Systemic Therapy for Metastatic Penile Cancer

Authored by Open Medicine, published on 2026-11-03 20:20:04.0

The algorithm is broadly consistent with guideline-supported practice by prioritizing platinum-based chemotherapy, performance-status assessment, clinical trials, and biomarker-directed pembrolizumab after progression. However, most penile-cancer chemotherapy evidence is nonrandomized, TIP data derive mainly from bulky regional disease rather than distant metastases, and carboplatin-paclitaxel has limited direct support. Recently reported phase II chemo-immunotherapy results are promising but remain investigational rather than definitive standards.

  1. Confirm Metastatic Penile Squamous Cell Carcinoma
    • Assess ECOG PS, Organ Function, Comorbidities, and Goals
      • Obtain MSI/MMR and TMB Testing (NGS if feasible)
        • Fit for Multiagent Chemotherapy?
          • Cisplatin Eligible?
            • Fit for Intensive TIP?
              • Start TIP: Paclitaxel 175 mg/m² D1; Ifosfamide 1,200 mg/m² D1–3 With Mesna; Cisplatin 25 mg/m² D1–3 q21d
                • Reassess Clinical and Radiographic Response After 2–3 Cycles
                  • Classify Initial-Therapy Outcome
                    • Continue Planned Regimen With Interval Reassessment
                      • Begin Observation or Surveillance After Chemotherapy Completion
                        • MSI-H/dMMR or TMB ≥13 mut/Mb (FDA-Authorized Test) With No Satisfactory Alternatives?
                          For US treatment selection, assess independent MSI-H/dMMR and TMB-high indications for pembrolizumab. MSI-H/dMMR: Evaluate eligibility under the applicable tumor-specific or tumor-agnostic indication, independently of TMB. TMB ≥13 mut/Mb: Qualifies for the current FDA tumor-agnostic TMB-high indication when confirmed by an FDA-authorized test in unresectable or metastatic disease progressing after prior treatment, with no satisfactory alternative treatment options. TMB 10–12 mut/Mb: Does not independently qualify under the updated October 16, 2026 FDA indication. Evaluate other established indications, biomarker-directed treatments, and clinical trials. Assay interpretation: Confirm the testing platform and current assay authorization. Do not assume TMB measurements from different assays are interchangeable. Outside the US: Apply local regulatory approvals and applicable disease-specific guidelines.
                          • Start Pembrolizumab 200 mg IV q3w or 400 mg IV q6w, Up to 24 Months
                          • Relevant Clinical Trial Available (Preferred)?
                            • Enroll in Biomarker-Selected or Novel-Therapy Clinical Trial
                            • Taxane-Naive and Clinically Suitable for Paclitaxel?
                              • Give Paclitaxel 175 mg/m² IV q21d; Reassess Every 2–3 Cycles Until Progression or Intolerance
                                • Assess Other Selected Salvage Options vs Best Supportive Care
                              • Assess Other Selected Salvage Options vs Best Supportive Care
                    • Hold or Reduce Offending Drugs; Switch Cisplatin to Carboplatin When Appropriate
                      • Resume Modified Therapy or Transition to Supportive Care
                    • MSI-H/dMMR or TMB ≥13 mut/Mb (FDA-Authorized Test) With No Satisfactory Alternatives?
                      For US treatment selection, assess independent MSI-H/dMMR and TMB-high indications for pembrolizumab. MSI-H/dMMR: Evaluate eligibility under the applicable tumor-specific or tumor-agnostic indication, independently of TMB. TMB ≥13 mut/Mb: Qualifies for the current FDA tumor-agnostic TMB-high indication when confirmed by an FDA-authorized test in unresectable or metastatic disease progressing after prior treatment, with no satisfactory alternative treatment options. TMB 10–12 mut/Mb: Does not independently qualify under the updated October 16, 2026 FDA indication. Evaluate other established indications, biomarker-directed treatments, and clinical trials. Assay interpretation: Confirm the testing platform and current assay authorization. Do not assume TMB measurements from different assays are interchangeable. Outside the US: Apply local regulatory approvals and applicable disease-specific guidelines.
                      • Start Pembrolizumab 200 mg IV q3w or 400 mg IV q6w, Up to 24 Months
                      • Relevant Clinical Trial Available (Preferred)?
                        • Enroll in Biomarker-Selected or Novel-Therapy Clinical Trial
                        • Taxane-Naive and Clinically Suitable for Paclitaxel?
                          • Give Paclitaxel 175 mg/m² IV q21d; Reassess Every 2–3 Cycles Until Progression or Intolerance
                            • Assess Other Selected Salvage Options vs Best Supportive Care
                          • Assess Other Selected Salvage Options vs Best Supportive Care
              • Start PF: Cisplatin 70 mg/m² D1 Plus Fluorouracil 1,000 mg/m²/Day D1–4 q21d
                • Reassess Clinical and Radiographic Response After 2–3 Cycles
                  • Classify Initial-Therapy Outcome
                    • Continue Planned Regimen With Interval Reassessment
                      • Begin Observation or Surveillance After Chemotherapy Completion
                        • MSI-H/dMMR or TMB ≥13 mut/Mb (FDA-Authorized Test) With No Satisfactory Alternatives?
                          For US treatment selection, assess independent MSI-H/dMMR and TMB-high indications for pembrolizumab. MSI-H/dMMR: Evaluate eligibility under the applicable tumor-specific or tumor-agnostic indication, independently of TMB. TMB ≥13 mut/Mb: Qualifies for the current FDA tumor-agnostic TMB-high indication when confirmed by an FDA-authorized test in unresectable or metastatic disease progressing after prior treatment, with no satisfactory alternative treatment options. TMB 10–12 mut/Mb: Does not independently qualify under the updated October 16, 2026 FDA indication. Evaluate other established indications, biomarker-directed treatments, and clinical trials. Assay interpretation: Confirm the testing platform and current assay authorization. Do not assume TMB measurements from different assays are interchangeable. Outside the US: Apply local regulatory approvals and applicable disease-specific guidelines.
                          • Start Pembrolizumab 200 mg IV q3w or 400 mg IV q6w, Up to 24 Months
                          • Relevant Clinical Trial Available (Preferred)?
                            • Enroll in Biomarker-Selected or Novel-Therapy Clinical Trial
                            • Taxane-Naive and Clinically Suitable for Paclitaxel?
                              • Give Paclitaxel 175 mg/m² IV q21d; Reassess Every 2–3 Cycles Until Progression or Intolerance
                                • Assess Other Selected Salvage Options vs Best Supportive Care
                              • Assess Other Selected Salvage Options vs Best Supportive Care
                    • Hold or Reduce Offending Drugs; Switch Cisplatin to Carboplatin When Appropriate
                      • Resume Modified Therapy or Transition to Supportive Care
                    • MSI-H/dMMR or TMB ≥13 mut/Mb (FDA-Authorized Test) With No Satisfactory Alternatives?
                      For US treatment selection, assess independent MSI-H/dMMR and TMB-high indications for pembrolizumab. MSI-H/dMMR: Evaluate eligibility under the applicable tumor-specific or tumor-agnostic indication, independently of TMB. TMB ≥13 mut/Mb: Qualifies for the current FDA tumor-agnostic TMB-high indication when confirmed by an FDA-authorized test in unresectable or metastatic disease progressing after prior treatment, with no satisfactory alternative treatment options. TMB 10–12 mut/Mb: Does not independently qualify under the updated October 16, 2026 FDA indication. Evaluate other established indications, biomarker-directed treatments, and clinical trials. Assay interpretation: Confirm the testing platform and current assay authorization. Do not assume TMB measurements from different assays are interchangeable. Outside the US: Apply local regulatory approvals and applicable disease-specific guidelines.
                      • Start Pembrolizumab 200 mg IV q3w or 400 mg IV q6w, Up to 24 Months
                      • Relevant Clinical Trial Available (Preferred)?
                        • Enroll in Biomarker-Selected or Novel-Therapy Clinical Trial
                        • Taxane-Naive and Clinically Suitable for Paclitaxel?
                          • Give Paclitaxel 175 mg/m² IV q21d; Reassess Every 2–3 Cycles Until Progression or Intolerance
                            • Assess Other Selected Salvage Options vs Best Supportive Care
                          • Assess Other Selected Salvage Options vs Best Supportive Care
            • Start Carboplatin AUC 5 D1 Plus Paclitaxel 175 mg/m² D1 q21d
              • Reassess Clinical and Radiographic Response After 2–3 Cycles
                • Classify Initial-Therapy Outcome
                  • Continue Planned Regimen With Interval Reassessment
                    • Begin Observation or Surveillance After Chemotherapy Completion
                      • MSI-H/dMMR or TMB ≥13 mut/Mb (FDA-Authorized Test) With No Satisfactory Alternatives?
                        For US treatment selection, assess independent MSI-H/dMMR and TMB-high indications for pembrolizumab. MSI-H/dMMR: Evaluate eligibility under the applicable tumor-specific or tumor-agnostic indication, independently of TMB. TMB ≥13 mut/Mb: Qualifies for the current FDA tumor-agnostic TMB-high indication when confirmed by an FDA-authorized test in unresectable or metastatic disease progressing after prior treatment, with no satisfactory alternative treatment options. TMB 10–12 mut/Mb: Does not independently qualify under the updated October 16, 2026 FDA indication. Evaluate other established indications, biomarker-directed treatments, and clinical trials. Assay interpretation: Confirm the testing platform and current assay authorization. Do not assume TMB measurements from different assays are interchangeable. Outside the US: Apply local regulatory approvals and applicable disease-specific guidelines.
                        • Start Pembrolizumab 200 mg IV q3w or 400 mg IV q6w, Up to 24 Months
                        • Relevant Clinical Trial Available (Preferred)?
                          • Enroll in Biomarker-Selected or Novel-Therapy Clinical Trial
                          • Taxane-Naive and Clinically Suitable for Paclitaxel?
                            • Give Paclitaxel 175 mg/m² IV q21d; Reassess Every 2–3 Cycles Until Progression or Intolerance
                              • Assess Other Selected Salvage Options vs Best Supportive Care
                            • Assess Other Selected Salvage Options vs Best Supportive Care
                  • Hold or Reduce Offending Drugs; Switch Cisplatin to Carboplatin When Appropriate
                    • Resume Modified Therapy or Transition to Supportive Care
                  • MSI-H/dMMR or TMB ≥13 mut/Mb (FDA-Authorized Test) With No Satisfactory Alternatives?
                    For US treatment selection, assess independent MSI-H/dMMR and TMB-high indications for pembrolizumab. MSI-H/dMMR: Evaluate eligibility under the applicable tumor-specific or tumor-agnostic indication, independently of TMB. TMB ≥13 mut/Mb: Qualifies for the current FDA tumor-agnostic TMB-high indication when confirmed by an FDA-authorized test in unresectable or metastatic disease progressing after prior treatment, with no satisfactory alternative treatment options. TMB 10–12 mut/Mb: Does not independently qualify under the updated October 16, 2026 FDA indication. Evaluate other established indications, biomarker-directed treatments, and clinical trials. Assay interpretation: Confirm the testing platform and current assay authorization. Do not assume TMB measurements from different assays are interchangeable. Outside the US: Apply local regulatory approvals and applicable disease-specific guidelines.
                    • Start Pembrolizumab 200 mg IV q3w or 400 mg IV q6w, Up to 24 Months
                    • Relevant Clinical Trial Available (Preferred)?
                      • Enroll in Biomarker-Selected or Novel-Therapy Clinical Trial
                      • Taxane-Naive and Clinically Suitable for Paclitaxel?
                        • Give Paclitaxel 175 mg/m² IV q21d; Reassess Every 2–3 Cycles Until Progression or Intolerance
                          • Assess Other Selected Salvage Options vs Best Supportive Care
                        • Assess Other Selected Salvage Options vs Best Supportive Care
          • Any Lower-Intensity, Biomarker-Directed Therapy, or Trial Appropriate?
            • Start Selected Therapy or Trial With Regimen-Specific Reassessment
            • Provide Best Supportive Care and Palliative Local Therapy
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