sizes.
- These findings represent a step forward toward the use of immunotherapy in the treatment of this orphan genitourinary tumor.
Writing support: Medica Scientia Innovation Research (MEDSIR), Barcelona, Spain, and New Jersey, USA.
Role of the sponsor: This study was sponsored by Medica Scientia Innovation Research (MEDSIR), who participated in the design and conduct of the study, data collection, data analysis, data interpretation, and writing of this comment as well as the original manuscript published in European Urology Oncology.
Funding Support: Incyte Bioscience International Sàrl funded the study and provided retifanlimab but did not participate in any of the tasks mentioned before.
References:
- Xavier Garcia del Muro, David Lopez-Bravo, Miler Cuellar-Rivas, et al. Retifanlimab in Advanced Penile Squamous Cell Carcinoma: The Phase 2 ORPHEUS Study. Eur Urol Oncol. 15 de mayo de 2024;
- Joshi VB, Chadha J, Chahoud J. Penile cancer: Updates in systemic therapy. Asian J Urol. 2022;9(4):374-88.
- Hielke M. de Vries, Tynisha S. Rafael, Alberto Gil-Jimenez, Jeantine M. de Feijter, Elise Bekers, Elsbeth van der Laan, et al. Atezolizumab With or Without Radiotherapy for Advanced Squamous Cell Carcinoma of the Penis (The PERICLES Study): A Phase II Trial. J Clin Oncol [Internet]. 24 de julio de 2023 [citado 28 de julio de 2023]; Disponible en: https://ascopubs.org/doi/pdf/10.1200/JCO.22.02894?role=tab
- Fernando Cotait Maluf, et al. A phase II trial of pembrolizumab plus platinum-based chemotherapy as first-line systemic therapy in advanced penile cancer: HERCULES (LACOG 0218) trial. J Clin Oncol. 2024;42(suppl 16; abstr 5009).