Safety and efficacy of immune checkpoint inhibitors in advanced penile cancer: report from the Global Society of Rare Genitourinary Tumors

Abstract

Background Treatment options for penile squamous cell carcinoma (PeCa) are limited. We sought to investigate clinical outcomes and safety profiles of patients with PeCa receiving immune checkpoint inhibitors (ICIs). Methods This retrospective study included patients with locally advanced or metastatic PeCa receiving ICIs during 2015-2022 across 24 centers in the United States, Europe, and Asia. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. Objective response rates (ORRs) were determined per RECIST 1.1 criteria. Treatment-related adverse events (trAEs) were graded per the Common Terminology Criteria for Adverse Events v5.0. Two-sided statistical tests were used for comparisons. Results Among 92 patients, 8 were Asian (8.7%), 6 (6.5%) were Black, and 24 (29%) were Hispanic/Latinx. Median age was 62 (inter-quartile range: 53 to 70) years. 83 (90%) had metastatic PeCa, and 74 (80%) received ≥2nd line treatment. Most patients received pembrolizumab monotherapy (n = 26, 28%), combination nivolumab/ipilimumab +/- multi-targeted tyrosine kinase inhibitors (n = 23, 25%), nivolumab (n = 16, 17%) or cemiplimab (n = 15, 16%) monotherapies. Median OS and PFS were 9.8 (95% CI: 7.7-12.8) months and 3.2 (95% CI: 2.5-4.2) months, respectively. ORR was 13% (n = 11/85) in the overall cohort and 35% (n = 7/20) in patients with lymph node-only metastases. Visceral metastases, ECOG performance status ≥1, and higher Neutrophil/Lymphocyte ratio (NLR) were associated with worse OS. TrAEs occurred in 29% (n = 27) and 9.8% (n = 9) were grade ≥3. Conclusions ICIs are active in a subset of patients with PeCa. Future translational studies are warranted to identify patients more likely to derive clinical benefit from ICIs.

Human papillomavirus infection affects treatment outcomes and the immune microenvironment in patients with advanced penile squamous cell carcinoma receiving programmed cell death protein 1 inhibitor–based combination therapy

“…To further evaluate the effect of HPV status on the efficacy and prognosis in patients receiving ICI, we searched for published data on HPV‐associated squamous cell cancers (HNSCC and PSCC) treated with anti‐PD1/programmed cell death protein ligand 1 and performed a meta‐analysis. In addition to our study, five articles 3,4,9,16–18 were included, and 635 patients were evaluated, including 207 HPV+ and 428 HPV– cases. Meta analyses showed HPV infection was associated with better ORR (OR, 1.82; 95% CI, 1.18–2.79; p = .006; I 2 = 23%) and 12‐month PFS (OR, 6.81; 95% CI, 2.43–19.07; p = .0003; I 2 = 0%) (Figure 3A,B).…”

“…Additionally, HPV infection induced wider benefits in our analyses: ORR (91.7%), DCR (100.0%), and OS (HR, 0.087). Another retrospective study (GSRGT PSCC cohort) on the use of ICIs against advanced PSCC also compared the survival outcomes between HPV+ and HPV– patients but did not find any markedly different PFS and OS, 3 which might have resulted from the relatively small number of cases (49 cases) examining HPV status and the potential heterogeneity of regimen, treatment line, race, etc.…”

“…Recently, immunotherapy has emerged as a novel treatment option for advanced PSCC. Several studies on immune checkpoint inhibitor (ICI) monotherapy or combination treatment against progressive PSCC reported an objective response rate (ORR) of 13.0%–16.7% and median overall survival (OS) of 9.8–11.3 months 3,4 . Moreover, we previously reported a better ORR (76.5%) and 2‐year OS rate (62.9%) among 17 advanced‐stage IV PSCCs treated with ICI plus chemotherapy and targeted therapy 5 .…”

Genomic Profiles and Clinical Outcomes of Penile Squamous Cell Carcinoma With Elevated Tumor Mutational Burden

“…Atezolizumab was investigated as monotherapy or in combination with locoregional radiotherapy in a phase 2 trial including stage IV PSCC: the ORR was 44% with combination therapy and 17% with monotherapy . Finally, various ICI regimens tested in a heterogeneous population of chemotherapy-naive and chemotherapy-treated PSCC were included in a retrospective study sponsored by the Global Society of Rare Genitourinary Cancers: the pooled ORR was 13%, with a median progression-free survival of 3.2 months . There are also several trials in progress with ICIs, the most interesting being represented by the HERCULES study (first-line pembrolizumab and platinum-based chemotherapy, NCT04224740) and the EPIC Trial sponsored by Cancer Research UK (cemiplimab, with or without chemotherapy) …”

“…31 Finally, various ICI regimens tested in a heterogeneous population of chemotherapy-naive and chemotherapy-treated PSCC were included in a retrospective study sponsored by the Global Society of Rare Genitourinary Cancers: the pooled ORR was 13%, with a median progression-free survival of 3.2 months. 32 There are also several trials in progress with ICIs, the most interesting being represented by the HERCULES study (first-line pembrolizumab and platinum-based chemotherapy, NCT04224740) 33 and the EPIC Trial sponsored by Cancer Research UK (cemiplimab, with or without chemotherapy). 34 When analyzing OS data from patients with metastatic penile cancer receiving frontline ICI treatment in routine clinical practice, representing a unique cohort in the literature, we realized that sustained OS could be achieved with up-front ICI, therefore representing a therapeutic possibility instead of standard chemotherapy in selected patients.…”