What is the role of immunotherapy, such as checkpoint inhibitors like pembrolizumab (pembrolizumab) or nivolumab (nivolumab), in the treatment of patients with advanced or recurrent penile cancer, particularly those with a high tumor mutational burden or evidence of Human Papillomavirus (HPV) infection?

Role of Immunotherapy in Penile Cancer

Pembrolizumab should be offered to patients with advanced or recurrent penile cancer who have specific biomarker-positive disease: PD-L1 CPS ≥1, TMB-high (≥10 mutations/megabase), or MSI-H/dMMR tumors, based on FDA tissue-agnostic approvals and extrapolation from related squamous cell carcinomas.

Biomarker-Directed Treatment Approach

PD-L1 Positive Disease (CPS ≥1)

• Pembrolizumab is FDA-approved for PD-L1-positive (CPS ≥1) recurrent or metastatic cervical cancer after chemotherapy progression, which can be extrapolated to penile squamous cell carcinoma given similar histology and HPV-association patterns 1
• In the KEYNOTE-158 trial evaluating vulvar squamous cell carcinoma (a closely related anogenital malignancy), pembrolizumab achieved an overall response rate of 10.9% with median OS of 6.2 months and median PFS of 2.1 months 1, 2
• Approximately 51% of penile cancers express PD-L1, making this a relevant biomarker for patient selection 3

TMB-High Disease (≥10 mutations/megabase)

• Pembrolizumab has FDA approval for TMB-high solid tumors (≥10 mutations/megabase) that progressed after prior therapy, regardless of tumor type 1
• In KEYNOTE-158, TMB-high vulvar cancer achieved approximately 17% ORR compared to only 3.4% in non-TMB-high disease 1
• Critical finding: TMB-high status appears exclusive to HPV16/18-positive penile cancers (30.8% prevalence), making HPV testing essential for identifying candidates 3
• Overall, approximately 10.7% of penile cancers demonstrate TMB-high status 3

MSI-H/dMMR Tumors

• Pembrolizumab is FDA-approved for MSI-H/dMMR solid tumors after progression on prior therapy, achieving 34.3% ORR with median OS of 23.5 months in the KEYNOTE-158 noncolorectal cohort 1, 2
• MSI-H/dMMR status is rare in penile cancer (1.1% prevalence) but represents the highest-yield biomarker when present 3

HPV Status and Treatment Selection

HPV-Positive Disease

• Nivolumab may be considered for HPV-related advanced or recurrent penile cancer based on CheckMate 358 data in HPV-positive vulvar/vaginal cancer, which showed 40% 6-month PFS and 40% 12-month OS 1
• Approximately 50-89% of penile cancers are HPV-positive, with HPV16/18 being the predominant subtypes 4, 3, 5
• HPV-positive tumors demonstrate distinct molecular profiles including KMT2C mutations (33%) and FGF3 amplifications (30.8%), and are the exclusive group with TMB-high status 3

HPV-Negative Disease

• HPV-negative penile cancers show CDKN2A mutations (37.5%) and have comparable PD-L1 expression to HPV-positive tumors but lack TMB-high status 3
• These patients should still undergo PD-L1 and MSI-H/dMMR testing, as these biomarkers remain relevant regardless of HPV status 3

Real-World Efficacy and Patient Selection

Response Rates in Unselected Populations

• Real-world data from Emory University (n=21) showed only 23.8% clinical benefit rate (3 partial responses, 2 stable disease) with median OS of 8.2 months and PFS of 1.9 months in unselected patients 4
• The three patients who responded had PD-L1 positivity, MSI-high, or high TMB, reinforcing the critical importance of biomarker selection 4

Prognostic Biomarkers

• Baseline neutrophil-to-lymphocyte ratio (NLR) at optimal cutoff predicts outcomes: higher NLR associates with shorter OS and PFS (HR 10.0,95% CI 2.73-54.2) 4
• Consider NLR assessment before ICI initiation to counsel patients on expected outcomes 4

Treatment Sequencing Algorithm

First-Line Advanced Disease

1. Obtain comprehensive biomarker testing: PD-L1 CPS, TMB, MSI-H/dMMR status, and HPV16/18 status 3
2. If any biomarker positive (PD-L1 CPS ≥1, TMB-high, or MSI-H/dMMR): Consider pembrolizumab monotherapy 1, 2
3. If HPV-positive without other biomarkers: Consider nivolumab as alternative 1
4. If all biomarkers negative: Proceed with platinum-based chemotherapy as standard of care 4

Second-Line or Later

• Pembrolizumab should be offered to biomarker-positive patients (PD-L1 CPS ≥1, TMB-high, or MSI-H/dMMR) who progress after platinum-based chemotherapy 1, 2
• Most real-world ICI use occurs in second-line (61.9%) or third-line (28.6%) settings 4

Safety Profile

• Immune checkpoint inhibitors demonstrate favorable toxicity compared to chemotherapy: grade 3/4 adverse events occur in 14.3% of penile cancer patients, substantially lower than chemotherapy rates 4
• Common immune-related adverse events include pneumonitis, colitis, hepatitis, endocrinopathies, and skin reactions 2

Critical Pitfalls to Avoid

Do Not Use ICIs Without Biomarker Testing

• Unselected use of ICIs in penile cancer yields poor response rates (10.9% ORR in KEYNOTE-158) 1
• The cost and potential toxicity of ICIs cannot be justified without identifying biomarker-positive subsets 4, 3

Do Not Assume HPV Status Predicts ICI Response Alone

• While HPV-positive status correlates with TMB-high disease, PD-L1 expression is comparable between HPV-positive and HPV-negative tumors 3
• HPV testing must be combined with PD-L1, TMB, and MSI-H/dMMR testing for comprehensive patient selection 3

Do Not Delay Chemotherapy in Rapidly Progressive Disease

• ICIs have response rates of only 20% even in biomarker-selected populations 4, 3
• For patients requiring rapid tumor reduction, platinum-based chemotherapy remains the appropriate first-line choice 4

Emerging Evidence and Future Directions

• High PD-L1 expression and CD8+ T-cell infiltration in penile cancer suggest potential for improved ICI response with combination strategies 6
• Therapeutic HPV vaccines represent a potential future treatment modality given the high prevalence of HPV-driven disease 7, 5
• Adoptive T-cell therapy has shown early efficacy in clinical trials but remains investigational 7